TW202302125A - Solid dosage forms - Google Patents

Solid dosage forms Download PDF

Info

Publication number
TW202302125A
TW202302125A TW111108035A TW111108035A TW202302125A TW 202302125 A TW202302125 A TW 202302125A TW 111108035 A TW111108035 A TW 111108035A TW 111108035 A TW111108035 A TW 111108035A TW 202302125 A TW202302125 A TW 202302125A
Authority
TW
Taiwan
Prior art keywords
solid dosage
dosage form
bacteria
bacterium
mev
Prior art date
Application number
TW111108035A
Other languages
Chinese (zh)
Inventor
賽易德 艾爾塔夫
黃瑞明
Original Assignee
美商艾弗洛生物科技股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 美商艾弗洛生物科技股份有限公司 filed Critical 美商艾弗洛生物科技股份有限公司
Publication of TW202302125A publication Critical patent/TW202302125A/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/02—Drugs for genital or sexual disorders; Contraceptives for disorders of the vagina
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Gynecology & Obstetrics (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

Methods and compositions related to improved solid dosage forms that facilitate the oral delivery of bacteria or agents of bacterial origin are provided herein.

Description

固體劑型solid dosage form

本揭露部分地基於發現某些改善固體劑型，該等固體劑型促進細菌和細菌來源的試劑（例如，微生物胞外囊泡或mEV）之口服遞送。例如，在某些實施方式中，本文揭露的固體劑型包括賦形劑之某些組合和/或量。在某些實施方式中，與具有常規固體劑型的藥物產品相比，本文提供的固體劑型使治療功效和/或生理作用增強。The present disclosure is based in part on the discovery of certain improved solid dosage forms that facilitate oral delivery of bacteria and agents of bacterial origin (eg, microbial extracellular vesicles or mEVs). For example, in certain embodiments, the solid dosage forms disclosed herein include certain combinations and/or amounts of excipients. In certain embodiments, the solid dosage forms provided herein provide enhanced therapeutic efficacy and/or physiological effects compared to pharmaceutical products having conventional solid dosage forms.

在某些方面，本文提供了藥物組成物的固體劑型。在某些實施方式中，固體劑型包含藥劑（例如，細菌和/或細菌來源的試劑（如mEV），包含細菌和/或細菌來源的試劑（如mEV）的粉末）和一種或多種賦形劑（例如，一種、兩種或三種賦形劑）。在某些實施方式中，固體劑型包含藥劑（例如，細菌和/或細菌來源的試劑（如mEV），包含細菌和/或細菌來源的試劑（如mEV）的粉末）和兩種賦形劑。在某些實施方式中，藥劑總質量係藥物組成物總質量的至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%或75%。在一些實施方式中，藥劑總質量不超過藥物組成物總質量的75%、70%、65%、60%、55%、50%、45%、40%、35%、30%或25%。在一些實施方式中，一種或多種賦形劑的總質量為藥物組成物總質量的至少5%、至少10%、至少20%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少65%、至少70%或至少75%。在一些實施方式中，一種或多種賦形劑的總質量不超過藥物組成物總質量的95%、90%、85%、80%、75%、70%、65%、60%、55%、50%、45%、40%或35%。在一些實施方式中，一種或多種賦形劑包含矽化微晶纖維素。在一些實施方式中，一種或多種賦形劑包含交聚維酮（聚乙烯基聚吡咯啶酮（PVPP），例如科利當（Kollidon）CL-F）。In certain aspects, provided herein are solid dosage forms of pharmaceutical compositions. In certain embodiments, a solid dosage form comprises a pharmaceutical agent (e.g., a bacterium and/or an agent of bacterial origin such as mEV, a powder comprising a bacterium and/or an agent of bacterial origin such as mEV) and one or more excipients (eg, one, two or three excipients). In certain embodiments, a solid dosage form comprises a pharmaceutical agent (eg, a bacterium and/or an agent of bacterial origin such as mEV, a powder comprising a bacterium and/or an agent of bacterial origin such as mEV) and two excipients. In certain embodiments, the total mass of the medicament is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% of the total mass of the pharmaceutical composition , 60%, 65%, 70% or 75%. In some embodiments, the total mass of the medicament does not exceed 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30% or 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more excipients is at least 5%, at least 10%, at least 20%, at least 30%, at least 35%, at least 40%, at least 45%, At least 50%, at least 55%, at least 65%, at least 70%, or at least 75%. In some embodiments, the total mass of one or more excipients does not exceed 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40% or 35%. In some embodiments, the one or more excipients comprise silicified microcrystalline cellulose. In some embodiments, the one or more excipients comprise crospovidone (polyvinylpolypyrrolidone (PVPP), eg, Kollidon CL-F).

在某些實施方式中，本文提供的固體劑型包含矽化微晶纖維素。在一些實施方式中，矽化微晶纖維素為HD90級。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的至少5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%。在某些實施方式中，矽化微晶纖維素總質量不超過藥物組成物總質量的5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約5%至約77%。在某些實施方式中，矽化微晶纖維素質量為藥物組成物總質量的10%至55%（例如，約10%至約55%）。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約10%、約20%、約30%、約40%或約50%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約76.4%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約72.5%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約20%。In certain embodiments, the solid dosage forms provided herein comprise silicified microcrystalline cellulose. In some embodiments, the silicified microcrystalline cellulose is grade HD90. In some embodiments, the total mass of silicified microcrystalline cellulose is at least 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21% of the total mass of the pharmaceutical composition. %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54% , 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72 %, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%. In certain embodiments, the total mass of silicified microcrystalline cellulose does not exceed 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21% of the total mass of the pharmaceutical composition %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54% , 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72 %, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%. In some embodiments, the total mass of silicified microcrystalline cellulose is about 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21% of the total mass of the pharmaceutical composition %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54% , 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72 %, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%. In certain embodiments, the total mass of silicified microcrystalline cellulose is about 5% to about 77% of the total mass of the pharmaceutical composition. In some embodiments, the mass of silicified microcrystalline cellulose is 10% to 55% (eg, about 10% to about 55%) of the total mass of the pharmaceutical composition. In some embodiments, the total mass of silicified microcrystalline cellulose is about 10%, about 20%, about 30%, about 40% or about 50% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of silicified microcrystalline cellulose is about 76.4% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of silicified microcrystalline cellulose is about 72.5% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of silicified microcrystalline cellulose is about 20% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含交聚維酮（例如PVPP、科利當CL-F、聚乙烯吡咯啶酮（PVP）CL-F）。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%。在某些實施方式中，交聚維酮總質量不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%。在某些實施方式中，交聚維酮總質量為藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%。在某些實施方式中，交聚維酮總質量為藥物組成物總質量的5%至20%。在某些實施方式中，交聚維酮總質量為藥物組成物總質量的約5%、6%、7%、10%、15%、18%、20%或30%。In certain embodiments, the solid dosage forms provided herein comprise crospovidone (eg, PVPP, Colidan CL-F, polyvinylpyrrolidone (PVP) CL-F). In certain embodiments, the total mass of crospovidone is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%. In some embodiments, the total mass of crospovidone does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%. In some embodiments, the total mass of crospovidone is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%. In some embodiments, the total mass of crospovidone is 5% to 20% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of crospovidone is about 5%, 6%, 7%, 10%, 15%, 18%, 20% or 30% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含：(i) 藥劑，藥劑總質量為藥物組成物總質量的至少5%且不超過75%，和 (ii) 矽化微晶纖維素，矽化微晶纖維素總質量為藥物組成物總質量的至少5%（例如至少5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%）且不超過90%（例如不超過5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%）。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的至少45%（例如至少45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%或92%）且不超過92%（例如不超過45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%）。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的約45%。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的約50%-56%。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的約62%-67%。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的約72%-77%。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的約80%-88%。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的約90.5%。In certain embodiments, the solid dosage form provided herein comprises: (i) a medicament, the total mass of the medicament is at least 5% and no more than 75% of the total mass of the pharmaceutical composition, and (ii) silicified microcrystalline cellulose, the silicified microcrystalline cellulose The total mass of crystalline cellulose is at least 5% (for example, at least 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%) of the total mass of the pharmaceutical composition , 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39 %, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72%, 73% , 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90% %) and not more than 90% (such as not more than 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% , 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58 %, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%). In certain embodiments, the total mass of the medicament and silicified microcrystalline cellulose is at least 45% (e.g., at least 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68% , 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86 %, 87%, 88%, 89%, 90%, 91% or 92%) and not exceeding 92% (such as not exceeding 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68% , 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86 %, 87%, 88%, 89% or 90%). In some embodiments, the total mass of the medicament and the silicified microcrystalline cellulose is about 45% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the medicament and the silicified microcrystalline cellulose is about 50%-56% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the medicament and the silicified microcrystalline cellulose is about 62%-67% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the medicament and the silicified microcrystalline cellulose is about 72%-77% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of the medicament and the silicified microcrystalline cellulose is about 80%-88% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of the medicament and the silicified microcrystalline cellulose is about 90.5% of the total mass of the pharmaceutical composition.

在某些實施方式中，固體劑型進一步包含總交聚維酮，交聚維酮總質量為藥物組成物總質量的至少5%（例如至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%）且不超過30%（不超過5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%）。In certain embodiments, the solid dosage form further comprises total crospovidone, the total mass of crospovidone is at least 5% (eg, at least 5%, 6%, 7%, 8%, 9%) of the total mass of the pharmaceutical composition , 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26 %, 27%, 28%, 29% or 30%) and not exceeding 30% (not exceeding 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14 %, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%) .

在某些實施方式中，矽化微晶纖維素總質量加上交聚維酮總質量為藥物組成物總質量的至少15%、17%、20%、25%、30%、35%、40%、45%、50%、55%、60%、70%、80%、90%或95%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約50%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約76.4%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約72.5%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約20%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約5%-43%，交聚維酮總質量為藥物組成物總質量的約15%。In some embodiments, the total mass of silicified microcrystalline cellulose plus the total mass of crospovidone is at least 15%, 17%, 20%, 25%, 30%, 35%, 40% of the total mass of the pharmaceutical composition , 45%, 50%, 55%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 50% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is approximately 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 76.4% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 72.5% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 20% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is approximately 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 5%-43% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含硬脂酸鎂（例如Mg s、Mg st或硬脂酸Mg）。在某些實施方式中，硬脂酸鎂總質量為藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，硬脂酸鎂總質量不超過藥物組成物總質量的0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，硬脂酸鎂總質量為藥物組成物總質量的約0.01%、0.1%、1%、1.5%、2%、2.5%、3%、3.5%、4%、4.5%、5%、5.5%、6%、6.5%、7%、7.5%、8%、8.5%、9%、9.5%、10%或11%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約0.5%至約1.5%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約1%至約2%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約1%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約1.5%。In certain embodiments, the solid dosage forms provided herein comprise magnesium stearate (eg, Mg s, Mg st, or Mg stearate). In certain embodiments, the total mass of magnesium stearate is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of magnesium stearate does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of magnesium stearate is about 0.01%, 0.1%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% of the total mass of the pharmaceutical composition , 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium stearate is about 1% to about 2% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium stearate is about 1% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium stearate is about 1.5% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含膠體二氧化矽（colloidal silica）（也稱為膠體二氧化矽（colloidal silicon dioxide）或SiO 2）。在一些實施方式中，膠體二氧化矽係Aerosil 200。在某些實施方式中，膠體二氧化矽總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，膠體二氧化矽總質量不超過藥物組成物總質量的0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，膠體二氧化矽總質量係藥物組成物總質量的約0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，膠體二氧化矽總質量係藥物組成物總質量的約0.5%至約3%。在某些實施方式中，膠體二氧化矽（例如Aerosil 200）總質量係藥物組成物總質量的約1%。在某些實施方式中，膠體二氧化矽（例如Aerosil 200）總質量係藥物組成物總質量的約3%。 In certain embodiments, the solid dosage forms provided herein comprise colloidal silica (also known as colloidal silicon dioxide or SiO 2 ). In some embodiments, the colloidal silica is Aerosil 200. In some embodiments, the total mass of colloidal silicon dioxide is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silicon dioxide does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of colloidal silicon dioxide is about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silicon dioxide is about 0.5% to about 3% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of colloidal silicon dioxide (such as Aerosil 200) is about 1% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of colloidal silicon dioxide (such as Aerosil 200) is about 3% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含纖維素的低取代羥丙基醚（例如L-HPC級LH-B1）。在某些實施方式中，L-HPC總質量為藥物組成物總質量的至少9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%或32%。在某些實施方式中，L-HPC總質量不超過藥物組成物總質量的9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%或32%。在某些實施方式中，L-HPC總質量為藥物組成物總質量的約9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%或32%。在某些實施方式中，L-HPC總質量為藥物組成物總質量的約9%、14%、17%、22%、27%或32%。In certain embodiments, the solid dosage forms provided herein comprise a low-substituted hydroxypropyl ether of cellulose (eg, L-HPC grade LH-B1). In certain embodiments, the total mass of L-HPC is at least 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, or 32%. In certain embodiments, the total mass of L-HPC is no more than 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, or 32%. In some embodiments, the total mass of L-HPC is about 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, or 32%. In certain embodiments, the total mass of L-HPC is about 9%, 14%, 17%, 22%, 27% or 32% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含交聯羧甲基纖維素鈉（例如AcDiSol）。在某些實施方式中，交聯羧甲基纖維素鈉總質量為藥物組成物總質量的至少1%、2%、3%、4%、5%、6%或7%。在某些實施方式中，交聯羧甲基纖維素鈉總質量不超過藥物組成物總質量的1%、2%、3%、4%、5%、6%或7%。在某些實施方式中，交聯羧甲基纖維素鈉總質量為藥物組成物總質量的約1%、2%、3%、4%、5%、6%或7%。在某些實施方式中，交聯羧甲基纖維素鈉總質量為藥物組成物總質量的約2%、4%或6%。In certain embodiments, the solid dosage forms provided herein comprise croscarmellose sodium (eg, AcDiSol). In some embodiments, the total mass of croscarmellose sodium is at least 1%, 2%, 3%, 4%, 5%, 6% or 7% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of croscarmellose sodium does not exceed 1%, 2%, 3%, 4%, 5%, 6% or 7% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of croscarmellose sodium is about 1%, 2%, 3%, 4%, 5%, 6% or 7% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of croscarmellose sodium is about 2%, 4% or 6% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含碳酸氫鈉。在某些實施方式中，碳酸氫鈉總質量為藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%或22%。在某些實施方式中，碳酸氫鈉總質量不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%或22%。在某些實施方式中，碳酸氫鈉總質量為藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%或22%。在某些實施方式中，碳酸氫鈉總質量為藥物組成物總質量的約6.5%、7.5%、10%、12%、15%、18%或20%。In certain embodiments, the solid dosage forms provided herein comprise sodium bicarbonate. In some embodiments, the total mass of sodium bicarbonate is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, or 22%. In some embodiments, the total mass of sodium bicarbonate is no more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, or 22%. In some embodiments, the total mass of sodium bicarbonate is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, or 22%. In some embodiments, the total mass of sodium bicarbonate is about 6.5%, 7.5%, 10%, 12%, 15%, 18% or 20% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含檸檬酸。在某些實施方式中，檸檬酸總質量為藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%或22%。在某些實施方式中，總檸檬酸不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%或22%。在某些實施方式中，檸檬酸總質量為藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%或22%。在某些實施方式中，檸檬酸總質量為藥物組成物總質量的約5%、7.5%、10%、12%、15%、18%或20%。In certain embodiments, the solid dosage forms provided herein comprise citric acid. In certain embodiments, the total mass of citric acid is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition. %, 16%, 17%, 18%, 19%, 20%, 21% or 22%. In some embodiments, the total citric acid does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21% or 22%. In some embodiments, the total mass of citric acid is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition %, 16%, 17%, 18%, 19%, 20%, 21% or 22%. In some embodiments, the total mass of citric acid is about 5%, 7.5%, 10%, 12%, 15%, 18% or 20% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含交聚維酮（例如聚乙烯吡咯啶酮-乙酸乙烯酯共聚物、PVP 64或科利當VA 64）。在某些實施方式中，交聚維酮總質量為藥物組成物總質量的至少3%、4%、5%、6%、7%、8%、9%或10%。在某些實施方式中，總交聚維酮不超過藥物組成物總質量的3%、4%、5%、6%、7%、8%、9%或10%。在某些實施方式中，交聚維酮總質量為藥物組成物總質量的約3%、4%、5%、6%、7%、8%、9%或10%。在某些實施方式中，檸檬酸總質量為藥物組成物總質量的約3%、3.5%、5%或10%。In certain embodiments, the solid dosage forms provided herein comprise crospovidone (eg, polyvinylpyrrolidone-vinyl acetate copolymer, PVP 64, or Corytan VA 64). In some embodiments, the total mass of crospovidone is at least 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the pharmaceutical composition. In certain embodiments, the total crospovidone does not exceed 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of crospovidone is about 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of citric acid is about 3%, 3.5%, 5% or 10% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含矽酸鋁鎂（例如維格姆（Veegum））。在某些實施方式中，矽酸鋁鎂總質量為藥物組成物總質量的至少3%、4%、5%、6%、7%、8%、9%或10%。在某些實施方式中，總矽酸鋁鎂不超過藥物組成物總質量的3%、4%、5%、6%、7%、8%、9%或10%。在某些實施方式中，矽酸鋁鎂總質量為藥物組成物總質量的約3%、4%、5%、6%、7%、8%、9%或10%。在某些實施方式中，矽酸鋁鎂總質量為藥物組成物總質量的約5%或10%。In certain embodiments, the solid dosage forms provided herein comprise magnesium aluminum silicate (eg, Veegum). In some embodiments, the total mass of magnesium aluminum silicate is at least 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium aluminum silicate does not exceed 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of magnesium aluminum silicate is about 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium aluminum silicate is about 5% or 10% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含約5%至約80%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）。在某些實施方式中，本文提供的固體劑型包含約6%至約75%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）。在某些實施方式中，本文提供的固體劑型包含約10%至約60%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）。在某些實施方式中，本文提供的固體劑型包含約25%至約55%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）。In certain embodiments, the solid dosage forms provided herein comprise from about 5% to about 80% pharmaceutical agent (eg, a powder comprising bacteria and/or agents of bacterial origin (eg, mEV)). In certain embodiments, the solid dosage forms provided herein comprise from about 6% to about 75% pharmaceutical agent (eg, a powder comprising bacteria and/or agents of bacterial origin (eg, mEV)). In certain embodiments, the solid dosage forms provided herein comprise from about 10% to about 60% pharmaceutical agent (eg, a powder comprising bacteria and/or agents of bacterial origin (eg, mEV)). In certain embodiments, the solid dosage forms provided herein comprise from about 25% to about 55% pharmaceutical agent (eg, powder comprising bacteria and/or agents of bacterial origin (eg, mEV)).

在某些實施方式中，本文提供的固體劑型包含約5%至約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約43%至約77%的矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise from about 5% to about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); from about 43% to about 77% siliconized Crystalline cellulose (eg, HD90); about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約5%至約35%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約48%至約77%矽化微晶纖維素（例如，HD90級）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise from about 5% to about 35% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); from about 48% to about 77% siliconized microcrystals Cellulose (eg, grade HD90); about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約5%至約10%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約70%至約80%的矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise from about 5% to about 10% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); from about 70% to about 80% siliconized microparticles; Crystalline cellulose (eg, HD90); about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約30%至約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約45%至約55%矽化微晶纖維素（例如，HD90級）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise from about 30% to about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 45% to about 55% siliconized microcrystals Cellulose (eg, grade HD90); about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約10%至約70%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約20%至約73%的矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise from about 10% to about 70% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); from about 20% to about 73% siliconized microparticles; Crystalline cellulose (eg, HD90); about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約33%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約50%矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 33% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 50% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約6.6%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約76.4%矽化微晶纖維素（例如，HD90）；約15%交聚維酮；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, the solid dosage forms provided herein comprise about 6.6% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 76.4% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone; about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200P).

在某些實施方式中，本文提供的固體劑型包含約10%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約72.5%矽化微晶纖維素（例如，HD90）；約15%交聚維酮；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, the solid dosage forms provided herein comprise about 10% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 72.5% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone; about 1.5% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200P).

在某些實施方式中，本文提供的固體劑型包含約62.5%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約20%矽化微晶纖維素（例如，HD90）；約15%交聚維酮；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, a solid dosage form provided herein comprises about 62.5% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 20% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone; about 1.5% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200P).

在某些實施方式中，本文提供的固體劑型包含約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約43%矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 43% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約33%矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 33% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約15.5%矽化微晶纖維素（例如，HD90）；約30%交聚維酮（例如，PVPP）；約1.5%硬脂酸鎂；和約3%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 15.5% silicified microcrystalline cellulose (e.g., HD90); about 30% crospovidone (eg, PVPP); about 1.5% magnesium stearate; and about 3% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約74.5%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約16%矽化微晶纖維素（例如，HD90）；約7%交聚維酮（例如，PVPP）；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, a solid dosage form provided herein comprises about 74.5% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 16% silicified microcrystalline cellulose (e.g., HD90); about 7% crospovidone (eg, PVPP); about 1.5% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約37%矽化微晶纖維素（例如，HD90）；約7%交聚維酮（例如，PVPP）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 37% silicified microcrystalline cellulose (e.g., HD90); About 7% crospovidone (eg, PVPP); about 4% croscarmellose sodium (eg, AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200 ).

在某些實施方式中，本文提供的固體劑型包含約60%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約27%矽化微晶纖維素（例如，HD90）；約7%交聚維酮（例如，PVPP）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 27% silicified microcrystalline cellulose (e.g., HD90); About 7% crospovidone (eg, PVPP); about 4% croscarmellose sodium (eg, AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200 ).

在某些實施方式中，本文提供的固體劑型包含約60%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約21%矽化微晶纖維素（例如，HD90）；約13%交聚維酮（例如，PVPP）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 21% silicified microcrystalline cellulose (e.g., HD90); About 13% crospovidone (eg, PVPP); about 4% croscarmellose sodium (eg, AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200 ).

在某些實施方式中，本文提供的固體劑型包含約8%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約42%矽化微晶纖維素（例如，HD90級）；約27%低取代的纖維素羥丙基醚（例如，L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。In certain embodiments, the solid dosage forms provided herein comprise about 8% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 42% silicified microcrystalline cellulose (e.g., grade HD90) ; about 27% low-substituted cellulose hydroxypropyl ether (for example, L-HPC grade LH-B1); about 6% croscarmellose sodium (for example, AcDiSol); about 15% crospovidone (PVPP , for example, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate.

在某些實施方式中，本文提供的固體劑型包含約23%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約27%矽化微晶纖維素（例如，HD90級）；約27%低取代的纖維素羥丙基醚（例如L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。In certain embodiments, the solid dosage forms provided herein comprise about 23% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 27% silicified microcrystalline cellulose (e.g., grade HD90) ; about 27% low-substituted cellulose hydroxypropyl ether (such as L-HPC grade LH-B1); about 6% croscarmellose sodium (such as AcDiSol); about 15% crospovidone (PVPP, For example, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate.

在某些實施方式中，本文提供的固體劑型包含約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約10%矽化微晶纖維素（例如，HD90級）；約27%低取代的纖維素羥丙基醚（例如L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。In certain embodiments, the solid dosage forms provided herein comprise about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 10% silicified microcrystalline cellulose (e.g., grade HD90) ; about 27% low-substituted cellulose hydroxypropyl ether (such as L-HPC grade LH-B1); about 6% croscarmellose sodium (such as AcDiSol); about 15% crospovidone (PVPP, For example, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate.

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約5%矽化微晶纖維素（例如，HD90級）；約22%低取代的纖維素羥丙基醚（例如L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 5% silicified microcrystalline cellulose (e.g., grade HD90) ; about 22% low-substituted cellulose hydroxypropyl ether (such as L-HPC grade LH-B1); about 6% croscarmellose sodium (such as AcDiSol); about 15% crospovidone (PVPP, For example, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate.

在某些實施方式中，本文提供的固體劑型包含約10%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約40%矽化微晶纖維素（例如，HD90級）；約27%低取代的纖維素羥丙基醚（例如，L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。In certain embodiments, the solid dosage forms provided herein comprise about 10% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 40% silicified microcrystalline cellulose (e.g., grade HD90) ; about 27% low-substituted cellulose hydroxypropyl ether (for example, L-HPC grade LH-B1); about 6% croscarmellose sodium (for example, AcDiSol); about 15% crospovidone (PVPP , for example, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate.

在某些實施方式中，本文提供的固體劑型包含約20%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約30%矽化微晶纖維素（例如，HD90級）；約27%低取代的纖維素羥丙基醚（例如，L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。In certain embodiments, the solid dosage forms provided herein comprise about 20% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 30% silicified microcrystalline cellulose (e.g., grade HD90) ; about 27% low-substituted cellulose hydroxypropyl ether (for example, L-HPC grade LH-B1); about 6% croscarmellose sodium (for example, AcDiSol); about 15% crospovidone (PVPP , for example, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate.

在某些實施方式中，本文提供的固體劑型包含約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約5%矽化微晶纖維素（例如，HD90級）；約32%低取代的纖維素羥丙基醚（例如，L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約52%矽化微晶纖維素（例如，HD90級）；約20%交聚維酮（PVPP，例如，科利當CL-F）；約1%滑石粉；約1%二氧化矽；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 5% silicified microcrystalline cellulose (e.g., grade HD90) ; about 32% low-substituted cellulose hydroxypropyl ether (for example, L-HPC grade LH-B1); about 6% croscarmellose sodium (for example, AcDiSol); about 15% crospovidone (PVPP , for example, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate. In certain embodiments, the solid dosage forms provided herein comprise about 25% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 52% silicified microcrystalline cellulose (e.g., grade HD90) about 20% crospovidone (PVPP, e.g., Corytan CL-F); about 1% talc; about 1% silicon dioxide; and about 1% sodium stearyl fumarate.

在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約47%矽化微晶纖維素（例如，HD90級）；約20%交聚維酮（PVPP，例如，科利當CL-F）；約5%交聚維酮（例如，PVP 64）；約1%滑石粉；約1%二氧化矽；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 25% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 47% silicified microcrystalline cellulose (e.g., grade HD90) ; about 20% crospovidone (PVPP, e.g., Corytan CL-F); about 5% crospovidone (e.g., PVP 64); about 1% talc; about 1% silicon dioxide; and about 1% Sodium stearyl fumarate.

在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約42%矽化微晶纖維素（例如，HD90級）；約20%交聚維酮（PVPP，例如，科利當CL-F）；約10%交聚維酮（例如，PVP 64）；約1%滑石粉；約1%二氧化矽；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 25% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 42% silicified microcrystalline cellulose (e.g., grade HD90) ; about 20% crospovidone (PVPP, e.g., Kolidan CL-F); about 10% crospovidone (e.g., PVP 64); about 1% talc; about 1% silicon dioxide; and about 1% Sodium stearyl fumarate.

在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約47%矽化微晶纖維素（例如，HD90級）；約20%交聚維酮（PVPP，例如，科利當CL-F）；約5%矽酸鋁鎂（例如，維格姆）；約1%滑石粉；約1%二氧化矽；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 25% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 47% silicified microcrystalline cellulose (e.g., grade HD90) about 20% crospovidone (PVPP, e.g., Corytan CL-F); about 5% magnesium aluminum silicate (e.g., Vigum); about 1% talc; about 1% silicon dioxide; and About 1% sodium stearyl fumarate.

在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約42%矽化微晶纖維素（例如，HD90級）；約20%交聚維酮（PVPP，例如，科利當CL-F）；約10%矽酸鋁鎂（例如，維格姆）；約1%滑石粉；約1%二氧化矽；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 25% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 42% silicified microcrystalline cellulose (e.g., grade HD90) about 20% crospovidone (PVPP, e.g., Corytan CL-F); about 10% magnesium aluminum silicate (e.g., Vigum); about 1% talc; about 1% silicon dioxide; and About 1% sodium stearyl fumarate.

在某些實施方式中，本文提供的固體劑型包含約30%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約22%矽化微晶纖維素（例如，HD90）；約20%檸檬酸；約20%碳酸氫鈉；約5%交聚維酮（例如，PVPP）；約1.5%硬脂酸鎂；和約1.5%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 30% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 22% silicified microcrystalline cellulose (e.g., HD90); about 20% citric acid; about 20% sodium bicarbonate; about 5% crospovidone (eg, PVPP); about 1.5% magnesium stearate; and about 1.5% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約16%矽化微晶纖維素（例如，HD90）；約18%檸檬酸；約18%碳酸氫鈉；約5%交聚維酮（例如，PVPP）；約1.5%硬脂酸鎂；和約1.5%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 16% silicified microcrystalline cellulose (e.g., HD90); about 18% citric acid; about 18% sodium bicarbonate; about 5% crospovidone (eg, PVPP); about 1.5% magnesium stearate; and about 1.5% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約12%矽化微晶纖維素（例如，HD90）；約15%檸檬酸；約15%碳酸氫鈉；約5%交聚維酮（例如，PVPP）；約1.5%硬脂酸鎂；和約1.5%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 12% silicified microcrystalline cellulose (e.g., HD90); about 15% citric acid; about 15% sodium bicarbonate; about 5% crospovidone (eg, PVPP); about 1.5% magnesium stearate; and about 1.5% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約17%矽化微晶纖維素（例如，HD90）；約10%檸檬酸；約10%碳酸氫鈉；約10%交聚維酮（例如，PVPP）；約1.5%硬脂酸鎂；和約1.5%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 17% silicified microcrystalline cellulose (e.g., HD90); about 10% citric acid; about 10% sodium bicarbonate; about 10% crospovidone (eg, PVPP); about 1.5% magnesium stearate; and about 1.5% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約15%矽化微晶纖維素（例如，HD90）；約12%檸檬酸；約12%碳酸氫鈉；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約4%羧基乙酸澱粉鈉；約1.5%硬脂酸鎂；和約1.5%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 15% silicified microcrystalline cellulose (e.g., HD90); About 12% citric acid; about 12% sodium bicarbonate; about 4% croscarmellose sodium (such as AcDiSol); about 4% sodium starch glycolate; about 1.5% magnesium stearate; and about 1.5% colloid Silicon dioxide (for example, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約55%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約7.5%矽化微晶纖維素（例如，HD90）；約7.5%檸檬酸；約7.5%碳酸氫鈉；約20%交聚維酮（例如，PVPP）；約1%硬脂醯富馬酸鈉；和約1.5%膠體二氧化矽（例如，Aerosil 200）；其中藥劑的20%被包衣。In certain embodiments, the solid dosage forms provided herein comprise about 55% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 7.5% silicified microcrystalline cellulose (e.g., HD90); about 7.5% citric acid; about 7.5% sodium bicarbonate; about 20% crospovidone (eg, PVPP); about 1% sodium stearyl fumarate; and about 1.5% colloidal silicon dioxide (eg, Aerosil 200 ); wherein 20% of the medicament is coated.

在某些實施方式中，本文提供的固體劑型包含約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約25.5%矽化微晶纖維素（例如，HD90）；約5%檸檬酸；約6.5%碳酸氫鈉；約18%交聚維酮（例如，PVPP）；約2%羧基乙酸澱粉鈉；約1%硬脂醯富馬酸鈉；約1%滑石粉；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 25.5% silicified microcrystalline cellulose (e.g., HD90); About 5% citric acid; about 6.5% sodium bicarbonate; about 18% crospovidone (eg, PVPP); about 2% sodium starch glycolate; about 1% sodium stearyl fumarate; about 1% talc and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約22%矽化微晶纖維素（例如，HD90）；約5%檸檬酸；約6.5%碳酸氫鈉；約20%交聚維酮（例如，PVPP）；約3.5%交聚維酮（PVP 64）；約1%硬脂醯富馬酸鈉；約1%滑石粉；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 22% silicified microcrystalline cellulose (e.g., HD90); About 5% citric acid; about 6.5% sodium bicarbonate; about 20% crospovidone (eg, PVPP); about 3.5% crospovidone (PVP 64); about 1% sodium stearyl fumarate; 1% talc; and about 1% colloidal silicon dioxide (for example, Aerosil 200).

在一些實施方式中，藥劑的濕法製粒產生包含藥劑的顆粒（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末的藥物物質顆粒）。在一些實施方式中，顆粒進一步包含一種或多種賦形劑（例如，一種、兩種或三種）。在一些實施方式中，顆粒視需要與一種或多種（例如，一種、兩種或三種）賦形劑組合以製備藥物組成物（例如片劑、膠囊或固體劑型）。In some embodiments, wet granulation of the medicament produces granules comprising the medicament (eg, drug substance granules comprising a powder of bacteria and/or agents of bacterial origin (eg, mEV)). In some embodiments, the particles further comprise one or more excipients (eg, one, two, or three). In some embodiments, the granules are optionally combined with one or more (eg, one, two or three) excipients to prepare a pharmaceutical composition (eg, tablet, capsule or solid dosage form).

在本文提供的一些實施方式中，顆粒包含60%-100%的藥劑（例如粉末，包含細菌和/或細菌來源的試劑，例如mEV）。在一些實施方式中，顆粒包含約60%、65%、70%、75%、80%、85%、90%、95%或100%的藥劑。在其他實施方式中，顆粒占藥物組成物總質量的35%-85%。在本文提供的一些實施方式中，顆粒占藥物組成物總質量的約40%、50%、55%、60%、70%、75%、80%或85%。In some embodiments provided herein, the particles comprise 60%-100% agent (eg, powder comprising bacteria and/or agents of bacterial origin, eg, mEV). In some embodiments, the particles comprise about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the agent. In other embodiments, the particles account for 35%-85% of the total mass of the pharmaceutical composition. In some embodiments provided herein, the particles account for about 40%, 50%, 55%, 60%, 70%, 75%, 80% or 85% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含約60%顆粒；約15%矽化微晶纖維素（例如，HD90）；約10%交聚維酮（例如，PVPP）；約9%低取代的纖維素羥丙基醚（例如L-HPC級LH-B1）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% granules; about 15% silicified microcrystalline cellulose (e.g., HD90); about 10% crospovidone (e.g., PVPP); about 9% low-substituted cellulose hydroxypropyl ether (such as L-HPC grade LH-B1); about 4% croscarmellose sodium (such as AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (for example, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約60%顆粒；約27%矽化微晶纖維素（例如，HD90）；約7%交聚維酮（例如，PVPP）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% granules; about 27% silicified microcrystalline cellulose (e.g., HD90); about 7% crospovidone (e.g., PVPP); about 4% cross-linked Sodium carboxymethylcellulose (eg, AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約60%顆粒；約27%矽化微晶纖維素（例如，HD90）；約13%交聚維酮（例如，PVPP）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% granules; about 27% silicified microcrystalline cellulose (e.g., HD90); about 13% crospovidone (e.g., PVPP); about 4% cross-linked Sodium carboxymethylcellulose (eg, AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約60%顆粒；約5%矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約14%低取代的纖維素羥丙基醚（例如L-HPC級LH-B1）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% granules; about 5% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone (e.g., PVPP); about 14% low-substituted cellulose hydroxypropyl ether (such as L-HPC grade LH-B1); about 4% croscarmellose sodium (such as AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (for example, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約60%顆粒；約17%交聚維酮（例如，PVPP）；約17%低取代的纖維素羥丙基醚（例如L-HPC級LH-B1）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% granules; about 17% crospovidone (e.g., PVPP); about 17% low-substituted cellulose hydroxypropyl ether (e.g., L-HPC grade LH -B1); about 4% croscarmellose sodium (eg, AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約55%顆粒；約25%矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約1%膠體二氧化矽（例如，Aerosil 200）；約1%羧基乙酸澱粉鈉；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 55% granules; about 25% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone (e.g., PVPP); about 1% colloidal bismuth Silicon oxide (for example, Aerosil 200); about 1% sodium starch glycolate; and about 1% sodium stearyl fumarate.

在某些實施方式中，本文提供的固體劑型包含約55%顆粒；約25%矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約1%膠體二氧化矽（例如，Aerosil 200）；約1%羧基乙酸澱粉鈉；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 55% granules; about 25% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone (e.g., PVPP); about 1% colloidal bismuth Silicon oxide (for example, Aerosil 200); about 1% sodium starch glycolate; and about 1% sodium stearyl fumarate.

在某些實施方式中，本文提供的固體劑型包含約50%顆粒；約32%矽化微晶纖維素（例如，HD90）；約10%交聚維酮（例如，PVPP）；約3%交聚維酮（例如，PVP-64）；約2%交聯羧甲基纖維素鈉；約1%膠體二氧化矽（例如，Aerosil 200）；約1%滑石粉；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 50% granules; about 32% silicified microcrystalline cellulose (e.g., HD90); about 10% crospovidone (e.g., PVPP); about 3% cross-polymerized Povidone (eg, PVP-64); about 2% croscarmellose sodium; about 1% colloidal silicon dioxide (eg, Aerosil 200); about 1% talc; sodium maleate.

在某些實施方式中，本文提供的固體劑型包含約40%顆粒；約32%矽化微晶纖維素（例如，HD90）；約20%交聚維酮（例如，PVPP）；約3%交聚維酮（例如，PVP-64）；約2%交聯羧甲基纖維素鈉；約1%膠體二氧化矽（例如，Aerosil 200）；約1%滑石粉；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 40% granules; about 32% silicified microcrystalline cellulose (e.g., HD90); about 20% crospovidone (e.g., PVPP); about 3% cross-polymerized Povidone (eg, PVP-64); about 2% croscarmellose sodium; about 1% colloidal silicon dioxide (eg, Aerosil 200); about 1% talc; sodium maleate.

在某些實施方式中，本文提供的固體劑型包含約70%顆粒；約17%矽化微晶纖維素（例如，HD90）；約5%交聚維酮（例如，PVPP）；約3%交聚維酮（例如，PVP-64）；約2%交聯羧甲基纖維素鈉；約1%膠體二氧化矽（例如，Aerosil 200）；約1%滑石粉；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 70% granules; about 17% silicified microcrystalline cellulose (e.g., HD90); about 5% crospovidone (e.g., PVPP); about 3% cross-polymerized Povidone (eg, PVP-64); about 2% croscarmellose sodium; about 1% colloidal silicon dioxide (eg, Aerosil 200); about 1% talc; sodium maleate.

在某些實施方式中，本文描述的藥劑的固體劑型包括片劑和微型片劑。在一些實施方式中，固體劑型經腸溶包衣（例如，包含腸溶衣；例如，用腸溶衣進行了包衣）。用一層腸溶衣或兩層腸溶衣（例如，內部腸溶衣和外部腸溶衣）包衣片劑或微型片劑。可以將腸溶包衣的微型片劑（具有一層腸溶衣或具有兩層腸溶衣（例如，內部腸溶衣和外部腸溶衣））裝入膠囊中；例如，膠囊不經腸溶包衣。In certain embodiments, solid dosage forms of the agents described herein include tablets and minitablets. In some embodiments, the solid dosage form is enteric coated (eg, comprises an enteric coating; eg, is coated with an enteric coating). Tablets or minitablets are coated with an enteric coating or with two enteric coatings (eg, an inner enteric coat and an outer enteric coat). Enteric-coated mini-tablets (with one enteric coat or with two enteric coats (e.g., an inner enteric coat and an outer enteric coat)) can be filled into capsules; e.g., capsules without an enteric coat Clothes.

在一些實施方式中，固體劑型包括片劑。在一些實施方式中，片劑（例如，經腸溶包衣的片劑）係5 mm、5.5 mm、6 mm、6.5 mm、7 mm、7.5 mm、8 mm、8.5 mm、9 mm、9.5 mm、10 mm、11 mm、12 mm、13 mm、14 mm、15 mm、16 mm、17 mm、或18 mm片劑。In some embodiments, solid dosage forms include tablets. In some embodiments, the tablet (e.g., an enteric-coated tablet) is 5 mm, 5.5 mm, 6 mm, 6.5 mm, 7 mm, 7.5 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm , 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm, or 18 mm tablets.

在一些實施方式中，固體劑型包含微型片劑。在一些實施方式中，微型片劑（例如，經腸溶包衣的微型片劑）係1 mm微型片劑、1.5 mm微型片劑、2 mm微型片劑、3 mm微型片劑或4 mm微型片劑。在一些實施方式中，在膠囊中包含多個經腸溶包衣的微型片劑（例如0號膠囊可以包含約31至約35（例如33）個微型片劑，其中微型片劑的尺寸為3 mm）。在一些實施方式中，膠囊係00號、0號、1號、2號、3號、4號或5號膠囊。在一些實施方式中，膠囊包含HPMC（羥丙基甲基纖維素）或明膠。In some embodiments, the solid dosage form comprises minitablets. In some embodiments, the minitablets (e.g., enteric coated minitablets) are 1 mm minitablets, 1.5 mm minitablets, 2 mm minitablets, 3 mm minitablets, or 4 mm minitablets. tablet. In some embodiments, the capsule contains a plurality of enteric-coated mini-tablets (e.g. a size 0 capsule may contain from about 31 to about 35 (e.g. 33) mini-tablets, wherein the mini-tablets are of size 3 mm). In some embodiments, the capsule is a size 00, size 0, size 1, size 2, size 3, size 4 or size 5 capsule. In some embodiments, the capsules comprise HPMC (hydroxypropylmethylcellulose) or gelatin.

在一些實施方式中，腸溶衣包含一層腸溶衣。In some embodiments, the enteric coating comprises an enteric coating.

在一些實施方式中，腸溶衣包括內部腸溶衣和外部腸溶衣。在一些實施方式中，腸溶衣包含內部腸溶衣和外部腸溶衣，並且其中內部和外部腸溶衣不相同（例如，內部和外部腸溶衣不包含相同量的相同組分）。In some embodiments, the enteric coating includes an inner enteric coating and an outer enteric coating. In some embodiments, the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings are not identical (eg, the inner and outer enteric coatings do not comprise the same amount of the same component).

在一些實施方式中，腸溶衣（例如，一層腸溶衣或內部腸溶衣和/或外部腸溶衣）包含基於聚甲基丙烯酸酯的共聚物。In some embodiments, the enteric coating (eg, one layer or an inner enteric coat and/or an outer enteric coat) comprises a polymethacrylate-based copolymer.

在一些實施方式中，腸溶衣（例如，一層腸溶衣或內部腸溶衣和/或外部腸溶衣）包含甲基丙烯酸丙烯酸乙酯（MAE）共聚物（1:1）。In some embodiments, the enteric coat (eg, one enteric coat or an inner enteric coat and/or an outer enteric coat) comprises ethyl methacrylate acrylate (MAE) copolymer (1:1).

在一些實施方式中，該一層腸溶衣包含甲基丙烯酸丙烯酸乙酯（MAE）共聚物（1:1）（如Kollicoat MAE 100P）。In some embodiments, the enteric coating comprises ethyl methacrylate (MAE) copolymer (1:1) (eg, Kollicoat MAE 100P).

在一些實施方式中，該一層腸溶衣包含Eudragit共聚物，例如，Eudragit L（例如，Eudragit L 100-55；Eudragit L 30 D-55）、Eudragit S、Eudragit RL、Eudragit RS、Eudragit E、或Eudragit FS（例如，Eudragit FS 30 D）。In some embodiments, the enteric coating comprises a Eudragit copolymer, e.g., Eudragit L (e.g., Eudragit L 100-55; Eudragit L 30 D-55), Eudragit S, Eudragit RL, Eudragit RS, Eudragit E, or Eudragit FS (for example, Eudragit FS 30 D).

在一些實施方式中，腸溶衣（例如，一層腸溶衣或內部腸溶衣和/或外部腸溶衣）包括鄰苯二甲酸乙酸纖維素（CAP）、偏苯三酸乙酸纖維素（CAT）、聚(醋酸乙烯鄰苯二甲酸酯)（PVAP）、羥丙基甲基纖維素鄰苯二甲酸酯（HPMCP）、脂肪酸、蠟、蟲膠（紫膠桐酸的酯）、塑膠、植物纖維、玉米醇溶蛋白、Aqua-Zein（不含醇的水性玉米醇溶蛋白配製物）、直鏈澱粉、澱粉衍生物、糊精、丙烯酸甲酯-甲基丙烯酸共聚物、醋酸琥珀酸纖維素、羥丙基甲基醋酸琥珀酸纖維素（醋酸琥珀酸羥丙甲纖維素）、甲基丙烯酸甲酯-甲基丙烯酸共聚物、或海藻酸鈉。In some embodiments, the enteric coating (e.g., one enteric coating or an inner enteric coating and/or an outer enteric coating) includes cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT ), poly(vinyl acetate phthalate) (PVAP), hydroxypropylmethylcellulose phthalate (HPMCP), fatty acids, waxes, shellac (esters of lacic acid), plastic , vegetable fiber, zein, Aqua-Zein (alcohol-free aqueous zein formulation), amylose, starch derivatives, dextrin, methyl acrylate-methacrylic acid copolymer, succinic acid acetate Cellulose, hydroxypropylmethylcellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymer, or sodium alginate.

在一些實施方式中，腸溶衣（例如，一層腸溶衣或內部腸溶衣和/或外部腸溶衣）包含陰離子聚合物材料。In some embodiments, the enteric coat (eg, one enteric coat or an inner enteric coat and/or an outer enteric coat) comprises an anionic polymeric material.

在一些實施方式中，固體劑型例如除了腸溶衣之外還包含底層包衣，例如，底層包衣在腸溶衣下面（例如，在固體劑型和腸溶衣之間）。在一些實施方式中，底層包衣包含歐巴代（Opadry）QX，例如歐巴代QX藍（Opadry QX Blue）。In some embodiments, the solid dosage form comprises a subcoat, eg, in addition to the enteric coating, eg, the subcoat underlies the enteric coating (eg, between the solid dosage form and the enteric coating). In some embodiments, the base coat comprises Opadry QX, such as Opadry QX Blue.

藥劑可以是細菌來源的（例如，所選菌株或其試劑（組分）的混合物，例如所選菌株的混合物的微生物胞外囊泡（mEV））。藥劑可以是細菌來源的（例如，單個所選菌株和/或其試劑（組分），例如該單個所選菌株的微生物胞外囊泡（mEV））。藥劑可以是粉末，粉末包含細菌和/或其組分，並且可以包含另外藥劑，例如冷凍保護劑。例如，在一些實施方式中，藥劑係細菌和/或其組分（例如，mEV）的凍乾粉末，凍乾粉末視需要還包含另外的藥劑，例如冷凍保護劑。The agent may be of bacterial origin (eg, a mixture of selected strains or agents (components) thereof, eg, microbial extracellular vesicles (mEVs) of a mixture of selected strains). The agent may be of bacterial origin (eg, a single selected strain and/or agents (components) thereof, such as microbial extracellular vesicles (mEVs) of the single selected strain). The agent may be a powder, the powder comprising the bacteria and/or components thereof, and may contain additional agents such as cryoprotectants. For example, in some embodiments, the agent is a lyophilized powder of bacteria and/or components thereof (eg, mEVs), optionally containing additional agents, such as cryoprotectants.

在一些實施方式中，藥劑包含細菌。In some embodiments, the agent comprises bacteria.

在一些實施方式中，藥劑包含微生物胞外囊泡（mEV）。In some embodiments, the agent comprises microbial extracellular vesicles (mEVs).

在一些實施方式中，藥劑包含細菌和微生物胞外囊泡（mEV）。In some embodiments, the agent comprises bacteria and microbial extracellular vesicles (mEVs).

在一些實施方式中，例如當口服施用固體劑型時，藥劑在胃腸道外具有一種或多種有益的免疫作用。In some embodiments, eg, when a solid dosage form is administered orally, the agent has one or more beneficial immunological effects outside the gastrointestinal tract.

在一些實施方式中，例如當口服施用固體劑型時，藥劑調節受試者的胃腸道外的免疫作用。In some embodiments, eg, when a solid dosage form is administered orally, the agent modulates parenteral immunization of the subject.

在一些實施方式中，例如當口服施用固體劑型時，藥劑引起系統性作用（例如，胃腸道外的作用）。In some embodiments, the agent causes systemic effects (eg, parenteral effects), such as when a solid dosage form is administered orally.

在一些實施方式中，例如當口服施用固體劑型時，藥劑對小腸中的免疫細胞和/或上皮細胞起作用（例如引起系統性作用（例如，胃腸道外的作用））。In some embodiments, the agent acts on immune cells and/or epithelial cells in the small intestine (eg, causes systemic effects (eg, parenteral effects)), eg, when a solid dosage form is administered orally.

在一些實施方式中，藥劑包含分離的細菌（例如，來自一種或多種細菌菌株（例如，目的細菌）（例如，其治療有效量））。例如，其中藥劑的至少50%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%的含量係分離的細菌（例如目的細菌）。In some embodiments, the medicament comprises isolated bacteria (eg, from one or more strains of bacteria (eg, bacteria of interest) (eg, a therapeutically effective amount thereof)). For example, wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the agent is isolated bacteria (eg, the bacteria of interest).

在一些實施方式中，藥劑包含細菌，並且該等細菌已經經γ照射、UV照射、熱滅活、酸處理或氧噴射。In some embodiments, the agent comprises bacteria, and the bacteria have been gamma irradiated, UV irradiated, heat inactivated, acid treated, or oxygen sparged.

在一些實施方式中，藥劑包含活細菌。In some embodiments, the medicament comprises live bacteria.

在一些實施方式中，藥劑包含死細菌。In some embodiments, the medicament comprises dead bacteria.

在一些實施方式中，藥劑包含非複製型細菌。In some embodiments, the agent comprises non-replicating bacteria.

在一些實施方式中，藥劑包含來自一種細菌菌株的細菌。In some embodiments, the medicament comprises bacteria from one bacterial strain.

在一些實施方式中，細菌被凍乾（例如，凍乾的產物還包含藥學上可接受的賦形劑）（例如，粉末形式）。In some embodiments, the bacteria are lyophilized (eg, the lyophilized product further comprises a pharmaceutically acceptable excipient) (eg, in powder form).

在一些實施方式中，細菌經γ照射。In some embodiments, the bacteria are gamma irradiated.

在一些實施方式中，細菌經UV照射。In some embodiments, the bacteria are UV irradiated.

在一些實施方式中，細菌經熱滅活（例如，在50°C下兩小時或在90°C下兩小時）。In some embodiments, the bacteria are heat inactivated (eg, two hours at 50°C or two hours at 90°C).

在一些實施方式中，細菌經酸處理。In some embodiments, the bacteria are acid-treated.

在一些實施方式中，細菌經氧噴射（例如，以0.1 vvm持續兩小時）。In some embodiments, bacteria are sparged with oxygen (eg, at 0.1 vvm for two hours).

在一些實施方式中，細菌來自革蘭氏陽性細菌。In some embodiments, the bacteria are from Gram-positive bacteria.

在一些實施方式中，細菌來自革蘭氏陰性細菌。In some embodiments, the bacteria are from Gram-negative bacteria.

在一些實施方式中，細菌係需氧細菌。In some embodiments, the bacteria are aerobic bacteria.

在一些實施方式中，細菌係厭氧細菌。在一些實施方式中，厭氧細菌包含專性厭氧菌。在一些實施方式中，厭氧細菌包含兼性厭氧菌。In some embodiments, the bacteria are anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

在一些實施方式中，細菌係嗜酸細菌。In some embodiments, the bacteria are acidophilic bacteria.

在一些實施方式中，細菌係嗜鹼細菌。In some embodiments, the bacteria are alkaliphilic bacteria.

在一些實施方式中，細菌係嗜中性細菌。In some embodiments, the bacteria are neutrophils.

在一些實施方式中，細菌係難養細菌。In some embodiments, the bacteria are fastidious bacteria.

在一些實施方式中，細菌係非難養細菌。In some embodiments, the bacteria are non-fastidious bacteria.

在一些實施方式中，細菌屬於表1、表2、表3或表4中列出的分類學組（例如，綱、目、科、屬、種或菌株）。In some embodiments, the bacterium belongs to a taxonomic group (eg, class, order, family, genus, species, or strain) listed in Table 1, Table 2, Table 3, or Table 4.

在一些實施方式中，藥劑包含分離的小韋榮氏球菌細菌（例如，來自一種或多種細菌菌株（例如，目的細菌）（例如，其治療有效量））。例如，其中藥劑的至少50%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%的含量係分離的小韋榮氏球菌細菌（例如目的細菌）。In some embodiments, the medicament comprises an isolated Veillonella parvum bacterium (eg, from one or more bacterial strains (eg, the bacterium of interest) (eg, a therapeutically effective amount thereof)). For example, wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the agent is isolated Veillonella parvum bacteria (eg, the bacterium of interest).

在一些實施方式中，藥劑包含分離的小韋榮氏球菌細菌（例如，來自一種或多種細菌菌株（例如，目的細菌）（例如，其治療有效量））。例如，其中藥劑的至少50%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%的含量係分離的小韋榮氏球菌細菌（例如目的細菌）。In some embodiments, the medicament comprises an isolated Veillonella parvum bacterium (eg, from one or more bacterial strains (eg, the bacterium of interest) (eg, a therapeutically effective amount thereof)). For example, wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the agent is isolated Veillonella parvum bacteria (eg, the bacterium of interest).

在一些實施方式中，小韋榮氏球菌細菌來自與小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）的核苷酸序列具有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，小韋榮氏球菌細菌來自與小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，韋榮氏球菌屬細菌來自小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）。In some embodiments, the Veillonella parvum bacterium is from a nucleotide sequence having at least 90% (or at least 97%) of the genome, 16S and/or Strains with CRISPR sequence identity. In some embodiments, the Veillonella parvum bacterium is from a strain that has at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of Veillonella parvum strain A (ATCC Accession No. PTA-125691) . In some embodiments, the Veillonella bacterium is from Veillonella parvum strain A (ATCC Accession No. PTA-125691).

在一些實施方式中，藥物組成物中至少50%、60%、70%、80%或90%的細菌係小韋榮氏球菌菌株A。In some embodiments, at least 50%, 60%, 70%, 80%, or 90% of the bacteria in the pharmaceutical composition are Veillonella parvum strain A.

在一些實施方式中，藥劑包含至少1 x 10 5、5 x 10 5、1 x 10 6、2 x 10 6、3 x 10 6、4 x 10 6、5 x 10 6、6 x 10 6、7 x 10 6、8 x 10 6、9 x 10 6、1 x 10 7、2 x 10 7、3 x 10 7、4 x 10 7、5 x 10 7、6 x 10 7、7 x 10 7、8 x 10 7、9 x 10 7、1 x 10 8、2 x 10 8、3 x 10 8、4 x 10 8、5 x 10 8、6 x 10 8、7 x 10 8、8 x 10 8、9 x 10 8或1 x 10 9個本文所述韋榮氏球菌屬細菌（例如，小韋榮氏球菌菌株A（ATCC保藏號PTA-125691））的總細胞（例如，其中細胞數目由總細胞計數確定（例如，由庫爾特計數器確定）。 In some embodiments, the medicament comprises at least 1 x 10 5 , 5 x 10 5 , 1 x 10 6 , 2 x 10 6 , 3 x 10 6 , 4 x 10 6 , 5 x 10 6 , 6 x 10 6 , 7 x 10 6 , 8 x 10 6 , 9 x 10 6 , 1 x 10 7 , 2 x 10 7 , 3 x 10 7 , 4 x 10 7 , 5 x 10 7 , 6 x 10 7 , 7 x 10 7 , 8 x 10 7 , 9 x 10 7 , 1 x 10 8 , 2 x 10 8 , 3 x 10 8 , 4 x 10 8 , 5 x 10 8 , 6 x 10 8 , 7 x 10 8 , 8 x 10 8 , 9 x 108 or 1 x 109 total cells of Veillonella bacteria described herein (e.g., Veillonella parvum strain A (ATCC Accession No. PTA-125691)) (e.g., where the number of cells is counted by total cells Determined (for example, by a Coulter counter).

根據用於專利程序目的的國際承認的微生物保藏的布達佩斯條約（Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure）的條款，將小韋榮氏球菌菌株A在2019年1月25日保藏於美國典型培養物保藏中心（American Type Culture Collection，ATCC）（美國維吉尼亞州馬納薩斯大學大道10801號，20110-2209（10801 University Boulevard, Manassas, Va. 20110-2209 USA））並且指定ATCC保藏號PTA-125691。Under the terms of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure (Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure), Veillonella parvum strain A was deposited in January 2019 Deposited at the American Type Culture Collection (ATCC) on the 25th (10801 University Boulevard, Manassas, Virginia, USA, 20110-2209 (10801 University Boulevard, Manassas, Va. 20110-2209 USA )) and assigned ATCC Deposit No. PTA-125691.

申請人表示，ATCC係保藏處，如果授予專利，則可永久保藏且公眾可隨時訪問。在授予專利後，將不可撤銷地取消對如此保藏材料的公眾可獲得性的所有限制。該材料可在專利申請未決期間提供給由有資格的專員依據37 CFR 1.14及35 U.S.C. 122所決定的人。在謹慎需要保持存活及無污染的情況下將保藏材料在最新請求提供保藏質體樣本之後維持至少五年的時間段，且在任一情形下在保藏日期之後維持至少三十（30）年的時間段或維持專利的可實施壽命（以較長時間段為准）。申請人確認，如果保藏處因保藏條件而不能在請求時提供樣本，則其有責任更換保藏地。The applicant indicated that the ATCC is the depository, and if a patent is granted, it is permanently deposited and readily accessible to the public. Upon grant of the patent, all restrictions on the public availability of the material so deposited will be irrevocably removed. This material may be provided during the pendency of a patent application to persons determined by a qualified commissioner pursuant to 37 CFR 1.14 and 35 U.S.C. 122. maintain the deposited material for a period of at least five years after the latest request for a deposited plastid sample, and in any case for a period of at least thirty (30) years after the date of deposit, where prudence is necessary to keep it viable and free from contamination period or maintain the enforceable life of the patent (whichever is longer). The applicant acknowledges that if the depository is unable to provide samples upon request due to deposit conditions, it is responsible for changing the depository.

在一些實施方式中，細菌係表1、表2、表3或表4中列出的細菌菌株。In some embodiments, the bacterial strains listed in Table 1, Table 2, Table 3 or Table 4 are bacterial strains.

在一些實施方式中，細菌屬於表J中列出的分類學組（例如，綱、目、科、屬、種或菌株）。In some embodiments, the bacterium belongs to a taxonomic group (eg, class, order, family, genus, species, or strain) listed in Table J.

在一些實施方式中，細菌係表J中列出的細菌菌株。In some embodiments, the bacteria are strains of bacteria listed in Table J.

在一些實施方式中，革蘭氏陰性細菌屬於 Negativicutes綱。 In some embodiments, the Gram-negative bacteria belong to the class Negativicutes .

在一些實施方式中，革蘭氏陰性細菌屬於韋榮氏球菌科（ Veillonellaceae）、月形單胞菌科（ Selenomonadaceae）、胺基酸球菌科（ Acidaminococcaceae）或 Sporomusaceae科。 In some embodiments, the Gram-negative bacterium belongs to the family Veillonellaceae , Selenomonadaceae , Acidaminococcaceae , or Sporomusaceae .

在一些實施方式中，細菌屬於巨型球菌屬（ Megasphaera） 、月形單胞菌科屬（ Selenomonas） 、 Propionospora屬 、或胺基酸球菌屬（ Acidaminococcus）。 In some embodiments, the bacterium belongs to the genus Megasphaera , Selenomonas , Propionospora , or Acidaminococcus .

在一些實施方式中，細菌係巨型球菌屬物種（ Megasphaera sp.）、菲利克斯月形單胞菌（ Selenomonas felix）、腸胺基酸球菌（ Acidaminococcus intestine）、或 Propionospora屬物種細菌。 In some embodiments, the bacteria are Megasphaera sp. , Selenomonas felix , Acidaminococcus intestine , or Propionospora sp . bacteria.

在一些實施方式中，細菌屬於乳球菌屬、普雷沃菌屬、雙歧桿菌屬、或韋榮氏球菌屬。In some embodiments, the bacteria belong to the genus Lactococcus, Prevotella, Bifidobacterium, or Veillonella.

在一些實施方式中，細菌係乳酸乳球菌乳脂亞種細菌。In some embodiments, the bacterium is Lactococcus lactis subsp. cremoris bacterium.

在一些實施方式中，細菌係棲組織普雷沃菌（ Prevotella histicola）細菌。 In some embodiments, the bacteria are Prevotella histicola bacteria.

在一些實施方式中，細菌係動物雙歧桿菌細菌。In some embodiments, the bacteria are Bifidobacterium animalis bacteria.

在一些實施方式中，細菌係小韋榮氏球菌（ Veillonella parvula）細菌。 In some embodiments, the bacterium is Veillonella parvula bacterium.

在一些實施方式中，細菌係乳酸乳球菌乳脂亞種細菌。在一些實施方式中，乳酸乳球菌乳脂亞種細菌係與乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）的核苷酸序列具有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，乳球菌屬細菌係與乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，乳球菌屬細菌係乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）。In some embodiments, the bacterium is Lactococcus lactis subsp. cremoris bacterium. In some embodiments, the Lactococcus lactis subsp. cremoris bacterial line shares at least 90% (or at least 97%) of the genome, 16S and and/or strains with CRISPR sequence identity. In some embodiments, the Lactococcus bacterium is a strain that has at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of Lactococcus lactis subsp. cremoris strain A (ATCC designation number PTA-125368). In some embodiments, the Lactococcus bacterium is Lactococcus lactis subsp. cremoris strain A (ATCC designation number PTA-125368).

在一些實施方式中，細菌係普雷沃菌屬細菌。在一些實施方式中，普雷沃菌屬細菌係包含與普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）的核苷酸序列具有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，普雷沃菌屬細菌係包含與普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，普雷沃菌屬細菌來自普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）。In some embodiments, the bacterium is a Prevotella bacterium. In some embodiments, the Prevotella strain comprises at least 90% (or at least 97%) genome, 16S and/or or strains with CRISPR sequence identity. In some embodiments, the Prevotella bacterial line comprises at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of Prevotella strain B 50329 (NRRL Accession No. B 50329). strain. In some embodiments, the Prevotella bacterium is from Prevotella strain B 50329 (NRRL Deposit No. B 50329).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普雷沃菌屬細菌，例如包含與普雷沃菌屬菌株C（ATCC保藏號PTA-126140）的核苷酸序列具有至少90%或至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普雷沃菌屬細菌，例如普雷沃菌屬菌株C（ATCC保藏號PTA-126140）。In some embodiments, the bacterium of the medicament or the mEV of the medicament is obtained from a bacterium of the genus Prevotella, for example comprising a nucleotide sequence having the same Strains with at least 90% or at least 99% genomic, 16S and/or CRISPR sequence identity. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Prevotella bacterium, eg, Prevotella strain C (ATCC Accession No. PTA-126140).

在一些實施方式中，細菌係雙歧桿菌屬細菌。在一些實施方式中，該雙歧桿菌屬細菌來自與雙歧桿菌屬細菌（保藏為ATCC指定編號PTA-125097）的核苷酸序列具有至少90%或至少97%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，雙歧桿菌屬細菌係與以ATCC指定編號PTA-125097保藏的雙歧桿菌屬細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，雙歧桿菌屬細菌係以ATCC指定編號PTA-125097保藏的雙歧桿菌屬細菌。In some embodiments, the bacterium is a Bifidobacterium bacterium. In some embodiments, the Bifidobacterium bacterium is from a nucleotide sequence having at least 90% or at least 97% of the genome, 16S and/or CRISPR sequence of a Bifidobacterium bacterium (deposited as ATCC Designation No. PTA-125097) identical strains. In some embodiments, the Bifidobacterium is a strain having at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Bifidobacterium deposited under ATCC designation number PTA-125097. In some embodiments, the Bifidobacterium bacterium is a Bifidobacterium bacterium deposited under ATCC Designation Number PTA-125097.

在一些實施方式中，細菌係韋榮氏球菌屬細菌。在一些實施方式中，韋榮氏球菌屬細菌係與以ATCC指定編號PTA-125691保藏的韋榮氏球菌屬細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，韋榮氏球菌屬細菌係與以ATCC指定編號PTA-125691保藏的韋榮氏球菌屬細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，韋榮氏球菌屬細菌係以ATCC指定編號PTA-125691保藏的韋榮氏球菌屬細菌。In some embodiments, the bacterium is a Veillonella bacterium. In some embodiments, the Veillonella strain shares at least 90% (or at least 97%) genome, 16S and/or Strains with CRISPR sequence identity. In some embodiments, the Veillonella strain is a strain having at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veillonella bacterium deposited under ATCC designation number PTA-125691 . In some embodiments, the Veillonella bacterium is a Veillonella bacterium deposited under ATCC Designation No. PTA-125691.

在一些實施方式中，細菌來自活潑瘤胃球菌細菌。在一些實施方式中，活潑瘤胃球菌細菌係與以ATCC指定編號PTA-126695保藏的活潑瘤胃球菌細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，活潑瘤胃球菌細菌係與以ATCC指定編號PTA-126695保藏的活潑瘤胃球菌細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，活潑瘤胃球菌細菌係以ATCC指定編號PTA-126695保藏的活潑瘤胃球菌細菌。In some embodiments, the bacteria are from Ruminococcus mobilis bacteria. In some embodiments, the Ruminococcus mobilis bacterial strain has at least 90% (or at least 97%) genomic, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus mobilis bacterium deposited under ATCC designation number PTA-126695 strains. In some embodiments, the Ruminococcus mobilis bacterium is a strain that has at least 99% genomic, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus mobilis bacterium deposited under ATCC designation number PTA-126695. In some embodiments, the Ruminococcus mobilis bacterium is the Ruminococcus mobilis bacterium deposited under ATCC designation number PTA-126695.

在一些實施方式中，細菌係巨型球菌屬物種細菌。在一些實施方式中，巨型球菌屬物種細菌係與以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，巨型球菌屬物種細菌係與以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，巨型球菌屬物種細菌係以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌。In some embodiments, the bacterium is a Megasphaera spp. bacterium. In some embodiments, the Megastococcus sp. bacterial strain has at least 90% (or at least 97%) genomic, 16S, and/or CRISPR sequences with the nucleotide sequence of the Megastococcus sp. bacterium deposited under ATCC designation number PTA-126770 identical strains. In some embodiments, the Megastococcus sp. bacterium is a strain that has at least 99% genomic, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Megastococcus sp. bacterium deposited under ATCC designation number PTA-126770. In some embodiments, the Megastococcus sp. bacterium is a Megastococcus sp. bacterium deposited under ATCC Designation No. PTA-126770.

在一些實施方式中，細菌係 Fournierella massiliensis細菌。在一些實施方式中， Fournierella massiliensis細菌係與以ATCC指定編號PTA-126696保藏的 Fournierella massiliensis細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中， Fournierella massiliensis細菌係與以ATCC指定編號PTA-126696保藏的 Fournierella massiliensis細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中， Fournierella massiliensis細菌係以ATCC指定編號PTA-126696保藏的 Fournierella massiliensis細菌。 In some embodiments, the bacteria is Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis strain has at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited under ATCC designation number PTA-126696 . In some embodiments, the Fournierella massiliensis strain is a strain that has at least 99% genomic, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited under ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacterium is the Fournierella massiliensis bacterium deposited under ATCC Designation Number PTA-126696.

在一些實施方式中，細菌係 Harryflintia acetispora細菌。在一些實施方式中， Harryflintia acetispora細菌係與以ATCC指定編號PTA-126694保藏的 Harryflintia acetispora細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中， Harryflintia acetispora細菌係與以ATCC指定編號PTA-126694保藏的 Harryflintia acetispora細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中， Harryflintia acetispora細菌係以ATCC指定編號PTA-126694保藏的 Harryflintia acetispora細菌。 In some embodiments, the bacterium is Harryflintia acetispora bacterium. In some embodiments, the Harryflintia acetispora bacterial strain is a strain having at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited under ATCC designation number PTA-126694 . In some embodiments, the Harryflintia acetispora bacterium is a strain that has at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacterium deposited under ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacterium is the Harryflintia acetispora bacterium deposited under ATCC designation number PTA-126694.

在一些實施方式中，細菌屬於胺基酸球菌科、產鹼桿菌科、阿克曼氏菌科、擬桿菌科、雙歧桿菌科、伯克霍爾德菌科、 Catabacteriaceae科、克裡斯滕森菌科、梭菌科、紅蝽菌科、腸桿菌科、腸球菌科、梭桿菌科、毛螺菌科、李斯特菌科、分枝桿菌科、奈瑟菌科、臭桿菌科、顫螺旋菌科、消化球菌科、消化鏈球菌科、卟啉單胞菌科、普雷沃菌科、丙酸桿菌科、理研菌科、瘤胃球菌科、月形單胞菌科、 Sporomusaceae科、鏈球菌科、鏈黴菌科、薩特氏菌科、互養菌科、坦納菌科或韋榮氏球菌科。 In some embodiments, the bacterium belongs to the family Aminococcaceae, Alcaligeneceae, Akkermansiaceae, Bacteroidaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae family, Christensen Mycobacteriaceae, Clostridiumceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcusceae, Fusobacteriaceae, Lachnospiraceae, Listeriaceae, Mycobacteriaceae, Neisseriaceae, Ostrichaceae, Trembling Spirals Mycobacteriaceae, Peptococcusceae, Peptostreptococcusceae, Porphyromonasceae, Prevotaceae, Propionibacteriaceae, Rikenbacteriaceae, Ruminococcusceae, Lunatomonadaceae, Sporomusaceae , Streptococcus Streptomycetaceae, Sutterellaceae, Syntrophyceae, Tannerellaceae, or Veillonellaceae.

在一些實施方式中，細菌屬於阿克曼氏菌屬、克裡斯滕森菌屬、布勞特氏菌屬、腸球菌屬、真桿菌屬、羅斯氏菌屬、擬桿菌屬、副擬桿菌屬、或丹毒絲梭菌屬。In some embodiments, the bacterium is of the genus Akkermansia, Christensenella, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides , or erysipelasia.

在一些實施方式中，細菌係產氫營養型布勞特氏菌、排泄物布勞特氏菌、韋氏布勞特氏菌、糞真桿菌、扭曲真桿菌、直腸真桿菌、糞腸球菌、耐久腸球菌、絨毛腸球菌、鶉雞腸球菌；乳酸雙歧桿菌、兩歧雙歧桿菌、長雙歧桿菌、動物雙歧桿菌或短雙歧桿菌細菌。In some embodiments, the bacteria are Brautia hydrotrophs, Blautia faecalis, Blautia weideri, Eubacterium faecalis, Eubacterium twistus, Eubacterium rectum, Enterococcus faecalis, Enterococcus dursus, Enterococcus villosa, Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium animalis, or Bifidobacterium breve bacteria.

在一些實施方式中，細菌係BCG（卡介苗）、副擬桿菌屬、布勞特氏菌屬、韋榮氏球菌屬、唾液乳桿菌、阿加薩桿菌屬（ Agathobaculum）、活潑瘤胃球菌、解苯副梭菌、 Turicibacter sanguinus、伯克霍爾德菌屬、類肺炎克雷伯氏菌擬肺炎亞種、催產克雷伯氏菌、納西利斯泰澤菌（ Tyzerella nexilis）或奈瑟菌屬細菌。 In some embodiments, the bacteria are BCG (Bacillus Calmette-Guerin), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum , Ruminococcus vivabilis, Benzene Clostridium paraclostridium, Turicibacter sanguinus , Burkholderia sp., Klebsiella pneumoniae subsp. pneumoniae, Klebsiella oxytoca, Tyzerella nexilis , or Neisseria sp. .

在一些實施方式中，細菌係產氫營養型布勞特氏菌細菌。In some embodiments, the bacterium is a hydrogenotrophic Blautia bacterium.

在一些實施方式中，細菌係排泄物布勞特氏菌細菌。In some embodiments, the bacteria are Blautia faecalis bacteria.

在一些實施方式中，細菌係韋氏布勞特氏菌細菌。In some embodiments, the bacterium is a Brautia weschleri bacterium.

在一些實施方式中，細菌係鶉雞腸球菌細菌。In some embodiments, the bacterium is Enterococcus gallinarum bacterium.

在一些實施方式中，細菌係屎腸球菌細菌。In some embodiments, the bacteria are Enterococcus faecium bacteria.

在一些實施方式中，細菌係兩歧雙歧桿菌細菌。In some embodiments, the bacteria are Bifidobacterium bifidum bacteria.

在一些實施方式中，細菌係短雙歧桿菌細菌。In some embodiments, the bacteria are Bifidobacterium breve bacteria.

在一些實施方式中，細菌係長雙歧桿菌細菌。In some embodiments, the bacteria are Bifidobacterium longum bacteria.

在一些實施方式中，細菌係人羅斯氏菌細菌。In some embodiments, the bacterium is a Roseburia hominis bacterium.

在一些實施方式中，細菌係多形擬桿菌（ Bacteroides thetaiotaomicron）細菌。 In some embodiments, the bacteria are Bacteroides thetaiotaomicron bacteria.

在一些實施方式中，細菌係糞居擬桿菌細菌。In some embodiments, the bacterium is a Bacteroides faecalis bacterium.

在一些實施方式中，細菌係 Erysipelatoclostridium ramosum細菌。 In some embodiments, the bacterium is Erysipelatoclostridium ramosum bacterium.

在一些實施方式中，細菌係馬賽巨型球菌細菌。In some embodiments, the bacterium is a M. marseini bacterium.

在一些實施方式中，細菌係真桿菌屬細菌。In some embodiments, the bacterium is a Eubacterium bacterium.

在一些實施方式中，細菌係狄氏副擬桿菌（ Parabacteroides distasonis）細菌。 In some embodiments, the bacterium is a Parabacteroides distasonis bacterium.

在一些實施方式中，細菌係植物乳桿菌細菌。In some embodiments, the bacterium is a Lactobacillus plantarum bacterium.

在一些實施方式中，細菌屬於 Negativicutes綱。 In some embodiments, the bacteria belong to the class Negativicutes .

在一些實施方式中，細菌屬於韋榮氏球菌科。In some embodiments, the bacterium is of the family Veillonellaceae.

在一些實施方式中，細菌屬於月形單胞菌科。In some embodiments, the bacterium is of the family Seuromonaceae.

在一些實施方式中，細菌屬於胺基酸球菌科。In some embodiments, the bacterium belongs to the family Aminococcae.

在一些實施方式中，細菌屬於 Sporomusaceae科。 In some embodiments, the bacteria belong to the family Sporomusaceae .

在一些實施方式中，細菌屬於巨型球菌屬。In some embodiments, the bacterium is of the genus Megasphaera.

在一些實施方式中，細菌屬於月形單胞菌屬。In some embodiments, the bacterium is of the genus Lueromonas.

在一些實施方式中，細菌屬於Propionospora屬。In some embodiments, the bacterium belongs to the genus Propionospora.

在一些實施方式中，細菌屬於胺基酸球菌屬。In some embodiments, the bacteria belong to the genus Aminococcus.

在一些實施方式中，細菌係巨型球菌屬物種細菌。In some embodiments, the bacterium is a Megasphaera spp. bacterium.

在一些實施方式中，細菌來自菲利克斯月形單胞菌細菌。In some embodiments, the bacterium is from a Lueromonas bacterium.

在一些實施方式中，細菌係腸胺基酸球菌。In some embodiments, the bacteria is Aminococcus enterica.

在一些實施方式中，細菌係 Propionospora屬物種細菌。 In some embodiments, the bacterium is a bacterium of the genus Propionospora .

在一些實施方式中，細菌屬於梭菌綱。In some embodiments, the bacteria are of the class Clostridia.

在一些實施方式中，細菌屬於顫螺旋菌科。In some embodiments, the bacterium is of the family Cyclospiraceae.

在一些實施方式中，細菌屬於糞桿菌屬（ Faecalibacterium）。 In some embodiments, the bacteria is of the genus Faecalibacterium .

在一些實施方式中，細菌屬於 Fournierella屬。 In some embodiments, the bacteria belong to the genus Fournierella .

在一些實施方式中，細菌屬於 Harryflintia屬。 In some embodiments, the bacterium belongs to the genus Harryflintia .

在一些實施方式中，細菌屬於阿加薩桿菌屬。In some embodiments, the bacterium belongs to the genus Agartsia.

在一些實施方式中，細菌係普氏棲糞桿菌（例如，普氏棲糞桿菌菌株A）細菌。In some embodiments, the bacterium is a Faecalibacterium prausnitzii (eg, Faecalibacterium prausnitzii strain A) bacterium.

在一些實施方式中，細菌係 Fournierella massiliensis（例如， Fournierella massiliensis菌株A）細菌。 In some embodiments, the bacterium is a Fournierella massiliensis (eg, Fournierella massiliensis strain A) bacterium.

在一些實施方式中，細菌係 Harryflintia acetispora（例如， Harryflintia acetispora菌株A）細菌。 In some embodiments, the bacterium is a Harryflintia acetispora (eg, Harryflintia acetispora strain A) bacterium.

在一些實施方式中，細菌係阿加薩桿菌屬物種（例如，阿加薩桿菌屬物種菌株A）細菌。In some embodiments, the bacteria is an Agartsia sp. (eg, Agartsia sp. strain A) bacterium.

在一些實施方式中，細菌係阿加薩桿菌屬物種的菌株。在一些實施方式中，阿加薩桿菌屬物種菌株係與阿加薩桿菌屬物種菌株A（ATCC保藏號PTA-125892）的核苷酸序列（例如，基因組序列、16S序列、CRISPR序列）具有至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，阿加薩桿菌屬物種菌株係阿加薩桿菌屬物種菌株A（ATCC保藏號PTA- 125892）細菌。In some embodiments, the bacterium is a strain of the Agartsia species. In some embodiments, the nucleotide sequence (eg, genomic sequence, 16S sequence, CRISPR sequence) of Agartsia sp. strain A (ATCC Deposit No. PTA-125892) has at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity sex, at least 99.9% sequence identity). In some embodiments, the Agartsia sp. strain is Agartsia sp. strain A (ATCC Accession No. PTA-125892) bacterium.

在一些實施方式中，細菌屬於擬桿菌綱[擬桿菌門]。在一些實施方式中，細菌屬於擬桿菌目。在一些實施方式中，細菌屬於紫單胞菌科。在一些實施方式中，細菌屬於普雷沃菌科。在一些實施方式中，細菌屬於擬桿菌綱，其中細菌的細胞被膜結構係雙層的（diderm）。在一些實施方式中，細菌屬於擬桿菌綱、革蘭氏陰性染色。在一些實施方式中，細菌屬於擬桿菌綱，其中細菌係雙層的並且細菌係革蘭氏陰性染色。In some embodiments, the bacterium belongs to the class Bacteroidetes [phylum Bacteroidetes]. In some embodiments, the bacteria are of the order Bacteroidetes. In some embodiments, the bacterium is of the family Porphyridaceae. In some embodiments, the bacterium is of the family Prevotellaceae. In some embodiments, the bacterium is of the class Bacteroides, wherein the cell envelope of the bacterium is a diderm. In some embodiments, the bacteria are of the class Bacteroidetes, Gram-negative staining. In some embodiments, the bacterium is of the class Bacteroidetes, wherein the bacterium is bilayered and the bacterium is Gram-negative staining.

在一些實施方式中，細菌屬於梭菌綱[厚壁菌門]。在一些實施方式中，細菌屬於真細菌目（ Eubacteriales）。在一些實施方式中，細菌屬於顫螺旋菌科。在一些實施方式中，細菌屬於毛螺菌科。在一些實施方式中，細菌屬於消化鏈球菌科。在一些實施方式中，細菌屬於梭菌目XIII科 /地位未定41。在一些實施方式中，細菌屬於梭菌綱，其中細菌的細胞被膜結構係單層的（monoderm）。在一些實施方式中，細菌屬於梭菌綱、革蘭氏陰性染色。在一些實施方式中，細菌屬於梭菌綱、革蘭氏陽性染色。在一些實施方式中，細菌屬於梭菌綱，其中細菌的細胞被膜結構係單層的並且細菌係革蘭氏陰性染色。在一些實施方式中，細菌屬於梭菌綱，其中細菌的細胞被膜結構係單層的並且細菌係革蘭氏陽性染色。 In some embodiments, the bacterium belongs to the class Clostridium [Firmicutes]. In some embodiments, the bacteria are of the order Eubacteriales . In some embodiments, the bacterium is of the family Cyclospiraceae. In some embodiments, the bacterium belongs to the Lachnospiraceae family. In some embodiments, the bacteria belong to the Peptostreptococcus family. In some embodiments, the bacterium belongs to the Clostridiaceae family XIII / status indeterminate 41 . In some embodiments, the bacterium is of the class Clostridia, wherein the cell envelope of the bacterium is monoderm. In some embodiments, the bacteria are of the class Clostridia, Gram-negative staining. In some embodiments, the bacteria are of the class Clostridia, Gram positive staining. In some embodiments, the bacterium is of the class Clostridium, wherein the cell envelope structure of the bacterium is monolayer and the bacterium is Gram-negative staining. In some embodiments, the bacterium is of the class Clostridia, wherein the cell envelope of the bacterium is monolayer and the bacterium stains Gram positive.

在一些實施方式中，細菌屬於Negativicutes綱[厚壁菌門]。在一些實施方式中，細菌屬於韋榮氏球菌目。在一些實施方式中，細菌屬於韋榮氏球菌科。在一些實施方式中，細菌屬於月形單胞菌目（ Selenomonadales）。在一些實施方式中，細菌屬於月形單胞菌科。在一些實施方式中，細菌屬於 Sporomusaceae科。在一些實施方式中，細菌屬於Negativicutes綱，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，細菌屬於Negativicutes綱、革蘭氏陰性染色。在一些實施方式中，細菌屬於 Negativicutes綱，其中細菌的細胞被膜結構係雙層的並且細菌係革蘭氏陰性染色。 In some embodiments, the bacteria belong to the class Negativicutes [Firmicutes]. In some embodiments, the bacterium is of the order Veillonellales. In some embodiments, the bacterium is of the family Veillonellaceae. In some embodiments, the bacteria are of the order Selenomonadales . In some embodiments, the bacterium is of the family Seuromonaceae. In some embodiments, the bacteria belong to the family Sporomusaceae . In some embodiments, the bacterium is of the class Negativicutes, wherein the cell envelope of the bacterium is bilayered. In some embodiments, the bacteria are of the class Negativicutes, Gram-negative staining. In some embodiments, the bacterium is of the class Negativicutes , wherein the cell envelope of the bacterium is bilayer and the bacterium is Gram-negative staining.

在一些實施方式中，細菌屬於互養菌綱[互養菌門]。在一些實施方式中，細菌屬於互養菌目。在一些實施方式中，細菌屬於互養菌科。在一些實施方式中，細菌屬於互養菌綱，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，細菌屬於互養菌綱、革蘭氏陰性染色。在一些實施方式中，細菌屬於互養菌綱，其中細菌的細胞被膜結構係雙層的並且細菌係革蘭氏陰性染色。In some embodiments, the bacterium belongs to the class Syntrophycetes [phylum Syntrophyta]. In some embodiments, the bacteria are of the order Syntrophyles. In some embodiments, the bacterium is of the family Syntrophyceae. In some embodiments, the bacterium is of the class Syntrophycetes, wherein the cell envelope of the bacterium is bilayered. In some embodiments, the bacteria are of the class Syntrophycetes, Gram-negative staining. In some embodiments, the bacterium is of the class Syntrophycetes, wherein the cell envelope of the bacterium is bilayer and the bacterium is Gram-negative staining.

在一些實施方式中，細菌係產生代謝產物的細菌，例如，細菌產生丁酸、肌苷、丙酸、或色胺酸代謝產物。In some embodiments, the bacterium is a bacterium that produces a metabolite, eg, the bacterium produces a butyrate, inosine, propionate, or tryptophan metabolite.

在一些實施方式中，細菌產生丁酸。在一些實施方式中，細菌來自布勞特氏菌屬 ；克裡斯滕森菌屬；糞球菌屬；真桿菌屬； Lachnosperacea ；巨型球菌屬；或羅斯氏菌屬。 In some embodiments, the bacteria produce butyrate. In some embodiments, the bacterium is from the genus Blautia; Christensen; Coprococcus ; Eubacterium;

在一些實施方式中，細菌產生肌苷。在一些實施方式中，細菌來自雙歧桿菌屬；乳桿菌屬；或歐陸森氏菌屬。In some embodiments, the bacteria produce inosine. In some embodiments, the bacterium is from the genus Bifidobacterium; Lactobacillus; or Eugenia.

在一些實施方式中，細菌產生丙酸。在一些實施方式中，細菌來自阿克曼氏菌屬；擬桿菌屬；戴阿利斯特菌屬（ Dialister）；真桿菌屬；巨型球菌屬；副擬桿菌屬；普雷沃菌屬；瘤胃球菌屬；或韋榮氏球菌屬。 In some embodiments, the bacteria produce propionic acid. In some embodiments, the bacterium is from the genus Akkermansia; Bacteroides ; Dialister; Eubacterium; genus; or Veillonella spp.

在一些實施方式中，細菌產生色胺酸代謝產物。在一些實施方式中，細菌來自乳桿菌屬或消化鏈球菌屬。In some embodiments, the bacteria produce tryptophan metabolites. In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

在一些實施方式中，細菌係產生組蛋白脫乙醯基酶3（HDAC3）的抑制劑的細菌。在一些實施方式中，細菌來自物種 Bariatricus massiliensis、普氏棲糞桿菌、馬賽巨型球菌或腸羅斯氏菌。 In some embodiments, the bacterium is a bacterium that produces an inhibitor of histone deacetylase 3 (HDAC3). In some embodiments, the bacterium is from the species Bariatricus massiliensis , Faecalibacterium prausnitzii, M. marseilles, or Rothia enterica.

在一些實施方式中，細菌來自不動桿菌屬； 異常球菌屬；螺桿菌屬；紅球菌屬；食竇魏斯氏菌；明串珠菌屬；羅氏菌屬；差異球菌屬；芽孢桿菌屬；鏈型桿菌屬；棒狀桿菌屬；貪銅菌屬；水棲菌屬；微小桿菌屬；糞桿菌屬； 土芽孢桿菌屬；甲基桿菌屬；微球菌屬；摩根氏菌屬；變形桿菌屬；假單胞菌屬；根瘤菌屬；或鞘胺醇單胞菌屬。 In some embodiments, the bacterium is from the genus Acinetobacter; Deinococcus; Helicobacter; Rhodococcus; Bacillus; Corynebacterium; Copperphyllum; Aquabacterium; Microbacterium; Faecalibacterium; Geobacillus; Methylobacterium; Micrococcus; Morganella; Proteus; Pseudomonas Sphingomonas; Rhizobium; or Sphingomonas.

在一些實施方式中，細菌來自物種鮑曼不動桿菌； 耐輻射異常球菌；幽門螺桿菌；馬紅球菌；食竇魏斯氏菌；耳炎差異球菌；陰道奇異菌；三井鏈型桿菌（ Catenibacterium mituokai ）；麩胺酸棒狀桿菌；金橙黃微小桿菌（ Exiguobacterium aurantiacum ）；嗜熱脂肪地桿菌； Methylobacterium jeotgali ；藤黃微球菌；摩根摩根氏菌；奇異變形桿菌；豌豆根瘤菌；污水溝羅斯氏菌（ Rothia amarae ）；少動鞘胺醇單胞菌；或朝鮮鞘胺醇單胞菌（Sphingomonas koreens）。 In some embodiments, the bacterium is from the species Acinetobacter baumannii; Deinococcus radiodurans; Helicobacter pylori; Rhodococcus equi ; ); Corynebacterium glutamicum; Exiguobacterium aurantiacum ; Geobacter stearothermophilus ; Methylobacterium jeotgali ; Micrococcus luteus; Morganella morganii; Proteus mirabilis; ( Rothia amarae ); Sphingomonas paucimobilis; or Sphingomonas koreaens.

在一些實施方式中，細菌來自 Cutibacterium屬。 In some embodiments, the bacteria are from the genus Cutibacterium .

在一些實施方式中，細菌來自物種 Cutibacterium avidum。 In some embodiments, the bacterium is from the species Cutibacterium avidum .

在一些實施方式中，細菌來自乳桿菌屬。In some embodiments, the bacteria are from the genus Lactobacillus.

在一些實施方式中，細菌來自物種加氏乳桿菌； 乾酪乳桿菌；副乾酪乳桿菌；鼠李糖乳桿菌；或清酒乳桿菌。 In some embodiments, the bacterium is from the species Lactobacillus gasseri; Lactobacillus casei; Lactobacillus paracasei; Lactobacillus rhamnosus; or Lactobacillus sake .

在一些實施方式中，細菌來自 Dysosmobacter屬。 In some embodiments, the bacteria are from the genus Dysosmobacter .

在一些實施方式中，細菌來自物種 Dysosmobacter welbionis。 In some embodiments, the bacterium is from the species Dysosmobacter welbionis .

在一些實施方式中，細菌來自 明串珠菌屬。在一些實施方式中，細菌來自賀氏明串珠菌細菌。在一些實施方式中，細菌來自賀氏明串珠菌Ceb-kc-003（KCCM11830P）。 In some embodiments, the bacteria are from the genus Leuconostoc . In some embodiments, the bacterium is from a Leuconostoc hushii bacterium. In some embodiments, the bacterium is from Leuconostoc heschii Ceb-kc-003 (KCCM11830P).

在一些實施方式中，細菌來自物種耐金屬貪銅菌或釀膿鏈球菌。In some embodiments, the bacterium is from the species C. metalloresistant or Streptococcus pyogenes.

在一些實施方式中，細菌來自巨型球菌屬物種細菌（例如，來自保藏號為NCIMB 43385、NCIMB 43386或NCIMB 43387的菌株）。In some embodiments, the bacterium is from a Megasphaera sp. bacterium (eg, from a strain deposited under NCIMB 43385, NCIMB 43386, or NCIMB 43387).

在一些實施方式中，細菌來自馬賽巨型球菌細菌（例如，來自保藏號為NCIMB 42787、NCIMB 43388或NCIMB 43389的菌株）。In some embodiments, the bacterium is from a M. marseille bacterium (eg, from a strain deposited under NCIMB 42787, NCIMB 43388, or NCIMB 43389).

在一些實施方式中，細菌來自馬賽巨型球菌細菌（例如，來自保藏號為DSM 26228的菌株）。In some embodiments, the bacterium is from M. marseilles bacterium (eg, from the strain deposited under DSM 26228).

在一些實施方式中，細菌來自狄氏副擬桿菌細菌（例如，來自保藏號為NCIMB 42382的菌株）。In some embodiments, the bacterium is from a Parabacteroides distirii bacterium (eg, from a strain deposited under NCIMB 42382).

在一些實施方式中，細菌來自馬賽巨型球菌細菌（例如，來自保藏號為NCIMB 43388或NCIMB 43389的菌株）或其衍生物。參見，例如，WO 2020/120714。在一些實施方式中，馬賽巨型球菌細菌係與來自保藏號為NCIMB 43388或NCIMB 43389的菌株的馬賽巨型球菌細菌的核苷酸序列（例如，基因組序列、16S序列、和/或CRISPR序列）包含至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，馬賽巨型球菌細菌係保藏號為NCIMB 43388或NCIMB 43389的菌株。In some embodiments, the bacterium is from a M. marseille bacterium (eg, from a strain deposited under NCIMB 43388 or NCIMB 43389) or a derivative thereof. See, eg, WO 2020/120714. In some embodiments, the M. marseilles bacterium strain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, Strains of at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity). In some embodiments, the M. marseille bacterium is a strain with deposit number NCIMB 43388 or NCIMB 43389.

在一些實施方式中，細菌來自保藏號為NCIMB 42787的馬賽巨型球菌細菌菌株，或其衍生物。參見，例如，WO 2018/229216。在一些實施方式中，馬賽巨型球菌細菌係與以保藏號NCIMB 42787保藏的馬賽巨型球菌細菌菌株的核苷酸序列（例如，基因組序列、16S序列、和/或CRISPR序列）包含至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，馬賽巨型球菌細菌係以保藏號NCIMB 42787保藏的菌株。In some embodiments, the bacterium is from a bacterial strain of M. marseilles deposited under NCIMB 42787, or a derivative thereof. See, eg, WO 2018/229216. In some embodiments, the M. marseilles bacterial strain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity identity, at least 99.8% sequence identity, at least 99.9% sequence identity). In some embodiments, the M. marseille bacterium is a strain deposited under accession number NCIMB 42787.

在一些實施方式中，細菌來自保藏號為NCIMB 43385、NCIMB 43386或NCIMB 43387的菌株的巨型球菌屬物種細菌，或其衍生物。參見，例如，WO 2020/120714。在一些實施方式中，巨型球菌屬物種細菌係與來自保藏號為NCIMB 43385，NCIMB 43386或NCIMB 43387的菌株的巨型球菌屬物種的核苷酸序列（例如，基因組序列、16S序列、和/或CRISPR序列）包含至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，巨型球菌屬物種細菌係保藏號為NCIMB 43385、NCIMB 43386或NCIMB 43387的菌株。In some embodiments, the bacterium is from a Megasphaera sp. bacterium of the strain deposited under NCIMB 43385, NCIMB 43386, or NCIMB 43387, or a derivative thereof. See, eg, WO 2020/120714. In some embodiments, the Megastococcus sp. bacterial strain is associated with a nucleotide sequence (e.g., a genome sequence, a 16S sequence, and/or a CRISPR sequence) comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity). In some embodiments, the Megastococcus sp. bacterium is a strain deposited under NCIMB 43385, NCIMB 43386, or NCIMB 43387.

在一些實施方式中，細菌來自保藏號為NCIMB 42382的狄氏副擬桿菌細菌，或其衍生物。參見，例如，WO 2018/229216。在一些實施方式中，狄氏副擬桿菌細菌係與以保藏號NCIMB 42382保藏的狄氏副擬桿菌細菌的核苷酸序列（例如，基因組序列、16S序列、和/或CRISPR序列）包含至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，狄氏副擬桿菌細菌係以保藏號NCIMB 42382保藏的菌株。In some embodiments, the bacterium is from a Parabacteroides distrobacter bacterium deposited under NCIMB 42382, or a derivative thereof. See, eg, WO 2018/229216. In some embodiments, the Parabacteroides distirii bacterial strain comprises at least 80 %, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity). In some embodiments, the Parabacteroides distirii bacterium is a strain deposited under accession number NCIMB 42382.

在一些實施方式中，細菌來自保藏號為DSM 26228的馬賽巨型球菌細菌，或其衍生物。參見，例如，WO 2018/229216。在一些實施方式中，馬賽巨型球菌細菌係與以保藏號DSM 26228保藏的馬賽巨型球菌細菌的核苷酸序列（例如，基因組序列、16S序列、和/或CRISPR序列）包含至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，馬賽巨型球菌細菌係以保藏號DSM 26228保藏的菌株。In some embodiments, the bacterium is from the M. marseille bacterium deposited under DSM 26228, or a derivative thereof. See, eg, WO 2018/229216. In some embodiments, the nucleotide sequence (for example, genome sequence, 16S sequence, and/or CRISPR sequence) of the M. marseille bacteria line and the M. marseille bacteria deposited under the deposit number DSM 26228 comprises at least 80%, at least 85% %, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity sex, at least 99.8% sequence identity, at least 99.9% sequence identity) strains. In some embodiments, the M. marseille bacterium is a strain deposited under accession number DSM 26228.

在一些實施方式中，藥劑包含分離的mEV（例如，來自一種或多種細菌菌株（例如，目的細菌）（例如，其治療有效量）。例如，其中藥劑的至少50%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%的含量係細菌（例如，目的細菌）的分離的mEV。In some embodiments, the medicament comprises isolated mEV (e.g., from one or more bacterial strains (e.g., the bacterium of interest) (e.g., in a therapeutically effective amount thereof). For example, wherein at least 50%, at least 75%, at least 80% of the medicament %, at least 85%, at least 90%, at least 95%, or at least 99% of the isolated mEV is a bacterium (eg, a bacterium of interest).

在一些實施方式中，藥劑包含mEV，並且mEV包含分泌型mEV（smEV）。In some embodiments, the agent comprises mEVs, and the mEVs comprise secreted mEVs (smEVs).

在一些實施方式中，藥劑包含mEV，並且mEV包含經處理的mEV（pmEV）。In some embodiments, the agent comprises mEVs, and the mEVs comprise processed mEVs (pmEVs).

在一些實施方式中，藥劑包含pmEV，並且pmEV由已經經γ照射、UV照射、熱滅活、酸處理或氧噴射的細菌產生。In some embodiments, the agent comprises pmEVs, and the pmEVs are produced by bacteria that have been gamma irradiated, UV irradiated, heat inactivated, acid treated, or oxygen sparged.

在一些實施方式中，藥劑包含pmEV，並且pmEV由活細菌產生。In some embodiments, the medicament comprises pmEVs, and the pmEVs are produced by living bacteria.

在一些實施方式中，藥劑包含pmEV，並且pmEV產生自死細菌。In some embodiments, the medicament comprises pmEV, and the pmEV is produced from dead bacteria.

在一些實施方式中，藥劑包含pmEV，並且pmEV產生自非複製型細菌。In some embodiments, the medicament comprises pmEVs, and the pmEVs are produced from non-replicating bacteria.

在一些實施方式中，藥劑包含mEV，並且mEV來自一種細菌菌株。In some embodiments, the medicament comprises mEV, and the mEV is from a bacterial strain.

在一些實施方式中，mEV被凍乾（例如，凍乾的產物進一步包含藥學上可接受的賦形劑）。In some embodiments, the mEV is lyophilized (eg, the lyophilized product further comprises a pharmaceutically acceptable excipient).

在一些實施方式中，mEV被γ照射。In some embodiments, mEVs are gamma irradiated.

在一些實施方式中，mEV被UV照射。In some embodiments, mEVs are UV irradiated.

在一些實施方式中，mEV被熱滅活（例如，在50°C下兩小時或在90°C下兩小時）。In some embodiments, mEVs are heat inactivated (eg, two hours at 50°C or two hours at 90°C).

在一些實施方式中，mEV被酸處理。In some embodiments, mEVs are acid-treated.

在一些實施方式中，mEV被噴氧（例如，以0.1 vvm持續兩小時）。In some embodiments, mEVs are sparged with oxygen (eg, at 0.1 vvm for two hours).

在一些實施方式中，mEV來自革蘭氏陽性細菌。In some embodiments, the mEVs are from Gram-positive bacteria.

在一些實施方式中，mEV來自革蘭氏陰性細菌。In some embodiments, the mEVs are from Gram-negative bacteria.

在一些實施方式中，mEV來自需氧細菌。In some embodiments, the mEVs are from aerobic bacteria.

在一些實施方式中，mEV來自厭氧細菌。在一些實施方式中，厭氧細菌包含專性厭氧菌。在一些實施方式中，厭氧細菌包含兼性厭氧菌。In some embodiments, the mEVs are from anaerobic bacteria. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

在一些實施方式中，mEV來自嗜酸細菌。In some embodiments, the mEVs are from acidophilic bacteria.

在一些實施方式中，mEV來自嗜鹼細菌。In some embodiments, the mEVs are from alkaliphilic bacteria.

在一些實施方式中，mEV來自嗜中性細菌。In some embodiments, the mEVs are from neutrophils.

在一些實施方式中，mEV來自難養細菌。In some embodiments, the mEVs are from fastidious bacteria.

在一些實施方式中，mEV來自非難養細菌。In some embodiments, the mEVs are from non-fastidious bacteria.

在一些實施方式中，mEV來自表1、表2、表3或表4中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌。In some embodiments, the mEV is from a bacterium of a taxonomic group (eg, class, order, family, genus, species, or strain) listed in Table 1, Table 2, Table 3, or Table 4.

在一些實施方式中，mEV來自表1、表2、表3或表4中列出的細菌菌株。In some embodiments, the mEV is from a bacterial strain listed in Table 1, Table 2, Table 3, or Table 4.

在一些實施方式中，mEV來自表J中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌。In some embodiments, the mEV is from a bacterium of a taxonomic group (eg, class, order, family, genus, species, or strain) listed in Table J.

在一些實施方式中，mEV來自表J中列出的細菌菌株。In some embodiments, the mEVs are from the bacterial strains listed in Table J.

在一些實施方式中，革蘭氏陰性細菌屬於 Negativicutes綱。 In some embodiments, the Gram-negative bacteria belong to the class Negativicutes .

在一些實施方式中，革蘭氏陰性細菌屬於韋榮氏球菌科（ Veillonellaceae）、月形單胞菌科（ Selenomonadaceae）、胺基酸球菌科（ Acidaminococcaceae）或 Sporomusaceae科。 In some embodiments, the Gram-negative bacterium belongs to the family Veillonellaceae , Selenomonadaceae , Acidaminococcaceae , or Sporomusaceae .

在一些實施方式中，mEV來自以下屬的細菌：巨型球菌屬 （ Megasphaera ）、月形單胞菌屬 （ Selenomonas ）、 Propionospora 、或胺基酸球菌屬（Acidaminococcus）。 In some embodiments , the mEV is from a bacterium of the genera Megasphaera , Selenomonas , Propionospora , or Acidaminococcus.

在一些實施方式中，mEV係巨型球菌屬物種（ Megasphaera sp.） 、菲利克斯新月形單胞菌（Selenomonas felix）、腸胺基酸球菌（Acidaminococcus intestine）、或Propionospora屬物種細菌。 In some embodiments, the mEV is a Megasphaera sp. , Selenomonas felix, Acidaminococcus intestine, or Propionospora sp. bacterium.

在一些實施方式中，mEV來自乳球菌屬、普雷沃菌屬、雙歧桿菌屬、或韋榮氏球菌屬的細菌。In some embodiments, the mEV is from a bacterium of the genus Lactococcus, Prevotella, Bifidobacterium, or Veillonella.

在一些實施方式中，mEV來自乳酸乳球菌乳脂亞種細菌。In some embodiments, the mEV is from Lactococcus lactis subsp. cremoris bacterium.

在一些實施方式中，mEV來自棲組織普雷沃菌（ Prevotella histicola）細菌。 In some embodiments, the mEV is from a Prevotella histicola bacterium.

在一些實施方式中，mEV來自動物雙歧桿菌細菌。In some embodiments, the mEVs are from Bifidobacterium animalis bacteria.

在一些實施方式中，mEV來自小韋榮氏球菌細菌。In some embodiments, the mEVs are from Veillonella parvum bacteria.

在一些實施方式中，mEV來自乳酸乳球菌乳脂亞種細菌。在一些實施方式中，該乳酸乳球菌乳脂亞種細菌來自與乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）的核苷酸序列具有至少90%或至少97%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該乳球菌屬細菌來自與乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該乳球菌屬細菌來自乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）。In some embodiments, the mEV is from Lactococcus lactis subsp. cremoris bacterium. In some embodiments, the Lactococcus lactis subsp. cremoris bacterium is from a nucleotide sequence having at least 90% or at least 97% of the genome, 16S and/or or strains with CRISPR sequence identity. In some embodiments, the Lactococcus bacterium is from a strain having at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of Lactococcus lactis subsp. cremoris strain A (ATCC designation number PTA-125368) . In some embodiments, the Lactococcus bacterium is from Lactococcus lactis subsp. cremoris strain A (ATCC designation number PTA-125368).

在一些實施方式中，mEV來自普雷沃菌屬細菌。在一些實施方式中，該普雷沃菌屬細菌來自包含與該普雷沃菌菌株B 50329 （NRRL保藏號B 50329）的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該普雷沃菌屬細菌來自包含與該普雷沃菌菌株B 50329 （NRRL保藏號B 50329）的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該普雷沃菌屬細菌來自普雷沃菌菌株B 50329 （NRRL保藏號B 50329）。In some embodiments, the mEV is from a Prevotella bacterium. In some embodiments, the Prevotella bacterium is from a group comprising at least 90% (or at least 97%) of the genome, 16S and and/or strains with CRISPR sequence identity. In some embodiments, the Prevotella bacterium is from a group comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella strain B 50329 (NRRL Accession No. B 50329) strains. In some embodiments, the Prevotella bacterium is from Prevotella strain B 50329 (NRRL Deposit No. B 50329).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普雷沃菌屬細菌，例如包含與普雷沃菌屬菌株C（ATCC保藏號PTA-126140）的核苷酸序列具有至少90%或至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普雷沃菌屬細菌，例如普雷沃菌屬菌株C（ATCC保藏號PTA-126140）。In some embodiments, the bacterium of the medicament or the mEV of the medicament is obtained from a bacterium of the genus Prevotella, for example comprising a nucleotide sequence having the same Strains with at least 90% or at least 99% genomic, 16S and/or CRISPR sequence identity. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Prevotella bacterium, eg, Prevotella strain C (ATCC Accession No. PTA-126140).

在一些實施方式中，mEV來自雙歧桿菌屬細菌。在一些實施方式中，該雙歧桿菌屬細菌來自與雙歧桿菌屬細菌（保藏為ATCC指定編號PTA-125097）的核苷酸序列具有至少90%或至少97%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該雙歧桿菌屬細菌來自與雙歧桿菌屬細菌（保藏為ATCC指定編號PTA-125097）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該雙歧桿菌屬細菌來自雙歧桿菌屬細菌（保藏為ATCC指定編號PTA-125097）。In some embodiments, the mEV is from a Bifidobacterium bacterium. In some embodiments, the Bifidobacterium bacterium is from a nucleotide sequence having at least 90% or at least 97% of the genome, 16S and/or CRISPR sequence of a Bifidobacterium bacterium (deposited as ATCC Designation No. PTA-125097) identical strains. In some embodiments, the Bifidobacterium is from a strain having at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of a Bifidobacterium (deposited as ATCC Designation No. PTA-125097) . In some embodiments, the Bifidobacterium bacterium is from the Bifidobacterium genus (deposited as ATCC Designation No. PTA-125097).

在一些實施方式中，mEV來自韋榮氏球菌屬細菌。在一些實施方式中，該韋榮氏球菌屬細菌來自與韋榮氏球菌屬細菌（保藏為ATCC指定編號PTA-125691）的核苷酸序列具有至少90%或至少97%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該韋榮氏球菌屬細菌來自與韋榮氏球菌屬細菌（保藏為ATCC指定編號PTA-125691）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該韋榮氏球菌屬細菌來自韋榮氏球菌屬細菌（保藏為ATCC指定編號PTA-125691）。In some embodiments, the mEV is from a Veillonella bacterium. In some embodiments, the Veillonella bacterium is from a nucleotide sequence having at least 90% or at least 97% of the genome, 16S and/or Strains with CRISPR sequence identity. In some embodiments, the Veillonella bacterium is from at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veillonella bacterium (deposited as ATCC Designation No. PTA-125691) strains. In some embodiments, the Veillonella bacterium is from a Veillonella bacterium (deposited as ATCC Designation No. PTA-125691).

在一些實施方式中，mEV來自活潑瘤胃球菌細菌。在一些實施方式中，該活潑瘤胃球菌細菌來自與活潑瘤胃球菌細菌（保藏為ATCC指定編號PTA-126695）的核苷酸序列具有至少90%或至少97%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該活潑瘤胃球菌細菌來自與活潑瘤胃球菌細菌（保藏為ATCC指定編號PTA-126695）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該活潑瘤胃球菌細菌來自活潑瘤胃球菌細菌（保藏為ATCC指定編號PTA-126695）。In some embodiments, the mEVs are from Ruminococcus mobilis bacteria. In some embodiments, the Ruminococcus mobilis bacterium is derived from having at least 90% or at least 97% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus mobilis bacterium (deposited as ATCC Designation No. PTA-126695) strains. In some embodiments, the Ruminococcus mobilis bacterium is from a strain having at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus mobilis bacterium (deposited as ATCC Designation No. PTA-126695). In some embodiments, the Ruminococcus mobilis bacterium is from Ruminococcus mobilis bacteria (deposited as ATCC designation number PTA-126695).

在一些實施方式中，mEV來自巨型球菌屬物種細菌。在一些實施方式中，巨型球菌屬物種細菌來自與以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該巨型球菌屬物種細菌來自與巨型球菌屬物種細菌（保藏為ATCC指定編號PTA-126770）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，該巨型球菌屬物種細菌來自巨型球菌屬物種細菌（保藏為ATCC指定編號PTA-126770）。In some embodiments, the mEV is from a Megasphaera sp. bacterium. In some embodiments, the Megastococcus spp. bacterium is from at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequences with the nucleotide sequence of the Megastococcus spp. bacterium deposited under ATCC designation number PTA-126770 identical strains. In some embodiments, the Megastococcus sp. bacterium is from a strain having at least 99% genomic, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Megastococcus sp. bacterium (deposited as ATCC Designation No. PTA-126770) . In some embodiments, the Megasococcus spp. bacterium is from a Megasococcus spp. bacterium (deposited as ATCC Designation No. PTA-126770).

在一些實施方式中，mEV來自 Fournierella massiliensis細菌。在一些實施方式中， Fournierella massiliensis細菌來自與以ATCC指定編號PTA-126696保藏的 Fournierella massiliensis細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中， Fournierella massiliensis細菌來自與以ATCC指定編號PTA-126696保藏的 Fournierella massiliensis細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中， Fournierella massiliensis細菌來自以ATCC指定編號PTA-126696保藏的 Fournierella massiliensis細菌。 In some embodiments, the mEV is from Fournierella massiliensis bacteria. In some embodiments, the Fournierella massiliensis bacterium is from a strain that has at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacterium deposited under ATCC designation number PTA-126696 . In some embodiments, the Fournierella massiliensis bacteria is from a strain that has at least 99% genomic, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited under ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacterium is from the Fournierella massiliensis bacterium deposited under ATCC Designation No. PTA-126696.

在一些實施方式中，mEV來自 Harryflintia acetispora細菌。在一些實施方式中， Harryflintia acetispora細菌來自與以ATCC指定編號PTA-126694保藏的 Harryflintia acetispora細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中， Harryflintia acetispora細菌來自與以ATCC指定編號PTA-126694保藏的 Harryflintia acetispora細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中， Harryflintia acetispora細菌來自以ATCC指定編號PTA-126694保藏的 Harryflintia acetispora細菌。 In some embodiments, the mEV is from Harryflintia acetispora bacteria. In some embodiments, the Harryflintia acetispora bacterium is from a strain having at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacterium deposited under ATCC designation number PTA-126694 . In some embodiments, the Harryflintia acetispora bacterium is from a strain that has at least 99% genomic, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacterium deposited under ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacterium is from the Harryflintia acetispora bacterium deposited under ATCC Designation No. PTA-126694.

在一些實施方式中，mEV來自以下科的細菌：胺基酸球菌科、產鹼桿菌科、阿克曼氏菌科、擬桿菌科、雙歧桿菌科、伯克霍爾德菌科、 Catabacteriaceae科、克裡斯滕森菌科、梭菌科、紅蝽菌科、腸桿菌科、腸球菌科、梭桿菌科、毛螺菌科、李斯特菌科、分枝桿菌科、奈瑟菌科、臭桿菌科、顫螺旋菌科、消化球菌科、消化鏈球菌科、卟啉單胞菌科、普雷沃菌科、丙酸桿菌科、理研菌科、瘤胃球菌科、月形單胞菌科、 Sporomusaceae科、鏈球菌科、鏈黴菌科、薩特氏菌科、互養菌科、坦納菌科或韋榮氏球菌科。 In some embodiments, the mEV is from a bacterium of the following families: Aminococcaceae, Alcaligenesaceae, Akkermansiaceae, Bacteroidesaceae, Bifidobacteriaceae, Burkholderiaceae, Catabacteriaceae , Christensenaceae, Clostridiumceae, Coriobacteriaceae, Enterobacteriaceae, Enterococcusceae, Fusobacteriaceae, Lachnospiraceae, Listeriaceae, Mycobacteriaceae, Neisseriaceae, Odor Bacteriaceae, Cyclospiraceae, Peptococcusceae, Peptostreptococcusceae, Porphyromonasceae, Prevotaceae, Propionibacteriaceae, Rikenbacteriaceae, Ruminococcusceae, Lunatomonasceae, Sporomusaceae , Streptococcus, Streptomycetaceae, Sutterellaceae, Syntrophyceae, Tannerellaceae or Veillonellaceae.

在一些實施方式中，mEV來自阿克曼氏菌屬、克裡斯滕森菌屬、布勞特氏菌屬、腸球菌屬、真桿菌屬、羅斯氏菌屬、擬桿菌屬、副擬桿菌屬、或丹毒絲梭菌屬的細菌。In some embodiments, the mEV is from Akkermansia, Christensenia, Blautia, Enterococcus, Eubacterium, Roseburia, Bacteroides, Parabacteroides , or bacteria of the genus Erysipelothrix.

在一些實施方式中，mEV來自產氫營養型布勞特氏菌 、排泄物布勞特氏菌、韋氏布勞特氏菌、糞真桿菌、扭曲真桿菌、直腸真桿菌、糞腸球菌、耐久腸球菌、 Enterococcus villorum 、鶉雞腸球菌；乳酸雙歧桿菌、兩歧雙歧桿菌、長雙歧桿菌、動物雙歧桿菌或短雙歧桿菌細菌。 In some embodiments, the mEV is from Blautia hydrotrophs , Blautia faecalis, Blautia weideri, Eubacterium faecalis, Eubacterium twistus, Eubacterium rectale, Enterococcus faecalis, Enterococcus dursus, Enterococcus villorum , Enterococcus gallinarum; Bifidobacterium lactis, Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium animalis, or Bifidobacterium breve bacteria.

在一些實施方式中，mEV來自 BCG （卡介苗），副擬桿菌屬、布勞特氏菌屬、韋榮氏球菌屬、唾液乳桿菌、阿加薩桿菌屬（ Agathobaculum ）、活潑瘤胃球菌、解苯副梭菌、 Turicibacter sanguinus 、伯克霍爾德菌屬、類肺炎克雷白氏菌擬肺炎亞種、催產克雷白氏菌、納西利斯泰澤菌（ Tyzerella nexilis ）或奈瑟菌屬細菌。 In some embodiments, the mEV is from BCG (BCG), Parabacteroides, Blautia, Veillonella, Lactobacillus salivarius, Agathobaculum , Ruminococcus vivabilis, Benzo Clostridium paraclostridium, Turicibacter sanguinus , Burkholderia sp., Klebsiella pneumoniae subsp. pneumoniae, Klebsiella oxytoca, Tyzerella nexilis , or Neisseria sp. .

在一些實施方式中，mEV來自產氫營養型布勞特氏菌（ Blautia hydrogenotrophica ）細菌。 In some embodiments, the mEV is from a Blautia hydrogenotrophica bacterium .

在一些實施方式中，mEV來自排泄物布勞特氏菌（ Blautia stercoris）細菌。 In some embodiments, the mEV is from Blautia stercoris bacteria.

在一些實施方式中，mEV來自韋氏布勞特氏菌（ Blautia wexlerae）細菌。 In some embodiments, the mEV is from the Blautia wexlerae bacterium.

在一些實施方式中，mEV來自鶉雞腸球菌（ Enterococcus gallinarum）細菌。 In some embodiments, the mEV is from Enterococcus gallinarum bacterium.

在一些實施方式中，mEV來自屎腸球菌（ Enterococcus faecium）細菌。 In some embodiments, the mEV is from Enterococcus faecium bacteria.

在一些實施方式中，mEV來自兩歧雙歧桿菌 （ Bifidobacterium bifidium ）細菌。 In some embodiments, the mEV is from a Bifidobacterium bifidium bacterium .

在一些實施方式中，mEV來自短雙歧桿菌（ Bifidobacterium breve）細菌。 In some embodiments, the mEV is from Bifidobacterium breve bacteria.

在一些實施方式中，mEV來自長雙歧桿菌（ Bifidobacterium longum）細菌。 In some embodiments, the mEV is from Bifidobacterium longum bacteria.

在一些實施方式中，mEV來自人羅斯拜瑞氏菌（ Roseburia hominis）細菌。 In some embodiments, the mEV is from a human Roseburia hominis bacterium.

在一些實施方式中，mEV來自多形擬桿菌（ Bacteroides thetaiotaomicron）細菌。 In some embodiments, the mEV is from a Bacteroides thetaiotaomicron bacterium.

在一些實施方式中，mEV來自糞居擬桿菌（ Bacteroides coprocola）細菌。 In some embodiments, the mEV is from the Bacteroides coprocola bacterium.

在一些實施方式中，mEV來自 Erysipelatoclostridium ramosum細菌。 In some embodiments, the mEV is from Erysipelatoclostridium ramosum bacteria.

在一些實施方式中，mEV來自馬賽巨型球菌（ Megasphera massiliensis）細菌。 In some embodiments, the mEV is from the bacterium Megasphera massiliensis .

在一些實施方式中，mEV來自真桿菌屬（ Eubacterium）細菌。 In some embodiments, the mEV is from a Eubacterium bacterium.

在一些實施方式中，mEV來自狄氏副擬桿菌（ Parabacteroides distasonis）細菌。 In some embodiments, the mEV is from the bacterium Parabacteroides distasonis .

在一些實施方式中，mEV來自植物乳桿菌細菌。In some embodiments, the mEVs are from Lactobacillus plantarum bacteria.

在一些實施方式中，mEV來自 Negativicutes綱的細菌。 In some embodiments, the mEV is from a bacterium of the class Negativicutes .

在一些實施方式中，mEV來自韋榮氏球菌科的細菌。In some embodiments, the mEV is from a bacterium of the family Veillonellaceae.

在一些實施方式中，mEV來自月形單胞菌科的細菌。In some embodiments, the mEV is from a bacterium of the family Luuemonadaceae.

在一些實施方式中，mEV來自胺基酸球菌科的細菌。In some embodiments, the mEV is from a bacterium of the family Aminococcae.

在一些實施方式中，mEV來自 Sporomusaceae科的細菌。 In some embodiments, the mEV is from a bacterium of the family Sporomusaceae .

在一些實施方式中，mEV來自巨型球菌屬的細菌。In some embodiments, the mEV is from a bacterium of the genus Megasphaera.

在一些實施方式中，mEV來自月形單胞菌屬的細菌。In some embodiments, the mEV is from a bacterium of the genus Lueromonas.

在一些實施方式中，mEV來自 Propionospora屬的細菌。 In some embodiments, the mEV is from a bacterium of the genus Propionospora .

在一些實施方式中，mEV來自胺基酸球菌屬的細菌。In some embodiments, the mEV is from a bacterium of the genus Aminococcus.

在一些實施方式中，mEV來自巨型球菌屬物種細菌。In some embodiments, the mEV is from a Megasphaera sp. bacterium.

在一些實施方式中，mEV來自菲利克斯月形單胞菌細菌。In some embodiments, the mEV is from the Lueromonas bacterium Felixis.

在一些實施方式中，mEV來自腸胺基酸球菌細菌。In some embodiments, the mEVs are from Aminococcus enterica bacteria.

在一些實施方式中，mEV來自 Propionospora屬物種細菌。 In some embodiments, the mEV is from a Propionospora species bacterium.

在一些實施方式中，mEV來自梭菌綱的細菌。In some embodiments, the mEV is from a bacterium of the class Clostridia.

在一些實施方式中，mEV來自顫螺旋菌科的細菌。In some embodiments, the mEV is from a bacterium of the family Cyclospiraceae.

在一些實施方式中，mEV來自糞桿菌屬的細菌。In some embodiments, the mEV is from a bacterium of the genus Faecalibacterium.

在一些實施方式中，mEV來自 Fournierella屬的細菌。 In some embodiments, the mEV is from a bacterium of the genus Fournierella .

在一些實施方式中，mEV來自 Harryflintia屬的細菌。 In some embodiments, the mEV is from a bacterium of the genus Harryflintia .

在一些實施方式中，mEV來自阿加薩桿菌屬的細菌。In some embodiments, the mEV is from a bacterium of the genus Agartsia.

在一些實施方式中，mEV來自普氏棲糞桿菌（例如，普氏棲糞桿菌菌株A）細菌。In some embodiments, the mEV is from a Faecalibacterium prausnitzii (eg, Faecalibacterium prausnitzii strain A) bacterium.

在一些實施方式中，mEV來自 Fournierella massiliensis（例如， Fournierella massiliensis菌株A）細菌。 In some embodiments, the mEV is from a Fournierella massiliensis (eg, Fournierella massiliensis strain A) bacterium.

在一些實施方式中，mEV來自Harryflintia acetispora（例如， Harryflintia acetispora菌株A）細菌。 In some embodiments, the mEV is from a Harryflintia acetispora (eg, Harryflintia acetispora strain A) bacterium.

在一些實施方式中，mEV來自阿加薩桿菌屬物種（例如，阿加薩桿菌屬物種菌株A）細菌。In some embodiments, the mEV is from an Agartsia sp. (eg, Agartsia sp. strain A) bacterium.

在一些實施方式中，mEV來自阿加薩桿菌屬物種的菌株。在一些實施方式中，阿加薩桿菌屬物種菌株係與阿加薩桿菌屬物種菌株A（ATCC保藏號PTA-125892）的核苷酸序列（例如，基因組序列、16S序列、CRISPR序列）具有至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，阿加薩桿菌屬物種菌株係阿加薩桿菌屬物種菌株A（ATCC保藏號PTA- 125892）細菌。In some embodiments, the mEV is from a strain of Agartsia sp. In some embodiments, the nucleotide sequence (eg, genomic sequence, 16S sequence, CRISPR sequence) of Agartsia sp. strain A (ATCC Deposit No. PTA-125892) has at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity sex, at least 99.9% sequence identity). In some embodiments, the Agartsia sp. strain is Agartsia sp. strain A (ATCC Accession No. PTA-125892) bacterium.

在一些實施方式中，mEV來自擬桿菌綱[擬桿菌門]的細菌。在一些實施方式中，mEV來自擬桿菌目的細菌。在一些實施方式中，mEV來自紫單胞菌科的細菌。在一些實施方式中，mEV來自普雷沃菌科的細菌。在一些實施方式中，mEV來自擬桿菌綱的細菌，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，mEV來自擬桿菌綱、革蘭氏陰性染色的細菌。在一些實施方式中，mEV來自擬桿菌綱的細菌，其中細菌係雙層的並且該細菌係革蘭氏陰性染色。In some embodiments, the mEV is from a bacterium of the class Bacteroides [phylum Bacteroidetes]. In some embodiments, the mEV is from a bacterium of the order Bacteroidetes. In some embodiments, the mEV is from a bacterium of the family Porphyromonadaceae. In some embodiments, the mEV is from a bacterium of the Prevotaceae family. In some embodiments, the mEV is from a bacterium of the class Bacteroidetes, wherein the cell envelope of the bacterium is bilayered. In some embodiments, the mEV is from the class Bacteroidetes, Gram-negative staining bacteria. In some embodiments, the mEV is from a bacterium of the class Bacteroidetes, wherein the bacterium is bilayered and the bacterium is Gram-negative staining.

在一些實施方式中，mEV來自梭菌綱[厚壁菌門]的細菌。在一些實施方式中，mEV來自真細菌目的細菌。在一些實施方式中，mEV來自顫螺旋菌科的細菌。在一些實施方式中，mEV來自毛螺菌科的細菌。在一些實施方式中，mEV來自消化鏈球菌科的細菌。在一些實施方式中，mEV來自梭菌目XIII科/地位未定41的細菌。在一些實施方式中，mEV來自梭菌綱的細菌，其中細菌的細胞被膜結構係單層的。在一些實施方式中，mEV來自梭菌綱、革蘭氏陰性染色的細菌。在一些實施方式中，mEV來自梭菌綱、革蘭氏陽性染色的細菌。在一些實施方式中，mEV來自梭菌綱的細菌，其中細菌的細胞被膜結構係單層的並且該細菌係革蘭氏陰性染色。在一些實施方式中，mEV來自梭菌綱的細菌，其中細菌的細胞被膜結構係單層的並且該細菌係革蘭氏陽性染色。In some embodiments, the mEV is from a bacterium of the class Clostridium [Firmicutes]. In some embodiments, the mEV is from a bacterium of the order Eubacteria. In some embodiments, the mEV is from a bacterium of the family Cyclospiraceae. In some embodiments, the mEV is from a bacterium of the family Lachnospiraceae. In some embodiments, the mEV is from a bacterium of the family Peptostreptococcus. In some embodiments, the mEV is from a bacterium of the family XIII/status indeterminate 41 of the Clostridiales. In some embodiments, the mEV is from a bacterium of the class Clostridia, wherein the cell envelope of the bacterium is monolayer. In some embodiments, the mEV is from a Clostridium, Gram-negative staining bacterium. In some embodiments, the mEV is from the Clostridium class, Gram-positive staining bacterium. In some embodiments, the mEV is from a bacterium of the class Clostridia, wherein the cell envelope of the bacterium is monolayer and the bacterium stains Gram-negative. In some embodiments, the mEV is from a bacterium of the class Clostridia, wherein the cell envelope of the bacterium is monolayer and the bacterium stains Gram-positive.

在一些實施方式中，mEV來自 Negativicutes綱[厚壁菌門]的細菌。在一些實施方式中，mEV來自韋榮氏球菌目的細菌。在一些實施方式中，mEV來自韋榮氏球菌科的細菌。在一些實施方式中，mEV來自月形單胞菌目的細菌。在一些實施方式中，mEV來自月形單胞菌科的細菌。在一些實施方式中，mEV來自 Sporomusaceae科的細菌。在一些實施方式中，mEV來自 Negativicutes綱的細菌，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，mEV來自 Negativicutes綱、革蘭氏陰性染色的細菌。在一些實施方式中，mEV來自 Negativicutes綱的細菌，其中細菌的細胞被膜結構係雙層的並且該細菌係革蘭氏陰性染色。 In some embodiments, the mEV is from a bacterium of the class Negativicutes [Firmicutes]. In some embodiments, the mEV is from a bacterium of the order Veillonellales. In some embodiments, the mEV is from a bacterium of the family Veillonellaceae. In some embodiments, the mEV is from a bacterium of the order Luemomonas. In some embodiments, the mEV is from a bacterium of the family Luuemonadaceae. In some embodiments, the mEV is from a bacterium of the family Sporomusaceae . In some embodiments, the mEV is from a bacterium of the class Negativicutes , wherein the cell envelope of the bacterium is bilayer. In some embodiments, the mEV is from the class Negativicutes , Gram-negative staining bacteria. In some embodiments, the mEV is from a bacterium of the class Negativicutes , wherein the cell envelope of the bacterium is bilayered and the bacterium stains Gram-negative.

在一些實施方式中，mEV來自互養菌綱[互養菌門]的細菌。在一些實施方式中，mEV來自互養菌目的細菌。在一些實施方式中，mEV來自互養菌科的細菌。在一些實施方式中，mEV來自互養菌綱的細菌，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，mEV來自互養菌綱、革蘭氏陰性染色的細菌。在一些實施方式中，mEV來自互養菌綱的細菌，其中細菌的細胞被膜結構係雙層的並且該細菌係革蘭氏陰性染色。In some embodiments, the mEV is from a bacterium of the class Syntrophycetes [phylum Syntrophyta]. In some embodiments, the mEV is from a bacterium of the order Syntrophyles. In some embodiments, the mEV is from a bacterium of the family Syntrophyceae. In some embodiments, the mEV is from a bacterium of the class Syntrophycetes, wherein the cell envelope of the bacterium is bilayered. In some embodiments, the mEVs are from the class Syntrophycetes, Gram-negative staining bacteria. In some embodiments, the mEV is from a bacterium of the class Syntrophycetes, wherein the cell envelope of the bacterium is bilayered and the bacterium stains Gram-negative.

在一些實施方式中，mEV來自產生代謝產物的細菌，例如，細菌產生丁酸、肌苷、丙酸、或色胺酸代謝產物。In some embodiments, the mEV is from a bacterium that produces a metabolite, eg, a bacterium that produces a butyrate, inosine, propionate, or tryptophan metabolite.

在一些實施方式中，mEV來自產生丁酸鹽的細菌。在一些實施方式中，mEV來自以下屬的細菌：布勞特氏菌屬 ；克裡斯滕森菌屬；糞球菌屬；真桿菌屬； Lachnosperacea ；巨型球菌屬；或羅斯氏菌屬。 In some embodiments, the mEVs are from butyrate-producing bacteria. In some embodiments, the mEV is from a bacterium of the following genera: Blautia ; Christensen; Coprococcus; Eubacterium ; Lachnosperacea ;

在一些實施方式中，mEV來自產生肌苷的細菌。在一些實施方式中，mEV來自以下屬的細菌：雙歧桿菌屬 ；乳桿菌屬；或歐陸森氏菌屬。 In some embodiments, the mEVs are from inosine-producing bacteria. In some embodiments, the mEV is from a bacterium of the genus Bifidobacterium ; Lactobacillus; or Eugenia.

在一些實施方式中，mEV來自產生丙酸鹽的細菌。在一些實施方式中，mEV來自以下屬的細菌：阿克曼氏菌屬；擬桿菌屬；戴阿利斯特菌屬；真桿菌屬；巨型球菌屬；副擬桿菌屬；普雷沃菌屬；瘤胃球菌屬；或韋榮氏球菌屬。In some embodiments, the mEVs are from propionate-producing bacteria. In some embodiments, the mEV is from a bacterium of the following genera: Akkermansia; Bacteroides; Diaalisteria; Eubacterium; Ruminococcus; or Veillonella.

在一些實施方式中，mEV來自產生色胺酸代謝物的細菌。在一些實施方式中，mEV來自乳桿菌屬或消化鏈球菌屬的細菌。In some embodiments, the mEVs are from bacteria that produce tryptophan metabolites. In some embodiments, the mEV is from a bacterium of the genus Lactobacillus or Peptostreptococcus.

在一些實施方式中，mEV來自產生組蛋白脫乙醯基酶3（HDAC3）的抑制劑的細菌。在一些實施方式中，mEV來自物種 Bariatricus massiliensis、普氏棲糞桿菌、馬賽巨型球菌或腸羅斯氏菌的細菌。 In some embodiments, the mEV is from a bacterium that produces an inhibitor of histone deacetylase 3 (HDAC3). In some embodiments, the mEV is from a bacterium of the species Bariatricus massiliensis , Faecalibacterium prausnitzii, M. marseilles, or Rothia enterica.

在一些實施方式中，mEV來自以下屬的細菌： 不動桿菌屬；異常球菌屬；螺桿菌屬；紅球菌屬；食竇魏斯氏菌；明串珠菌屬；羅氏菌屬；差異球菌屬；芽孢桿菌屬；鏈型桿菌屬；棒狀桿菌屬；貪銅菌屬；水棲菌屬；微小桿菌屬；糞桿菌屬； 土芽孢桿菌屬；甲基桿菌屬；微球菌屬；摩根氏菌屬；變形桿菌屬；假單胞菌屬；根瘤菌屬；或鞘胺醇單胞菌屬。 In some embodiments, the mEV is from a bacterium of the following genera: Acinetobacter; Deinococcus; Helicobacter; Rhodococcus; Bacillus; Streptobacillus; Corynebacterium; Coppercoronas; Aquabacterium; Microbacterium; Faecalibacterium; Geobacillus; Methylobacterium; Micrococcus; Morganella; Proteus Bacillus; Pseudomonas; Rhizobium; or Sphingomonas.

在一些實施方式中，mEV來自物種鮑曼不動桿菌； 耐輻射異常球菌；幽門螺桿菌；馬紅球菌；食竇魏斯氏菌；耳炎差異球菌；陰道奇異菌；三井鏈型桿菌（ Catenibacterium mituokai ）；麩胺酸棒狀桿菌；金橙黃微小桿菌（ Exiguobacterium aurantiacum ）；嗜熱脂肪地桿菌； Methylobacterium jeotgali ；藤黃微球菌；摩根摩根氏菌；奇異變形桿菌；豌豆根瘤菌；污水溝羅斯氏菌（ Rothia amarae ）；少動鞘胺醇單胞菌；或朝鮮鞘胺醇單胞菌（Sphingomonas koreens）。 In some embodiments, the mEV is from the species Acinetobacter baumannii; Deinococcus radiodurans; Helicobacter pylori; Rhodococcus equi ; ); Corynebacterium glutamicum; Exiguobacterium aurantiacum ; Geobacter stearothermophilus ; Methylobacterium jeotgali ; Micrococcus luteus; Morganella morganii; Proteus mirabilis; ( Rothia amarae ); Sphingomonas paucimobilis; or Sphingomonas koreaens.

在一些實施方式中，mEV來自 Cutibacterium屬的細菌。 In some embodiments, the mEV is from a bacterium of the genus Cutibacterium .

在一些實施方式中，mEV來自物種 Cutibacterium avidum的細菌。 In some embodiments, the mEV is from a bacterium of the species Cutibacterium avidum .

在一些實施方式中，mEV來自乳桿菌屬屬的細菌。In some embodiments, the mEV is from a bacterium of the genus Lactobacillus.

在一些實施方式中，mEV來自物種加氏乳桿菌； 乾酪乳桿菌；副乾酪乳桿菌；鼠李糖乳桿菌；或清酒乳桿菌。 In some embodiments, the mEV is from the species Lactobacillus gasseri; Lactobacillus casei; Lactobacillus paracasei; Lactobacillus rhamnosus; or Lactobacillus sake .

在一些實施方式中，mEV來自 Dysosmobacter屬的細菌。 In some embodiments, the mEV is from a bacterium of the genus Dysosmobacter .

在一些實施方式中，mEV來自物種 Dysosmobacter welbionis的細菌。 In some embodiments, the mEV is from a bacterium of the species Dysosmobacter welbionis .

在一些實施方式中，mEV來自明串珠菌屬的細菌。In some embodiments, the mEV is from a bacterium of the genus Leuconostoc.

在一些實施方式中，mEV來自賀氏明串珠菌細菌。在一些實施方式中，mEV來自賀氏明串珠菌Ceb-kc-003（KCCM11830P）細菌。In some embodiments, the mEV is from a Leuconostoc hayesi bacterium. In some embodiments, the mEVs are from Leuconostoc heschii Ceb-kc-003 (KCCM11830P) bacteria.

在一些實施方式中，mEV來自物種耐金屬貪銅菌或釀膿鏈球菌。In some embodiments, the mEV is from the species C. metalloresistant or Streptococcus pyogenes.

在一些實施方式中，mEV來自巨型球菌屬物種細菌（例如，來自保藏號為NCIMB 43385、NCIMB 43386或NCIMB 43387的菌株）。In some embodiments, the mEV is from a Megasphaera sp. bacterium (eg, from a strain deposited under NCIMB 43385, NCIMB 43386, or NCIMB 43387).

在一些實施方式中，mEV來自馬賽巨型球菌細菌（例如，來自保藏號為NCIMB 42787、NCIMB 43388或NCIMB 43389的菌株）。In some embodiments, the mEV is from a M. marseille bacterium (eg, from a strain deposited under NCIMB 42787, NCIMB 43388, or NCIMB 43389).

在一些實施方式中，mEV來自馬賽巨型球菌細菌（例如，來自保藏號為DSM 26228的菌株）。In some embodiments, the mEV is from a M. marseille bacterium (eg, from a strain deposited under DSM 26228).

在一些實施方式中，mEV來自狄氏副擬桿菌細菌（例如，來自保藏號為NCIMB 42382的菌株）。In some embodiments, the mEV is from a Parabacteroides distirii bacterium (eg, from a strain deposited under NCIMB 42382).

在一些實施方式中，mEV來自馬賽巨型球菌細菌（例如，來自保藏號為NCIMB 43388或NCIMB 43389的菌株）或其衍生物。參見，例如，WO 2020/120714。在一些實施方式中，馬賽巨型球菌細菌係與來自保藏號為NCIMB 43388或NCIMB 43389的菌株的馬賽巨型球菌細菌的核苷酸序列（例如，基因組序列、16S序列、和/或CRISPR序列）包含至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，馬賽巨型球菌細菌係保藏號為NCIMB 43388或NCIMB 43389的菌株。In some embodiments, the mEV is from a M. marseille bacterium (eg, from a strain deposited under NCIMB 43388 or NCIMB 43389) or a derivative thereof. See, eg, WO 2020/120714. In some embodiments, the M. marseilles bacterium strain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, Strains of at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity). In some embodiments, the M. marseille bacterium is a strain with deposit number NCIMB 43388 or NCIMB 43389.

在一些實施方式中，mEV來自保藏號為NCIMB 42787的馬賽巨型球菌細菌菌株，或其衍生物。參見，例如，WO 2018/229216。在一些實施方式中，馬賽巨型球菌細菌係與以保藏號NCIMB 42787保藏的馬賽巨型球菌細菌菌株的核苷酸序列（例如，基因組序列、16S序列、和/或CRISPR序列）包含至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，馬賽巨型球菌細菌係以保藏號NCIMB 42787保藏的菌株。In some embodiments, the mEV is from a bacterial strain of M. marseilles deposited under NCIMB 42787, or a derivative thereof. See, eg, WO 2018/229216. In some embodiments, the M. marseilles bacterial strain comprises at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity identity, at least 99.8% sequence identity, at least 99.9% sequence identity). In some embodiments, the M. marseille bacterium is a strain deposited under accession number NCIMB 42787.

在一些實施方式中，mEV來自來自保藏號為NCIMB 43385、NCIMB 43386或NCIMB 43387的菌株的巨型球菌屬物種細菌，或其衍生物。參見，例如，WO 2020/120714。在一些實施方式中，巨型球菌屬物種細菌係與來自保藏號為NCIMB 43385，NCIMB 43386或NCIMB 43387的菌株的巨型球菌屬物種的核苷酸序列（例如，基因組序列、16S序列、和/或CRISPR序列）包含至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，巨型球菌屬物種細菌係保藏號為NCIMB 43385、NCIMB 43386或NCIMB 43387的菌株。In some embodiments, the mEV is from a Megasphaera sp. bacterium from the strain deposited under NCIMB 43385, NCIMB 43386, or NCIMB 43387, or a derivative thereof. See, eg, WO 2020/120714. In some embodiments, the Megastococcus sp. bacterial strain is associated with a nucleotide sequence (e.g., a genome sequence, a 16S sequence, and/or a CRISPR sequence) comprising at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity). In some embodiments, the Megastococcus sp. bacterium is a strain deposited under NCIMB 43385, NCIMB 43386, or NCIMB 43387.

在一些實施方式中，mEV來自保藏號為NCIMB 42382的狄氏副擬桿菌細菌，或其衍生物。參見，例如，WO 2018/229216。在一些實施方式中，狄氏副擬桿菌細菌係與以保藏號NCIMB 42382保藏的狄氏副擬桿菌細菌的核苷酸序列（例如，基因組序列、16S序列、和/或CRISPR序列）包含至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，狄氏副擬桿菌細菌係以保藏號NCIMB 42382保藏的菌株。In some embodiments, the mEV is from the Parabacteroides distrobacter bacterium deposited under NCIMB 42382, or a derivative thereof. See, eg, WO 2018/229216. In some embodiments, the Parabacteroides distirii bacterial strain comprises at least 80 %, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity). In some embodiments, the Parabacteroides distirii bacterium is a strain deposited under accession number NCIMB 42382.

在一些實施方式中，mEV來自保藏號為DSM 26228的馬賽巨型球菌細菌，或其衍生物。參見，例如，WO 2018/229216。在一些實施方式中，馬賽巨型球菌細菌係與以保藏號DSM 26228保藏的馬賽巨型球菌細菌的核苷酸序列（例如，基因組序列、16S序列、和/或CRISPR序列）包含至少80%、至少85%、至少90%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，馬賽巨型球菌細菌係以保藏號DSM 26228保藏的菌株。In some embodiments, the mEV is derived from the M. marseille bacterium deposited under the accession number DSM 26228, or a derivative thereof. See, eg, WO 2018/229216. In some embodiments, the nucleotide sequence (for example, genome sequence, 16S sequence, and/or CRISPR sequence) of the M. marseille bacteria line and the M. marseille bacteria deposited under the deposit number DSM 26228 comprises at least 80%, at least 85% %, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity sex, at least 99.8% sequence identity, at least 99.9% sequence identity) strains. In some embodiments, the M. marseille bacterium is a strain deposited under accession number DSM 26228.

在一些實施方式中，藥劑包含細菌並且細菌的劑量為約1 x 10 7至約2 x 10 12（例如，約3 x 10 10或約1.5 x 10 11或約1.5 x 10 12）細胞（例如，其中藉由Coulter計數器確定的總細胞計數來確定細胞數），其中劑量係按每膠囊或片劑計或按膠囊中的微型片劑的總數計。在一些實施方式中，藥劑包含細菌並且細菌的劑量為約1 x 10 10至約2 x 10 12（例如，約1.6 x 10 11或約8 x 10 11或約9.6 x 10 11約12.8 x 10 11或約1.6 x 10 12）細胞（例如，其中藉由Coulter計數器確定的總細胞計數來確定細胞數），其中劑量係按每膠囊或片劑計或按膠囊中的微型片劑的總數計。 In some embodiments, the agent comprises bacteria and the dose of bacteria is about 1 x 10 7 to about 2 x 10 12 (eg, about 3 x 10 10 or about 1.5 x 10 11 or about 1.5 x 10 12 ) cells (eg, wherein the cell number is determined by total cell count determined by a Coulter counter), wherein the dosage is per capsule or tablet or the total number of minitablets in a capsule. In some embodiments, the medicament comprises bacteria and the dose of bacteria is about 1 x 10 10 to about 2 x 10 12 (eg, about 1.6 x 10 11 or about 8 x 10 11 or about 9.6 x 10 11 to about 12.8 x 10 11 or about 1.6 x 10 12 ) cells (eg, where cell number is determined by total cell count determined by a Coulter counter), where the dose is per capsule or tablet or the total number of minitablets in a capsule.

在一些實施方式中，藥劑包含細菌並且細菌的劑量為約1 x 10 9、約3 x 10 9、約5 x 10 9、約1.5 x 10 10、約3 x 10 10、約5 x 10 10、約1.5 x 10 11、約1.5 x 10 12或約2 x 10 12細胞，其中劑量係按每膠囊或片劑計或按膠囊中的微型片劑的總數計。 In some embodiments, the agent comprises bacteria and the dose of bacteria is about 1 x 10 9 , about 3 x 10 9 , about 5 x 10 9 , about 1.5 x 10 10 , about 3 x 10 10 , about 5 x 10 10 , About 1.5 x 1011 , about 1.5 x 1012 , or about 2 x 1012 cells, where the dosage is per capsule or tablet or the total number of minitablets in a capsule.

在一些實施方式中，藥劑包含mEV並且mEV的劑量為約1 x 10 5至約7 x 10 13個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中該劑量按每膠囊或片劑計或按膠囊中微型片劑的總數計。在一些實施方式中，藥劑包含mEV並且mEV的劑量為約1 x 10 10至約7 x 10 13個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中該劑量按每膠囊或片劑計或按膠囊中微型片劑的總數計。 In some embodiments, the medicament comprises mEV and the dose of mEV is about 1 x 10 5 to about 7 x 10 13 particles (eg, where the particle count is determined by NTA (Nanoparticle Tracking Analysis)), wherein the dose is expressed as Per capsule or tablet or total number of minitablets in a capsule. In some embodiments, the medicament comprises mEV and the dose of mEV is about 1 x 1010 to about 7 x 1013 particles (eg, where the particle count is determined by NTA (Nanoparticle Tracking Analysis)), wherein the dose is expressed as Per capsule or tablet or total number of minitablets in a capsule.

在一些實施方式中，藥劑包括粉末，該粉末包含細菌和/或mEV，並且該藥劑（例如，包含細菌和/或mEV的粉末）的劑量為約10 mg至約3500 mg，其中該劑量按每膠囊或片劑計或按膠囊中微型片劑的總數計。In some embodiments, the medicament comprises a powder comprising bacteria and/or mEV, and the dose of the medicament (eg, powder comprising bacteria and/or mEV) is from about 10 mg to about 3500 mg, wherein the dose is Capsules or tablets or the total number of microtablets in a capsule.

在一些實施方式中，藥劑包括粉末，該粉末包含細菌和/或mEV，並且該藥劑（例如，包含細菌和/或mEV的粉末）的劑量為約10 mg至約1500 mg，其中該劑量按每膠囊或片劑計或按膠囊中微型片劑的總數計。In some embodiments, the medicament comprises a powder comprising bacteria and/or mEV, and the dose of the medicament (eg, powder comprising bacteria and/or mEV) is from about 10 mg to about 1500 mg, wherein the dose is Capsules or tablets or the total number of microtablets in a capsule.

在一些實施方式中，藥劑包括粉末，該粉末包含細菌和/或mEV，並且該藥劑（例如，包含細菌和/或mEV的粉末）的劑量為約30 mg至約1300 mg（按細菌和/或mEV粉末的重量計）（約25、約30、約35、約50、約75、約100、約120、約150、約250、約300、約350、約400、約500、約600、約700、約750、約800、約900、約1000、約1100、約1200、約1250、約1300、約2000、約2500、約3000、或約3500 mg），其中該劑量按每膠囊或片劑計或按膠囊中微型片劑的總數計。In some embodiments, the medicament comprises a powder comprising bacteria and/or mEV, and the dose of the medicament (e.g., powder comprising bacteria and/or mEV) is about 30 mg to about 1300 mg (in terms of bacteria and/or mEV Weight of mEV powder) (about 25, about 30, about 35, about 50, about 75, about 100, about 120, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg), wherein the dose is calculated per capsule or tablet or by the total number of minitablets in the capsule.

在一些實施方式中，藥劑包含細菌和/或mEV，並且該藥劑（例如，細菌和/或mEV）的劑量為約2x10 6至約2x10 16個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中該劑量按每膠囊或片劑計或按膠囊中微型片劑的總數計。 In some embodiments, the agent comprises bacteria and/or mEV, and the dose of the agent (e.g., bacteria and/or mEV) is about 2×10 6 to about 2×10 16 particles (e.g., wherein NTA (nanoparticle tracking analysis) to determine the particle count), where the dose is per capsule or tablet or the total number of minitablets in a capsule.

在一些實施方式中，藥劑包含細菌和/或mEV，並且該藥劑（例如，細菌和/或mEV）的劑量為約5 mg至約900 mg總蛋白（例如，其中總蛋白藉由布拉德福測定法（Bradford assay）或BCA確定），其中該劑量按每膠囊或片劑計或按膠囊中微型片劑的總數計。In some embodiments, the agent comprises bacteria and/or mEV, and the dose of the agent (e.g., bacteria and/or mEV) is about 5 mg to about 900 mg total protein (e.g., wherein total protein is determined by Bradford method (Bradford assay) or BCA), where the dose is per capsule or tablet or the total number of minitablets in a capsule.

在一些實施方式中，固體劑型還包含一種或多種另外的治療劑。In some embodiments, the solid dosage form further comprises one or more additional therapeutic agents.

在一些方面，本揭露提供了治療受試者（例如人）（例如需要治療的受試者）之方法，該方法包括向受試者施用本文提供的固體劑型。在一些方面，本揭露提供了本文提供的固體劑型，其用於治療受試者（例如人）（例如需要治療的受試者）。在一些方面，本揭露提供了本文提供的固體劑型在製備用於治療受試者（例如人）（例如需要治療的受試者）的藥物中的用途。In some aspects, the present disclosure provides methods of treating a subject (eg, a human), eg, a subject in need of treatment, comprising administering to the subject a solid dosage form provided herein. In some aspects, the disclosure provides solid dosage forms provided herein for use in treating a subject (eg, a human) (eg, a subject in need of treatment). In some aspects, the disclosure provides use of a solid dosage form provided herein in the manufacture of a medicament for treating a subject (eg, a human), eg, a subject in need of treatment.

在一些實施方式中，固體劑型經口服施用（例如用於口服施用）。In some embodiments, the solid dosage form is administered orally (eg, for oral administration).

在一些實施方式中，將固體劑型施用給處於進食或禁食狀態的受試者。在一些實施方式中，將固體劑型施用給空腹（例如，進食前一小時或進食後兩小時）受試者。在一些實施方式中，固體劑型在進食前一小時施用給受試者。在一些實施方式中，固體劑型在進食後兩小時施用給受試者。In some embodiments, the solid dosage form is administered to a subject in a fed or fasted state. In some embodiments, the solid dosage form is administered to a fasted (eg, one hour before or two hours after a meal) subject. In some embodiments, the solid dosage form is administered to the subject one hour before eating. In some embodiments, the solid dosage form is administered to the subject two hours after eating.

在一些實施方式中，固體劑型（例如，片劑或多個微型片劑（例如，包含在膠囊中））被施用（例如，用於施用）每天1、2、3或4次。在一些實施方式中，固體劑型包含片劑或多個微型片劑（例如，包含在膠囊中）並且每天1、2、3或4次施用（例如，用於施用）1、2、3或4個固體劑型（例如，片劑或多個微型片劑（例如，包含在膠囊中）。In some embodiments, a solid dosage form (eg, a tablet or a plurality of minitablets (eg, contained in a capsule)) is administered (eg, for administration) 1, 2, 3, or 4 times per day. In some embodiments, the solid dosage form comprises a tablet or a plurality of mini-tablets (e.g., contained in a capsule) and is administered (e.g., for administering) 1, 2, 3, or 4 times per day A solid dosage form (for example, a tablet or multiple mini-tablets (for example, contained in a capsule).

在一些實施方式中，固體劑型提供了藥劑在小腸中例如包含在固體劑型中的藥劑在小腸上部中的釋放。In some embodiments, the solid dosage form provides for release of the agent in the small intestine, eg, the upper small intestine of the agent contained in the solid dosage form.

在一些實施方式中，固體劑型將藥劑遞送至小腸，其中藥劑可作用於小腸中（例如在小腸上部）的免疫細胞和/或上皮細胞，以在整個身體引起作用（例如系統性作用）。In some embodiments, the solid dosage form delivers the agent to the small intestine, where the agent can act on immune cells and/or epithelial cells in the small intestine (eg, in the upper small intestine) to cause an effect throughout the body (eg, a systemic effect).

在一些實施方式中，例如當口服施用時，藥劑在胃腸道外提供一種或多種有益的免疫作用。In some embodiments, the agent provides one or more beneficial immune effects parenterally, eg, when administered orally.

在一些實施方式中，例如當口服施用時，藥劑調節受試者的胃腸道外的免疫作用。In some embodiments, the agent modulates parenteral immunity in a subject, eg, when administered orally.

在一些實施方式中，例如當口服施用時，藥劑引起系統性作用（例如，胃腸道外的作用）。In some embodiments, the agent causes systemic effects (eg, parenteral effects), eg, when administered orally.

在一些實施方式中，例如當口服施用時，藥劑對小腸中（例如在小腸上部）的免疫細胞和/或上皮細胞起作用，例如引起系統性作用（例如，胃腸道外的作用）。In some embodiments, eg, when administered orally, the agent acts on immune cells and/or epithelial cells in the small intestine (eg, in the upper small intestine), eg, causes a systemic effect (eg, a parenteral effect).

在一些實施方式中，固體劑型經口服施用並且在胃腸道外具有一種或多種有益的免疫作用（例如，藥劑與小腸中的細胞之間的相互作用調節系統性免疫應答）。In some embodiments, the solid dosage form is administered orally and has one or more beneficial immune effects parenterally (eg, interactions between the agent and cells in the small intestine modulate systemic immune responses).

在一些實施方式中，固體劑型經口服施用並且在胃腸道外調節免疫作用（例如，藥劑與小腸中（例如在小腸上部）的細胞之間的相互作用調節系統性免疫應答）。In some embodiments, the solid dosage form is administered orally and modulates immune effects parenterally (eg, interaction of the agent with cells in the small intestine (eg, in the upper small intestine) modulates a systemic immune response).

在一些實施方式中，固體劑型經口服施用並激活先天抗原呈遞細胞（例如在小腸中，例如在小腸上部）。In some embodiments, the solid dosage form is administered orally and activates innate antigen presenting cells (eg, in the small intestine, eg, in the upper small intestine).

在一些實施方式中，受試者需要治療（和/或預防）癌症。In some embodiments, the subject is in need of treatment (and/or prevention) of cancer.

在一些實施方式中，受試者需要治療（和/或預防）自體免疫性疾病。In some embodiments, the subject is in need of treatment (and/or prevention) of an autoimmune disease.

在一些實施方式中，受試者需要治療（和/或預防）炎性疾病。In some embodiments, the subject is in need of treatment (and/or prevention) of an inflammatory disease.

在一些實施方式中，受試者需要治療（和/或預防）代謝性疾病。In some embodiments, the subject is in need of treatment (and/or prevention) of a metabolic disease.

在一些實施方式中，受試者需要治療（和/或預防）生態失調（dysbiosis）。In some embodiments, the subject is in need of treatment (and/or prevention) of dysbiosis.

在一些實施方式中，固體劑型與治療劑（例如，另外的治療劑）組合施用。In some embodiments, a solid dosage form is administered in combination with a therapeutic agent (eg, an additional therapeutic agent).

在某些方面，本文提供了製備藥物組成物的固體劑型之方法，該方法包括將藥劑（例如，本文公開的細菌和/或細菌來源的試劑，例如本文公開的mEV）和一種或多種（例如一種、兩種或三種）賦形劑組合成藥物組成物。在某些實施方式中，藥劑總質量係藥物組成物總質量的至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%或75%。在一些實施方式中，藥劑總質量不超過藥物組成物總質量的75%、70%、65%、60%、55%、50%、45%、40%、35%、30%或25%。在一些實施方式中，一種或多種賦形劑的總質量為藥物組成物總質量的至少5%、至少10%、至少20%、至少30%、至少35%、至少40%、至少45%或至少50%。在一些實施方式中，一種或多種賦形劑的總質量不超過藥物組成物總質量的95%、90%、85%、80%、75%、70%、65%、60%或55%。In certain aspects, provided herein is a method of preparing a solid dosage form of a pharmaceutical composition, the method comprising combining an agent (e.g., a bacterium disclosed herein and/or a bacterial-derived agent, such as an mEV disclosed herein) and one or more (e.g., One, two or three) excipients are combined into a pharmaceutical composition. In certain embodiments, the total mass of the medicament is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% of the total mass of the pharmaceutical composition , 60%, 65%, 70% or 75%. In some embodiments, the total mass of the medicament does not exceed 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30% or 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more excipients is at least 5%, at least 10%, at least 20%, at least 30%, at least 35%, at least 40%, at least 45%, or At least 50%. In some embodiments, the total mass of one or more excipients does not exceed 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60% or 55% of the total mass of the pharmaceutical composition.

在一些實施方式中，一種或多種賦形劑包含矽化微晶纖維素。在一些實施方式中，一種或多種賦形劑包括交聚維酮（PVPP）。在某些實施方式中，本文提供的固體劑型包含矽化微晶纖維素。在一些實施方式中，矽化微晶纖維素為HD90級。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的至少5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%。在某些實施方式中，矽化微晶纖維素總質量不超過藥物組成物總質量的5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%。在某些實施方式中，本文提供的固體劑型包含交聚維酮。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%。在某些實施方式中，交聚維酮總質量不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%。在某些實施方式中，交聚維酮總質量為藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%。In some embodiments, the one or more excipients comprise silicified microcrystalline cellulose. In some embodiments, the one or more excipients include crospovidone (PVPP). In certain embodiments, the solid dosage forms provided herein comprise silicified microcrystalline cellulose. In some embodiments, the silicified microcrystalline cellulose is grade HD90. In some embodiments, the total mass of silicified microcrystalline cellulose is at least 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21% of the total mass of the pharmaceutical composition. %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54% , 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72 %, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%. In certain embodiments, the total mass of silicified microcrystalline cellulose does not exceed 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21% of the total mass of the pharmaceutical composition %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54% , 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72 %, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%. In some embodiments, the total mass of silicified microcrystalline cellulose is about 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21% of the total mass of the pharmaceutical composition %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, or 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54% , 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72 %, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%. In certain embodiments, the solid dosage forms provided herein comprise crospovidone. In certain embodiments, the total mass of crospovidone is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%. In some embodiments, the total mass of crospovidone does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%. In some embodiments, the total mass of crospovidone is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%.

在某些實施方式中，本文提供的固體劑型包含：(i) 藥劑，藥劑總質量為藥物組成物總質量的至少5%且不超過75%，和 (ii) 矽化微晶纖維素，矽化微晶纖維素總質量為藥物組成物總質量的至少5%（例如至少5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%）且不超過90%（例如不超過5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%）。在某些實施方式中，固體劑型進一步包含總交聚維酮，交聚維酮總質量為藥物組成物總質量的至少5%（例如至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%）且不超過30%（不超過5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%）。在某些實施方式中，矽化微晶纖維素總質量加上交聚維酮總質量為藥物組成物總質量的至少60%、70%、80%或90%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約50%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約76.4%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約72.5%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約20%，交聚維酮總質量為藥物組成物總質量的約15%。In certain embodiments, the solid dosage form provided herein comprises: (i) a medicament, the total mass of the medicament is at least 5% and no more than 75% of the total mass of the pharmaceutical composition, and (ii) silicified microcrystalline cellulose, the silicified microcrystalline cellulose The total mass of crystalline cellulose is at least 5% (for example, at least 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%) of the total mass of the pharmaceutical composition , 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39 %, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72%, 73% , 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90% %) and not more than 90% (such as not more than 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% , 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58 %, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%). In certain embodiments, the solid dosage form further comprises total crospovidone, the total mass of crospovidone is at least 5% (eg, at least 5%, 6%, 7%, 8%, 9%) of the total mass of the pharmaceutical composition , 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26 %, 27%, 28%, 29% or 30%) and not exceeding 30% (not exceeding 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14 %, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%) . In some embodiments, the total mass of silicified microcrystalline cellulose plus the total mass of crospovidone is at least 60%, 70%, 80% or 90% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 50% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is approximately 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 76.4% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 72.5% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 20% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is approximately 15% of the total mass of the pharmaceutical composition.

在一些實施方式中，固體劑型包含一定量（例如，劑量）的活性成分（例如，細菌和細菌來源的試劑（例如，組分）（例如，微生物胞外囊泡或mEV））。在一些實施方式中，可以根據在藥劑的給定製劑（例如批次）中包含的活性成分的量來調節摻入固體劑型中的藥劑（包含活性成分）的量。在一些實施方式中，然後相應地調整矽化微晶纖維素的量。在一些實施方式中，當藥劑的量增加時，矽化微晶纖維素的量減少；並且反之亦然。在一些實施方式中，可以對藥劑和矽化微晶纖維素的量進行調整，但一種或多種賦形劑（例如，一種、兩種或三種賦形劑）的量保持不變，例如，對於給定的固體劑型配方的批次之間。在一些實施方式中，硬脂酸鎂和膠體二氧化矽的量也可以保持恒定，例如，對於給定的固體劑型配方的批次之間。例如，在本文提供的工作實例中，使用含有小韋榮氏球菌粉末的藥劑來製備兩種片劑固體劑型。兩種製劑都含有15%交聚維酮。另外，兩種製劑中的硬脂酸鎂和膠體二氧化矽分別分別為1%和1%。然而在一種製劑中，使用了33%藥劑。在另一種製劑中，使用了6.6%藥劑。為了針對不同的藥劑量進行調節，矽化微晶纖維素的量也不同：當使用33%藥劑時，50%矽化微晶纖維素；當使用6.6%藥劑時，76.4%矽化微晶纖維素。In some embodiments, solid dosage forms comprise an amount (eg, dose) of an active ingredient (eg, bacteria and bacterially derived agents (eg, components) (eg, microbial extracellular vesicles or mEVs)). In some embodiments, the amount of medicament (comprising an active ingredient) incorporated into a solid dosage form can be adjusted according to the amount of active ingredient contained in a given formulation (eg, batch) of medicament. In some embodiments, the amount of silicified microcrystalline cellulose is then adjusted accordingly. In some embodiments, when the amount of agent is increased, the amount of silicified microcrystalline cellulose is decreased; and vice versa. In some embodiments, the amount of the agent and the silicified microcrystalline cellulose can be adjusted, but the amount of one or more excipients (e.g., one, two, or three excipients) remains constant, e.g., for between batches of defined solid dosage form formulations. In some embodiments, the amounts of magnesium stearate and colloidal silicon dioxide can also be kept constant, eg, between batches for a given solid dosage form formulation. For example, in the working examples provided herein, two tablet solid dosage forms were prepared using a medicament containing Veillonella parvum powder. Both formulations contained 15% crospovidone. In addition, magnesium stearate and colloidal silicon dioxide in the two preparations were 1% and 1%, respectively. In one formulation, however, 33% medicament was used. In another formulation, 6.6% agent was used. In order to adjust for different drug doses, the amount of silicified microcrystalline cellulose is also different: when using 33% medicament, 50% silicified microcrystalline cellulose; when using 6.6% medicament, 76.4% silicified microcrystalline cellulose.

在某些實施方式中，該方法進一步包括壓製藥物組成物，從而形成片劑或微型片劑。在一些實施方式中，該方法進一步包括對片劑或微型片劑進行腸溶包衣，從而製備經腸溶包衣的片劑。在某些實施方式中，該方法進一步包括將微型片劑裝載到膠囊中。In certain embodiments, the method further comprises compressing the pharmaceutical composition, thereby forming a tablet or minitablet. In some embodiments, the method further comprises enteric coating the tablet or mini-tablet, thereby preparing an enteric coated tablet. In certain embodiments, the method further comprises loading the mini-tablets into a capsule.

在某些實施方式中，該方法包括在將藥劑（例如，細菌（例如，本文揭露的細菌）和/或細菌來源的試劑，例如mEV（例如，本文揭露的mEV））和一種或多種（例如，一種、兩種或三種）賦形劑組合成藥物組成物之前對藥劑進行濕法製粒。在一些實施方式中，濕法製粒包括 (i) 將藥劑與製粒流體（例如，水、乙醇或異丙醇，單獨或組合）混合。在一些實施方式中，濕法製粒包括將藥劑與水混合。在一些實施方式中，濕法製粒包括 (ii) 乾燥混合的藥劑和製粒流體（例如，在流化床乾燥器上乾燥）。在一些實施方式中，濕法製粒包括 (iii) 研磨乾燥的藥劑和製粒流體。然後將研磨的藥劑和製粒流體與一種或多種（例如，一種、兩種或三種）賦形劑組合以製備藥物組成物。In certain embodiments, the method comprises combining an agent (e.g., a bacterium (e.g., a bacterium disclosed herein) and/or an agent of bacterial origin, e.g., an mEV (e.g., a mEV disclosed herein)) with one or more (e.g., , one, two or three) excipients are wet granulated before being combined into a pharmaceutical composition. In some embodiments, wet granulation involves (i) mixing the agent with a granulation fluid (eg, water, ethanol, or isopropanol, alone or in combination). In some embodiments, wet granulation involves mixing the agent with water. In some embodiments, wet granulation includes (ii) drying the mixed pharmaceutical agent and granulation fluid (eg, drying on a fluid bed dryer). In some embodiments, wet granulation includes (iii) milling a dry medicament and a granulation fluid. The milled medicament and granulation fluid are then combined with one or more (eg, one, two or three) excipients to prepare a pharmaceutical composition.

在一些方面，本文提供包含藥劑的顆粒，例如，其中藥劑包含細菌（例如，本文揭露的細菌）和/或細菌來源的試劑，例如mEV（例如，本文揭露的mEV）（例如，藥劑可以是。該粉末包含細菌和/或細菌來源的試劑，例如mEV）。In some aspects, provided herein are particles comprising an agent, e.g., wherein the agent comprises a bacterium (e.g., a bacterium disclosed herein) and/or an agent of bacterial origin, such as an mEV (e.g., an mEV disclosed herein) (e.g., the agent can be. The powder contains bacteria and/or reagents of bacterial origin, such as mEV).

相關申請的交叉引用Cross References to Related Applications

本申請要求2021年3月5日提交的美國臨時申請案號63/157,138以及2021年8月18日提交的美國臨時申請案號63/234,490之權益，將其各自的全部內容藉由引用併入本文。 定義 This application claims the benefit of U.S. Provisional Application No. 63/157,138, filed March 5, 2021, and U.S. Provisional Application No. 63/234,490, filed Aug. 18, 2021, each of which is incorporated by reference in its entirety This article. definition

「佐劑」或「輔助療法」在廣義上係指影響受試者（例如人類）中的免疫學或生理學應答的藥劑。例如，佐劑可增加抗原隨時間或在目的區域（如腫瘤）中的存在，幫助吸收抗原呈遞細胞抗原，活化巨噬細胞及淋巴細胞並且支持細胞介素的產生。藉由改變免疫應答，佐劑可允許使用較小劑量的免疫相互作用劑以增加特定劑量的免疫相互作用劑的有效性或安全性。例如，佐劑可預防T細胞耗竭且因此增加特定免疫相互作用劑的有效性或安全性。"Adjuvant" or "adjuvant therapy" refers broadly to an agent that affects an immunological or physiological response in a subject, eg, a human. For example, adjuvants can increase the presence of antigen over time or in an area of interest (such as a tumor), aid in the uptake of antigen by antigen-presenting cells, activate macrophages and lymphocytes, and support the production of cytokines. By altering the immune response, adjuvants may allow the use of smaller doses of the immune interacting agent to increase the effectiveness or safety of a particular dose of the immune interacting agent. For example, an adjuvant can prevent T cell exhaustion and thus increase the effectiveness or safety of a particular immune interactor.

「施用」廣義上係指將組成物（例如，藥物組成物，例如本文描述的藥劑的固體劑型）施用給受試者的途徑。施用途徑的實例包含口服施用、直腸施用、局部施用、吸入（經鼻）或注射。注射施用包括靜脈內（IV）、肌內（IM）、腫瘤內（IT）及皮下（SC）施用。本文描述的藥物組成物可以任何形式藉由任何有效途徑施用，包括（但不限於）瘤內、經口、非經腸、腸內、靜脈內、腹膜內、局部、經皮（例如，使用任何標準貼劑）、皮內、經眼、經鼻（鼻內）、局部、非經口（諸如噴霧）、吸入、皮下、肌內、頰、舌下、（經）直腸、陰道、動脈內及鞘內、經黏膜（例如，舌下、經舌、（經）頰、（經）尿道、陰道（例如，經陰道及陰道周圍）、植入、膀胱內、肺內、十二指腸內、胃內及支氣管內。在較佳的實施方式中，藉由以下形式施用本文所述之藥物組成物：經口、經直腸、經腫瘤內、經局部、經膀胱內、藉由注射至引流淋巴結中或毗鄰引流淋巴結處、經靜脈內、藉由吸入或氣溶膠或經皮下。在另一個較佳的實施方式中，本文所述之藥物組成物口服、瘤內或靜脈內施用。在另一個實施方式中，本文所述之藥物組成物經口服施用。"Administering" broadly refers to the route by which a composition (eg, a pharmaceutical composition, such as a solid dosage form of an agent described herein) is administered to a subject. Examples of routes of administration include oral administration, rectal administration, topical administration, inhalation (nasal) or injection. Administration by injection includes intravenous (IV), intramuscular (IM), intratumoral (IT) and subcutaneous (SC) administration. The pharmaceutical compositions described herein may be administered in any form by any effective route, including but not limited to intratumoral, oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patch), intradermal, ophthalmic, nasal (intranasal), topical, parenteral (such as spray), inhalation, subcutaneous, intramuscular, buccal, sublingual, (trans)rectal, vaginal, intraarterial and Intrathecal, transmucosal (eg, sublingual, translingual, buccal, (trans)urethral, vaginal (eg, transvaginal and perivaginal), implanted, intravesical, intrapulmonary, intraduodenal, intragastric, and Intrabronchial. In a preferred embodiment, the pharmaceutical compositions described herein are administered by oral, rectal, intratumoral, topically, intravesical, by injection into or adjacent to draining lymph nodes Draining lymph nodes, intravenously, by inhalation or aerosol or subcutaneously. In another preferred embodiment, the pharmaceutical composition described herein is administered orally, intratumorally or intravenously. In another embodiment , the pharmaceutical composition described herein is administered orally.

如本文所用，術語「抗體」可指完整抗體及其抗原結合片段二者。完整抗體係包含由二硫鍵相互連接的至少兩條重（H）鏈及兩條輕（L）鏈的糖蛋白。每條重鏈包含重鏈可變區（在本文中縮寫為V H）及重鏈恒定區。每條輕鏈包含輕鏈可變區（在本文中縮寫為V L）及輕鏈恒定區。V H及V L區可進一步細分成超變區（稱為互補決定區（CDR））及更保守區（稱為框架區（FR）），二者散佈排列。每個V H及V L由三個CDR及四個FR構成，其自胺基-末端至羧基-末端按下列順序排列：FR1、CDR1、FR2、CDR2、FR3、CDR3、FR4。重鏈及輕鏈的可變區含有與抗原相互作用的結合結構域。術語「抗體」包含例如單株抗體、多株抗體、嵌合抗體、人類源化抗體、人類抗體、多特異性抗體（例如雙特異性抗體）、單鏈抗體及抗原結合抗體片段。 As used herein, the term "antibody" can refer to both whole antibodies and antigen-binding fragments thereof. The complete antibody system consists of glycoproteins with at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds. Each heavy chain comprises a heavy chain variable region (abbreviated herein as VH ) and a heavy chain constant region. Each light chain comprises a light chain variable region (abbreviated herein as VL ) and a light chain constant region. The VH and VL regions can be further subdivided into hypervariable regions called complementarity determining regions (CDRs) and more conserved regions called framework regions (FRs), both interspersed. Each VH and VL consists of three CDRs and four FRs, which are arranged in the following order from the amino-terminus to the carboxy-terminus: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain binding domains that interact with the antigen. The term "antibody" includes, for example, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, multispecific antibodies (eg, bispecific antibodies), single chain antibodies, and antigen-binding antibody fragments.

如本文所用，術語抗體的「抗原結合片段」及「抗原結合部分」係指抗體中保留結合抗原的能力的一個或多個片段。術語抗體的「抗原結合片段」內所涵蓋結合片段的實例包含Fab、Fab'、F(ab') 2、Fv、scFv、二硫化物連接的Fv、Fd、雙抗體、單鏈抗體、NANOBODIES®、經分離CDRH3及其他保留完整抗體的至少一部分可變區的抗體片段。該等抗體片段可使用常規重組和/或酶促技術來獲得且可以與完整抗體相同的方式針對抗原結合進行篩選。 As used herein, the terms "antigen-binding fragment" and "antigen-binding portion" of an antibody refer to one or more fragments of an antibody that retain the ability to bind antigen. Examples of binding fragments encompassed within the term "antigen-binding fragment" of an antibody include Fab, Fab', F(ab') 2 , Fv, scFv, disulfide-linked Fv, Fd, diabodies, single chain antibodies, NANOBODIES® , isolated CDRH3 and other antibody fragments that retain at least a portion of the variable region of an intact antibody. Such antibody fragments can be obtained using conventional recombinant and/or enzymatic techniques and can be screened for antigen binding in the same manner as whole antibodies.

「癌症」在廣義上係指宿主自有細胞的不受控、異常生長，這種生長導致對周圍組織及潛在地遠離宿主異常細胞生長初始位點的組織的侵襲。主要種類包括係上皮組織（例如皮膚、鱗狀細胞）癌症的癌；係結締組織（例如骨、軟骨、脂肪、肌肉、血管等）癌症的肉瘤；係血液形成組織（例如骨髓組織）癌症的白血病；係免疫細胞癌症的淋巴瘤及骨髓瘤；及包括腦及脊柱組織癌症的中樞神經系統癌症。「一種或多種癌症」和「一種或多種贅瘤」在本文中可互換使用。如本文所用，「癌症」係指所有類型的新發或復發癌症或贅瘤或惡性腫瘤，包括白血病、癌及肉瘤。癌症的具體實例係：癌、肉瘤、骨髓瘤、白血病、淋巴瘤及混合型腫瘤。癌症的非限制性實例係以下新發或復發癌症：腦癌、黑色素瘤、膀胱癌、乳癌、宮頸癌、大腸癌、頭頸癌、腎癌、肺癌、非小細胞肺癌、間皮瘤、卵巢癌、前列腺癌、肉瘤、胃癌、子宮癌及髓母細胞瘤。在一些實施方式中，癌症包括實性瘤。在一些實施方式中，癌症包括轉移。"Cancer" refers broadly to the uncontrolled, abnormal growth of a host's own cells that results in the invasion of surrounding tissues and potentially tissues remote from the host's initial site of abnormal cell growth. Major types include carcinomas of epithelial tissues (e.g., skin, squamous cell); sarcomas, of cancers of connective tissues (e.g., bone, cartilage, fat, muscle, blood vessels, etc.); leukemias, of cancers of blood-forming tissues (e.g., bone marrow tissue) ; lymphoma and myeloma, which are cancers of the immune cells; and cancers of the central nervous system, including cancers of the brain and spinal tissues. "One or more cancers" and "one or more neoplasms" are used interchangeably herein. As used herein, "cancer" refers to all types of new or recurrent cancers or neoplasms or malignancies, including leukemias, carcinomas and sarcomas. Specific examples of cancer are: carcinoma, sarcoma, myeloma, leukemia, lymphoma and mixed tumors. Non-limiting examples of cancer are the following new or recurrent cancers: brain cancer, melanoma, bladder cancer, breast cancer, cervical cancer, colorectal cancer, head and neck cancer, kidney cancer, lung cancer, non-small cell lung cancer, mesothelioma, ovarian cancer , prostate cancer, sarcoma, gastric cancer, uterine cancer and medulloblastoma. In some embodiments, the cancer comprises solid tumors. In some embodiments, the cancer comprises metastasis.

「碳水化合物」係指糖或糖聚合物。術語「糖」、「多糖」、「碳水化合物」及「寡糖」可互換使用。大部分碳水化合物係具有許多羥基的醛或酮，通常在分子的每一碳原子上具有一個羥基。碳水化合物通常具有分子式C nH 2nO n。碳水化合物可為單糖、二糖、三糖、寡糖或多糖。最基本的碳水化合物係單糖，如葡萄糖、蔗糖、半乳糖、甘露糖、核糖、阿拉伯糖、木糖及果糖。二糖係兩個接合的單糖。示例性二糖包括蔗糖、麥芽糖、纖維二糖及乳糖。通常，寡糖包含三至六個單糖單元（例如棉子糖、水蘇糖），且多糖包含六個或更多個單糖單元。示例性多糖包含澱粉、糖原及纖維素。碳水化合物可含有經修飾糖單元，例如2’-去氧核糖，其中去除羥基，2’-氟核糖，其中羥基經氟代替；或N-乙醯基葡萄糖胺，其為葡萄糖的含氮形式（例如2’-氟核糖、去氧核糖及己糖）。碳水化合物可以許多不同形式存在，例如構象異構物、環狀形式、非環狀形式、立體異構物、互變異構物、端基差向異構物及異構物。 "Carbohydrate" means sugar or sugar polymers. The terms "sugar", "polysaccharide", "carbohydrate" and "oligosaccharide" are used interchangeably. Most carbohydrates are aldehydes or ketones with many hydroxyl groups, usually one on each carbon atom of the molecule. Carbohydrates generally have the molecular formula C n H 2n O n . Carbohydrates can be monosaccharides, disaccharides, trisaccharides, oligosaccharides or polysaccharides. The most basic carbohydrates are monosaccharides such as glucose, sucrose, galactose, mannose, ribose, arabinose, xylose and fructose. Disaccharides are two joined monosaccharides. Exemplary disaccharides include sucrose, maltose, cellobiose, and lactose. Typically, oligosaccharides contain three to six monosaccharide units (eg, raffinose, stachyose), and polysaccharides contain six or more monosaccharide units. Exemplary polysaccharides include starch, glycogen, and cellulose. Carbohydrates may contain modified sugar units such as 2'-deoxyribose, in which the hydroxyl group is removed, 2'-fluororibose, in which the hydroxyl group is replaced by fluorine, or N-acetylglucosamine, which is the nitrogen-containing form of glucose ( such as 2'-fluororibose, deoxyribose and hexose). Carbohydrates can exist in many different forms, such as conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers, and isomers.

「細胞增強」在廣義上指細胞的流入或細胞在環境中的擴增，該等細胞在施用組成物之前基本上不存在於該環境中且不存在於該組成物本身中。增強環境的細胞包括免疫細胞、基質細胞、細菌及真菌細胞。特別受關注的環境係其中癌細胞駐留或定位的微環境。在一些情況下，該微環境係腫瘤微環境或腫瘤引流淋巴結。在其他情況下，該微環境係癌前組織位點或組成物的局部施用位點或其中該組成物在遠端施用後將積聚的位點。"Cell enhancement" broadly refers to the influx of cells or the expansion of cells in an environment that is substantially absent from the environment prior to administration of the composition and not present in the composition itself. Cells that enhance the environment include immune cells, stromal cells, bacterial and fungal cells. An environment of particular interest is the microenvironment in which cancer cells reside or localize. In some instances, the microenvironment is a tumor microenvironment or a tumor draining lymph node. In other cases, the microenvironment is a precancerous tissue site or site of local administration of the composition or a site where the composition will accumulate after distal administration.

「進化枝」指系統發育樹的OTU或成員，它們係系統發育樹中的統計有效節點的下游。進化枝包含系統發育樹中的一組末端葉，其係不同的單系進化單元且在某種程度上共用序列相似性。"Clade" refers to an OTU or member of a phylogenetic tree that is downstream of a statistically valid node in the phylogenetic tree. A clade comprises a group of terminal leaves in a phylogenetic tree that are distinct monophyletic evolutionary units and share sequence similarity to some degree.

來自兩種或更多種菌株的細菌的「組合」包括細菌在相同材料或產品中或在物理上連接的產品中的物理共存，及來自兩種或更多種菌株的細菌的在時間上的共施用或共定位。A "combination" of bacteria from two or more strains includes the physical coexistence of bacteria in the same material or product or in physically linked products, and the temporal separation of bacteria from two or more strains. Coadministration or colocalization.

來自兩個或更多個微生物（如細菌）菌株的mEV（如smEV和/或pmEV）的「組合」包括作為mEV（如smEV和/或pmEV）的獲得來源的微生物在相同材料或產品中或在物理上連接的產品中的物理共存，以及來自兩種或更多種菌株的mEV（如smEV和/或pmEV）在時間上的共施用或共定位。A "combination" of mEVs (such as smEV and/or pmEV) from two or more strains of microorganisms (such as bacteria) includes microorganisms from which mEVs (such as smEV and/or pmEV) were obtained in the same material or product or Physical coexistence in physically linked products, and temporal co-administration or co-localization of mEVs (such as smEV and/or pmEV) from two or more strains.

術語「降低」或「消耗」意指變化，該變化使治療後與治療前狀態相比的差異（視情況而定）為至少10%、20%、30%、40%、50%、60%、70%、80%、90%、1/100、1/1000、1/10,000、1/100,000、1/1,000,000或不可檢測。可降低的性質包括免疫細胞、細菌細胞、基質細胞、髓源性抑制細胞、成纖維細胞、代謝物的數量；細胞介素的水平；或另一物理參數（如耳厚度（例如，在DTH動物模型中）或腫瘤的大小）。The term "decrease" or "deplete" means a change that results in a difference (as the case may be) of at least 10%, 20%, 30%, 40%, 50%, 60% after treatment compared to the pre-treatment state , 70%, 80%, 90%, 1/100, 1/1000, 1/10,000, 1/100,000, 1/1,000,000, or undetectable. Properties that can be reduced include numbers of immune cells, bacterial cells, stromal cells, myeloid-derived suppressor cells, fibroblasts, metabolites; levels of cytokines; or another physical parameter such as ear thickness (e.g., in DTH animals model) or tumor size).

「生態失調」係指腸道或其他身體區域的微生物群或微生物組的狀態，其他身體區域包括例如，黏膜或皮膚表面（或任何其他微生物組生態位），在該狀態下宿主腸道微生物組生態網路「微生物組」的正常的多樣性和/或功能被破壞。生態失調的狀態可能導致疾病狀態，或者僅在某些條件下或只有長期存在時可能是不健康的。生態失調可能是由於多種因素引起的，包括環境因素、感染原、宿主基因型、宿主飲食和/或壓力。生態失調可能導致：一個或多個細菌類型（例如，厭氧菌）、物種和/或菌株的普遍度發生變化（例如，增加或減少），宿主微生物組群體組成的多樣性發生變化（例如，增加或減少）；導致一個或多個有益效應減少或喪失的一個或多個共生生物群體的變化（例如，增加或減少）；一個或多個病原體（例如，病原細菌）群體的過度生長；和/或僅當存在某些條件時引起疾病的共生生物的存在、和/或過度生長。"Dysbiosis" means the state of the microbiota or microbiome in the gut or other body regions, including, for example, the mucosa or skin surface (or any other microbiome niche), in which the host gut microbiome The normal diversity and/or function of the ecological network "microbiome" is disrupted. A state of dysbiosis may lead to a disease state, or may be unhealthy only under certain conditions or only in the long term. Dysbiosis can be due to a variety of factors, including environmental factors, infectious agents, host genotype, host diet, and/or stress. Dysbiosis can result in: changes (e.g., increases or decreases) in the prevalence of one or more bacterial types (e.g., anaerobic bacteria), species, and/or strains, changes in the diversity of the composition of the host microbiome population (e.g., increase or decrease); a change (e.g., increase or decrease) in one or more commensal populations that results in a decrease or loss of one or more beneficial effects; overgrowth of one or more pathogenic (e.g., pathogenic bacteria) populations; and / or the presence, and/or overgrowth, of commensal organisms that cause disease only when certain conditions are present.

術語「生態聚生體（ecological consortium）」係交換代謝物且彼此正性共調控的一組細菌，這與經由激活互補宿主通路來誘導宿主協同作用以改進功效的兩種細菌形成對比。The term "ecological consortium" refers to a group of bacteria that exchange metabolites and positively co-regulate each other, in contrast to two bacteria that induce host synergy to improve efficacy by activating complementary host pathways.

術語「有效劑量」或「有效量」係對於特定的藥用劑、組成物和施用方式有效地在受試者中實現期望的治療反應的藥劑的量。The term "effective dose" or "effective amount" refers to the amount of an agent effective for a particular pharmaceutical agent, composition and mode of administration to achieve a desired therapeutic response in a subject.

如本文所用，「工程化細菌」係藉由人類活動已在遺傳上自天然狀態改變的任何細菌及任何這種細菌的子代。工程化細菌包括例如靶向遺傳修飾的產物、隨機誘變篩選的產物及定向演化的產物。As used herein, an "engineered bacterium" is any bacterium and any progeny of such a bacterium that has been genetically altered from its natural state by human activity. Engineered bacteria include, for example, products of targeted genetic modification, products of random mutagenesis screens, and products of directed evolution.

術語「表位」意指能夠特異性結合至抗體或T細胞受體的蛋白質決定子。表位通常由如胺基酸或糖側鏈等分子的化學活性表面分組組成。某些表位可藉由抗體能夠結合的胺基酸的特定序列來定義。The term "epitope" means a protein determinant capable of specifically binding to an antibody or T cell receptor. Epitopes usually consist of chemically active surface groupings of molecules such as amino acids or sugar side chains. Certain epitopes can be defined by specific sequences of amino acids to which antibodies are able to bind.

術語「基因」在廣義上用於指與生物功能有關的任一核酸。術語「基因」適用於特定基因組序列以及由該基因組序列編碼的cDNA或mRNA。The term "gene" is used broadly to refer to any nucleic acid involved in a biological function. The term "gene" applies to a particular genomic sequence as well as to the cDNA or mRNA encoded by that genomic sequence.

兩種核酸分子的核酸序列間「同一性」可使用已知電腦演算法（如「FASTA」程式）使用例如Pearson等人 (1988) Proc. Natl. Acad. Sci. USA [美國國家科學院院刊] 85:2444中的預設參數測定為同一性百分比（其他程式包括GCG套裝程式（Devereux, J.等人, Nucleic Acids Research [核酸研究] 12(I): 387 (1984)）、BLASTP、BLASTN、FASTA Atschul, S. F.等人, J Molec Biol [分子生物學雜誌] 215:403 (1990)；Guide to Huge Computers [巨型電腦指南], Mrtin J. Bishop編輯, Academic Press [學術出版社], San Diego [聖地牙哥], 1994及Carillo等人(1988) SIAM J Applied Math [工業和應用數學學會應用數學雜誌] 48:1073）。例如，可使用國家生物技術資訊中心資料庫（National Center for Biotechnology Information database）的BLAST功能來測定同一性。其他可商業或公開獲得的程式包括DNAStar 「MegAlign」程式（威斯康辛州麥迪森市（Madison, Wis.））及威斯康辛大學遺傳學電腦集團（University of Wisconsin Genetics Computer Group）（UWG）「Gap」程式（威斯康辛州麥迪森市）。The "identity" between the nucleic acid sequences of two nucleic acid molecules can be determined using known computer algorithms (such as the "FASTA" program) such as Pearson et al. (1988) Proc. Natl. Acad. Sci. USA [Proceedings of the National Academy of Sciences of the United States of America] 85:2444 with default parameters determined as percent identity (other programs include the GCG suite of programs (Devereux, J. et al., Nucleic Acids Research [Nucleic Acids Research] 12(I): 387 (1984)), BLASTP, BLASTN, FASTA Atschul, S. F. et al., J Molec Biol 215:403 (1990); Guide to Huge Computers, edited by Mrtin J. Bishop, Academic Press, San Diego [ San Diego], 1994 and Carillo et al. (1988) SIAM J Applied Math 48:1073). For example, identity can be determined using the BLAST function of the National Center for Biotechnology Information database. Other commercially or publicly available programs include the DNAStar "MegAlign" program (Madison, Wis.) and the University of Wisconsin Genetics Computer Group (UWG) "Gap" program ( Madison, Wisconsin).

如本文所用，術語「免疫障礙」係指由免疫系統的活動引起的任何疾病、障礙或疾病症狀，包括自體免疫性疾病、炎性疾病及過敏。免疫障礙包括（但不限於）自體免疫性疾病（例如，牛皮癬、特應性皮炎、狼瘡、硬皮病、溶血性貧血、血管炎、一型糖尿病、格雷夫病（Grave’s disease）、類風濕性關節炎、多發性硬化、古德帕斯雷綜合症（Goodpasture’s syndrome）、惡性貧血和/或肌病）、炎性疾病（例如，尋常型痤瘡、氣喘、乳糜瀉、慢性前列腺炎、腎小球性腎炎、炎性腸病、盆腔炎、再灌注損傷、類風濕性關節炎、肉狀瘤病、移植排斥、血管炎和/或間質性膀胱炎），和/或過敏（例如，食物過敏、藥物過敏和/或環境過敏）。As used herein, the term "immune disorder" refers to any disease, disorder or disease symptom caused by the activity of the immune system, including autoimmune diseases, inflammatory diseases and allergies. Immune disorders include, but are not limited to, autoimmune diseases (eg, psoriasis, atopic dermatitis, lupus, scleroderma, hemolytic anemia, vasculitis, type 1 diabetes, Grave's disease, rheumatoid arthritis, multiple sclerosis, Goodpasture's syndrome, pernicious anemia and/or myopathy), inflammatory diseases (eg, acne vulgaris, asthma, celiac disease, chronic prostatitis, renal glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, and/or interstitial cystitis), and/or allergies (eg, food allergies, drug allergies, and/or environmental allergies).

「免疫療法」係使用受試者的免疫系統以治療疾病（例如，免疫疾病、炎性疾病、代謝性疾病、癌症）的治療且包括（例如）檢查點抑制劑、癌症疫苗、細胞介素、細胞療法、CAR-T細胞及樹突細胞療法。"Immunotherapy" is treatment that uses a subject's immune system to treat a disease (e.g., immune disease, inflammatory disease, metabolic disease, cancer) and includes, for example, checkpoint inhibitors, cancer vaccines, cytokines, Cell therapy, CAR-T cell and dendritic cell therapy.

術語「增加」意指變化，該變化使治療後與治療前狀態相比的差異（視情況而定）為至少高10%、20%、30%、40%、50%、60%、70%、80%、90%、2倍、4倍、10倍、100倍、10^3倍、10^4倍、10^5倍、10^6倍和/或10^7倍。可增加的性質包括免疫細胞、細菌細胞、基質細胞、髓源性抑制細胞、成纖維細胞、代謝物的數量；細胞介素的水平；或另一物理參數（如耳厚度（例如，在DTH動物模型中）或腫瘤的大小）。The term "increase" means a change which results in a difference (as the case may be) of at least 10%, 20%, 30%, 40%, 50%, 60%, 70% higher after treatment compared to the pre-treatment state , 80%, 90%, 2 times, 4 times, 10 times, 100 times, 10^3 times, 10^4 times, 10^5 times, 10^6 times and/or 10^7 times. Properties that can be increased include numbers of immune cells, bacterial cells, stromal cells, myeloid-derived suppressor cells, fibroblasts, metabolites; levels of cytokines; or another physical parameter such as ear thickness (e.g., in DTH animals model) or tumor size).

「先天免疫促効劑」或「免疫佐劑」係特異性靶向先天免疫受體（包括Toll樣受體（TLR）、NOD受體、RLR、C型凝集素受體、STING-cGAS途徑組分、炎性體複合物）的小分子、蛋白質或其他藥劑。例如，LPS係細菌源的或合成的TLR-4促効劑且可使用鋁作為免疫刺激佐劑。免疫佐劑係特定類別的更廣泛的佐劑或輔助療法。STING促効劑的實例包括但不限於2'3'-cGAMP、3'3'-cGAMP、c-di-AMP、c-di-GMP、2'2'-cGAMP及2'3'-cGAM(PS)2（Rp/Sp）（2'3'-cGAMP的雙硫代磷酸酯類似物的Rp、Sp異構物）。TLR促効劑的實例包括但不限於TLRl、TLR2、TLR3、TLR4、TLR5、TLR6、TLR7、TLR8、TLR9、TLR10和TLR11。NOD促効劑的實例包括但不限於N-乙醯基胞壁醯基-L-丙胺醯基-D-異麩醯胺酸（胞壁醯二肽（MDP））、γ-D-麩胺醯基-內消旋-二胺基庚二酸（iE-DAP）及去胞壁醯肽（desmuramylpeptide（DMP））。"Innate immune stimulants" or "immune adjuvants" specifically target innate immune receptors (including Toll-like receptors (TLR), NOD receptors, RLR, C-type lectin receptors, STING-cGAS pathway group components, inflammasome complexes), small molecules, proteins or other agents. For example, LPS is a bacterially derived or synthetic TLR-4 agonist and aluminum can be used as an immunostimulatory adjuvant. Immunological adjuvants are a specific class of broader adjuvants or adjuvant therapies. Examples of STING agonists include, but are not limited to, 2'3'-cGAMP, 3'3'-cGAMP, c-di-AMP, c-di-GMP, 2'2'-cGAMP, and 2'3'-cGAM ( PS)2(Rp/Sp) (Rp, Sp isomers of phosphorobisthioate analogs of 2'3'-cGAMP). Examples of TLR agonists include, but are not limited to, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, and TLR11. Examples of NOD agonists include, but are not limited to, N-acetylmurayl-L-alanyl-D-isoglutamine (muramyl dipeptide (MDP)), gamma-D-glutamine Acyl-meso-diaminopimelic acid (iE-DAP) and desmuramylpeptide (DMP).

「內轉錄間隔區」或「ITS」係位於通常用於識別真核物種（特別地，真菌）的共同先質轉錄本上的結構核糖體RNA（rRNA）之間的一段非功能性RNA。形成核糖體的核的真菌的rRNA經轉錄為信號基因且由8S、5.8S及28S區域及分別在8S與5.8S之間及5.8S與28S區域之間的ITS4及5組成。如先前描述，在18S與5.8S之間及5.8S與28S區域之間的這類兩個雙譯基因嵌段（intercistronic segment）藉由剪接去除且出於條碼的目的在物種之間含有顯著變化（Schoch等人, Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DNA barcode marker for Fungi [核糖體內轉錄間隔區（ITS）係真菌的通用DNA條碼標誌物].PNAS [美國國家科學院院刊] 109:6241-6246.2012）。18S rDNA傳統上用於系統發育重建，然而ITS可發揮此功能，因為其通常是高度保守的，但含有高變區，該等高變區具有足夠的核苷酸多樣性來區分大多數真菌的屬及物種。The "internal transcribed spacer" or "ITS" is a non-functional stretch of RNA located between structural ribosomal RNAs (rRNAs) commonly used to recognize common precursor transcripts in eukaryotic species (in particular, fungi). The fungal rRNA forming the nucleus of the ribosome is transcribed as a signal gene and consists of the 8S, 5.8S and 28S regions and ITS4 and 5 between the 8S and 5.8S and 5.8S and 28S regions, respectively. As previously described, these two intercistronic segments between 18S and 5.8S and between 5.8S and 28S regions are removed by splicing and contain significant variation between species for barcoding purposes (Schoch et al., Nuclear ribosomal internal transcribed spacer (ITS) region as a universal DNA barcode marker for Fungi [ribosomal internal transcribed spacer (ITS) is a universal DNA barcode marker for fungi]. PNAS [Proceedings of the National Academy of Sciences] 109 :6241-6246.2012). 18S rDNA has traditionally been used for phylogenetic reconstruction, however ITS can serve this function as it is generally highly conserved but contains hypervariable regions with sufficient nucleotide diversity to distinguish between most fungal genera and species.

術語「分離的」或「富集的」涵蓋具有以下特徵的微生物（如細菌）、mEV（如smEV和/或pmEV）或其他實體或物質：(1) 已與在最初產生（不論在自然界中或在實驗環境中）時與其締合的至少一些組分分離，和/或 (2) 係人工產生、製備、純化和/或製造的。分離的微生物或mEV可與至少約10%、約20%、約30%、約40%、約50%、約60%、約70%、約80%、約90%或更多的其最初締合的其他組分分離。在一些實施方式中，分離的微生物或mEV係大於約80%、約85%、約90%、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%、約99%或大於約99%純的。如本文所用，物質基本上不含其他組分時係「純的」。術語「純化（purify、purifying及purified）」係指已與在最初產生或生成（例如不論在自然界中或在實驗環境中）時或在其最初產生之後的任一時間期間與其締合的至少一些組分分離的微生物或mEV或其他材料。如果微生物或微生物群體或mEV在產生時或在產生之後如從含有該微生物或微生物群體的材料或環境中分離，則可將該微生物或微生物群體或mEV視為經純化的，且經純化的微生物或微生物群體或mEV可含有高達約10%、約20%、約30%、約40%、約50%、約60%、約70%、約80%、約90%或高於約90%的其他材料且仍將其視為「分離的」。在一些實施方式中，經純化的微生物或微生物群體或mEV係大於約80%、約85%、約90%、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%、約99%或大於約99%純的。在本文提供的微生物組成物的情況下，存在於組成物中的一種或多種微生物類型可從含有該微生物類型的材料或環境中產生和/或存在的一種或多種其他微生物中獨立地純化。微生物組成物及其微生物組分（例如mEV）通常從殘餘生境產物中純化。The terms "isolated" or "enriched" encompass microorganisms (such as bacteria), mEVs (such as smEVs and/or pmEVs), or other entities or substances that: (1) have been associated with or in an experimental setting), and/or (2) are artificially produced, prepared, purified and/or manufactured. The isolated microorganism or mEV can be associated with at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of its original associates. Combined other components are separated. In some embodiments, the isolated microorganism or mEV is greater than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99% pure. As used herein, a substance is "pure" when it is substantially free of other components. The terms "purifying, purifying and purified" refer to at least some of the Component isolated microorganisms or mEVs or other materials. A microorganism or population of microorganisms or mEV may be considered to be purified if the microorganism or population of microorganisms or mEV is isolated at the time of production or after production, such as from a material or environment containing the microorganism or population of microorganisms, and a purified microorganism Or the population of microorganisms or mEVs may contain up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more than about 90% other material and still consider it "separate". In some embodiments, the purified microorganism or population of microorganisms or mEVs are greater than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or greater than about 99% pure. In the case of the microbial compositions provided herein, one or more types of microorganisms present in the composition can be purified independently from one or more other types of microorganisms produced and/or present in the material or environment containing the type of microorganisms. Microbial compositions and their microbial components (e.g. mEVs) are often purified from residual habitat products.

如本文所用，「脂質」包括脂肪、油、三酸甘油酯、膽固醇、磷脂質、和任何形式的脂肪酸（包括游離脂肪酸）。脂肪、油及脂肪酸可為飽和、不飽和（順式或反式）或部分不飽和（順式或反式）。As used herein, "lipid" includes fats, oils, triglycerides, cholesterol, phospholipids, and fatty acids in any form (including free fatty acids). Fats, oils and fatty acids can be saturated, unsaturated (cis or trans) or partially unsaturated (cis or trans).

術語「LPS突變體或脂多糖突變體」廣義上係指所選的包含LPS損失的細菌。LPS損失可能是由於參與脂質A生物合成的基因如 lpxA、 lpxC和 lpxD的突變或破壞所致。包含LPS突變體的細菌可能對胺基糖苷類和多黏菌素（多黏菌素B和黏菌素）具有抗性。 The term "LPS mutant or lipopolysaccharide mutant" refers broadly to selected bacteria comprising a loss of LPS. LPS loss may be due to mutation or disruption of genes involved in lipid A biosynthesis, such as lpxA , lpxC , and lpxD . Bacteria harboring LPS mutants may be resistant to aminoglycosides and colistins (polymyxin B and colistin).

如本文所用的「代謝物」係指在任何細胞或微生物代謝反應中用作底物或作為產物化合物、組成物、分子、離子、輔助因子、催化劑或營養素產生自任何細胞或微生物代謝反應的任何及所有分子化合物、組成物、分子、離子、輔助因子、催化劑或營養素。As used herein, "metabolite" refers to any cellular or microbial metabolic reaction that is used as a substrate in, or produced as a product compound, constituent, molecule, ion, cofactor, catalyst, or nutrient from any cellular or microbial metabolic reaction. And all molecular compounds, constituents, molecules, ions, cofactors, catalysts or nutrients.

「微生物」係指表徵為古生菌、寄生蟲、細菌、真菌、微觀藻類、原生動物及與該生物體相關的發育階段或生命週期階段（例如，植物、孢子（包括孢子形成、休眠及萌發）、潛伏、生物膜）的任何天然或經改造的生物體。腸道微生物的實例包括：葛氏放線菌（ Actinomyces graevenitzii）、齲齒放線菌（ Actinomyces odontolyticus）、嗜黏蛋白阿克曼氏菌（ Akkermansia muciniphila）、糞擬桿菌（ Bacteroides caccae ）、脆弱擬桿菌（ Bacteroides fragilis）、腐敗擬桿菌（ Bacteroides putredinis）、多形擬桿菌（ Bacteroides thetaiotaomicron）、普通擬桿菌（ Bacteroides vultagus）、青春雙歧桿菌（ Bifidobacterium adolescentis）、兩歧雙歧桿菌（ Bifidobacterium bifidum）、對沃氏嗜膽菌（ Bilophila wadsworthia）、布勞特氏菌屬（ Blautia）、丁酸弧菌屬（ Butyrivibrio）、纖細彎曲桿菌（ Campylobacter gracilis）、梭菌群III（ Clostridia cluster III）、梭菌群IV（ Clostridia cluster IV）、梭菌群IX（ Clostridia cluster IX）（胺基酸球菌科群（ Acidaminococcaceae group））、梭菌群XI（ Clostridia cluster XI）、梭菌群XIII（ Clostridia cluster XIII）（消化鏈球菌群（ Peptostreptococcus group））、梭菌群XIV（ Clostridia cluster XIV）、梭菌群XV（ Clostridia cluster XV）、產氣柯林斯菌（ Collinsella aerofaciens）、糞球菌屬（ Coprococcus）、桑氏棒狀桿菌（ Corynebacterium sunsvallense）、豬脫硫單胞菌（ Desulfomonas pigra）、產甲酸多爾氏菌（ Dorea formicigenerans）、長鏈多爾氏菌（ Dorea longicatena）、大腸桿菌（ Escherichia coli）、龐大真桿菌（ Eubacterium hadrum）、直腸真桿菌（ Eubacterium rectale）、普拉梭菌（ Faecalibacteria prausnitzii）、孿生球菌屬（ Gemella）、乳球菌屬（ Lactococcus）、蘭氏螺菌屬（ Lanchnospira）、柔膜細菌群XVI（ Mollicutes cluster XVI）、柔膜細菌群XVIII（ Mollicutes cluster XVIII）、普雷沃菌屬（ Prevotella）、黏滑羅氏菌（ Rothia mucilaginosa）、伶俐瘤胃球菌（ Ruminococcus callidus）、活潑瘤胃球菌（ Ruminococcus gnavus）、扭鏈瘤胃球菌（ Ruminococcus torques）及鏈球菌屬（ Streptococcus）。 "Microorganism" means any stage of development or life cycle characterized by archaea, parasites, bacteria, fungi, microscopic algae, protozoa and associated with such organisms (e.g., plants, spores (including sporulation, dormancy, and germination) ), latent, biofilm) any natural or engineered organism. Examples of gut microbes include: Actinomyces graevenitzii, Actinomyces odontolyticus , Akkermansia muciniphila, Bacteroides caccae , Bacteroides fragilis ), Bacteroides putredinis , Bacteroides thetaiotaomicron , Bacteroides vultagus , Bifidobacterium adolescentis , Bifidobacterium bifidum , Bilophila wadsworthia , Blautia , Butyrivibrio , Campylobacter gracilis , Clostridia cluster III, Clostridia group IV ( Clostridia cluster IV ), Clostridia cluster IX ( Acidaminococcaceae group), Clostridia cluster XI ( Clostridia cluster XI ), Clostridia cluster XIII ( Clostridia cluster XIII ) (peptostreptococcus Peptostreptococcus group), Clostridia cluster XIV, Clostridia cluster XV , Collinsella aerofaciens , Coprococcus , Corynebacterium sunsvallense ), Desulfomonas pigra , Dorea formicigenerans , Dorea longicatena , Escherichia coli , Eubacterium hadrum , Eubacterium rectum ( Eubact erium rectale ), Faecalibacteria prausnitzii , Gemella , Lactococcus , Lanchnospira , Mollicutes cluster XVI , Mollicus Mollicutes cluster XVIII, Prevotella , Rothia mucilaginosa , Ruminococcus callidus , Ruminococcus gnavus , Ruminococcus torques and Streptococcus .

「微生物胞外囊泡」（mEV）可從微生物如細菌、古菌、真菌、微觀藻類、原生動物和寄生蟲獲得。在一些實施方式中，mEV從細菌獲得。mEV包括分泌的微生物胞外囊泡（smEV）和經加工的微生物胞外囊泡（pmEV）。「分泌的微生物胞外囊泡」（smEV）係來源於微生物的自然產生的囊泡。smEV由微生物脂質和/或微生物蛋白質和/或微生物核酸和/或微生物碳水化合物部分構成，並從培養上清液中分離。該等囊泡的自然產生可以藉由操縱細菌細胞正在培養的環境（例如，藉由培養基或溫度改變）來人為地增強（例如，增加）或減少。此外，smEV組成物可以被修飾以減少，增加，添加或去除微生物成分或外來物質，以改變功效、免疫刺激、穩定性、免疫刺激能力、穩定性、器官靶向性（例如，淋巴結）、吸收（例如，胃腸道）和/或產率（例如，由此改變功效）。如本文所用，術語「純化的smEV組成物」或「smEV組成物」係指smEV的製劑，其已經從源材料中發現的至少一種相關聯物質（例如，從至少一種其他微生物組分分離）或用於製備該製劑的任何方法中與smEV相關聯的任何材料分離。也可指針對特定組分已顯著富集的組成物。「經加工的微生物胞外囊泡」（pmEV）係從人工裂解的微生物（例如，細菌）純化的微生物膜組分（例如，已與其他胞內微生物細胞組分分離的微生物膜組分）的非天然存在的集合，並且其可包含根據純化方法而具有變化的或選定的尺寸範圍的顆粒。藉由化學破壞（例如，藉由溶菌酶和/或溶葡萄球菌素）和/或物理破壞（例如，藉由機械力）微生物細胞並藉由離心和/或超速離心或其他方法將微生物膜組分與胞內組分分離來獲得pmEV池。所得pmEV混合物含有富集的微生物膜及其組分（例如，外周締合的或完整的膜蛋白、脂質、聚糖、多糖、碳水化合物、其他聚合物），使得相對於完整微生物，微生物膜組分的濃度增加，並且胞內內容物的濃度降低（例如，稀釋）。對於革蘭氏陽性細菌，pmEV可以包括細胞膜或細胞質膜。對於革蘭氏陰性細菌，pmEV可以包括內膜和外膜。pmEV可以被修飾以增加純度，調節組成物中顆粒的尺寸，和/或被修飾以減少、增加、添加或去除微生物組分或外來物質，以改變功效、免疫刺激、穩定性、免疫刺激能力、穩定性、器官靶向性（例如淋巴結）、吸收（例如胃腸道）和/或產率（例如由此改變功效）。pmEV可以藉由添加、去除、富集或稀釋特定組分（包括來自相同或其他微生物的細胞內組分）被修飾。如本文所用，術語「純化的pmEV組成物」或「pmEV組成物」係指pmEV的製劑，其已經從源材料中發現的至少一種相關聯物質（例如，從至少一種其他微生物組分分離）或用於製備該製劑的任何方法中與pmEV相關聯的任何材料分離。也可指針對特定組分已顯著富集的組成物。"Microbiological extracellular vesicles" (mEVs) can be obtained from microorganisms such as bacteria, archaea, fungi, microscopic algae, protozoa and parasites. In some embodiments, mEVs are obtained from bacteria. mEVs include secreted microbial extracellular vesicles (smEVs) and processed microbial extracellular vesicles (pmEVs). "Secreted microbial extracellular vesicles" (smEVs) are naturally occurring vesicles derived from microorganisms. smEVs are composed of microbial lipids and/or microbial proteins and/or microbial nucleic acids and/or microbial carbohydrate moieties and are isolated from culture supernatants. The natural production of such vesicles can be artificially enhanced (eg, increased) or decreased by manipulating the environment in which the bacterial cells are being cultured (eg, by media or temperature changes). In addition, smEV composition can be modified to reduce, increase, add or remove microbial components or foreign substances to alter efficacy, immunostimulation, stability, immunostimulatory capacity, stability, organ targeting (e.g., lymph nodes), absorption (e.g., gastrointestinal tract) and/or yield (e.g., thereby altering efficacy). As used herein, the term "purified smEV composition" or "smEV composition" refers to a preparation of smEVs that has been isolated from at least one associated species found in source material (e.g., from at least one other microbial component) or Any material associated with smEVs in any method used to prepare the formulation is isolated. It can also refer to a composition that has been significantly enriched for a particular component. "Processed microbial extracellular vesicles" (pmEVs) are microbial membrane fractions purified from artificially lysed microorganisms (eg, bacteria) (eg, fractions of microbial membranes that have been separated from other intracellular microbial cell components) A collection that does not occur in nature, and which may comprise particles of varying or selected size ranges depending on the purification method. By chemically disrupting (for example, by lysozyme and/or lysostaphin) and/or physically disrupting (for example, by mechanical force) microbial cells and by centrifugation and/or ultracentrifugation or other methods The pmEV pool was obtained by fractionating the intracellular fraction. The resulting pmEV mixture contains enriched microbial membranes and their components (e.g., peripheral associated or intact membrane proteins, lipids, glycans, polysaccharides, carbohydrates, other polymers) such that, relative to intact microorganisms, microbial membrane The concentration of the fraction increases, and the concentration of the intracellular content decreases (eg, dilution). For Gram-positive bacteria, pmEVs can include the cell membrane or the plasma membrane. For Gram-negative bacteria, pmEVs can include inner and outer membranes. pmEVs can be modified to increase purity, adjust the size of particles in the composition, and/or be modified to reduce, increase, add or remove microbial components or foreign substances to alter efficacy, immunostimulation, stability, immunostimulatory capacity, Stability, organ targeting (e.g. lymph nodes), absorption (e.g. gastrointestinal tract) and/or yield (e.g. thereby altering efficacy). pmEVs can be modified by adding, removing, enriching or diluting specific components, including intracellular components from the same or other microorganisms. As used herein, the term "purified pmEV composition" or "pmEV composition" refers to a preparation of pmEVs that has been isolated from at least one associated species found in source material (e.g., from at least one other microbial component) or Any material associated with pmEV in any method used to prepare the formulation is isolated. It can also refer to a composition that has been significantly enriched for a particular component.

「微生物組」在廣義上指棲居於受試者或患者的身體部位上或中的微生物。微生物組中的微生物可包括細菌、病毒、真核微生物和/或病毒。微生物組中的各個微生物可以是有代謝活性的、休眠的、潛伏的或作為孢子存在，可以浮游生物形式存在或存在於生物膜中，或能以可持續或短暫的方式存在於該微生物組中。微生物組可以是共生或健康狀態微生物組或疾病狀態微生物組。微生物組對受試者或患者而言可以是天然的，或微生物組的組分可因健康狀態（例如，癌前狀態或癌狀態）或處理條件（例如，抗生素治療、暴露於不同微生物）的變化而經調整、引入或消除。在一些方面，微生物組出現於黏膜表面。在一些方面，微生物組係腸道微生物組。在一些方面，微生物組係腫瘤微生物組。"Microbiome" refers broadly to the microorganisms that inhabit a body part of a subject or patient. Microorganisms in a microbiome can include bacteria, viruses, eukaryotic microorganisms, and/or viruses. Individual microorganisms in the microbiome may be metabolically active, dormant, latent, or exist as spores, may exist as plankton or in biofilms, or may be present in the microbiome in a sustainable or transient manner . The microbiome can be a commensal or healthy state microbiome or a disease state microbiome. The microbiome can be native to the subject or patient, or components of the microbiome can vary from state of health (e.g., precancerous or cancerous state) or treatment conditions (e.g., antibiotic treatment, exposure to different microorganisms) adjusted, introduced or eliminated. In some aspects, the microbiome is present on mucosal surfaces. In some aspects, the microbiome is a gut microbiome. In some aspects, the microbiome is a tumor microbiome.

組織或樣本的「微生物組譜（microbiome profile）」或「微生物組簽名（microbiome signature）」係指微生物組的細菌組成的至少部分表徵。在一些實施方式中，微生物組譜指示是否至少2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100或更多個細菌菌株存在於微生物組中或不存在於微生物組中。在一些實施方式中，微生物組譜指示是否至少2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50、55、60、65、70、75、80、85、90、95、100或更多個癌症相關細菌菌株存在於樣本中。在一些實施方式中，微生物組譜指示樣本中檢測的各細菌菌株的相對量或絕對量。在一些實施方式中，微生物組譜係癌症相關微生物組譜。癌症相關微生物組譜係以比一般群體更大的頻率出現於患有癌症的受試者中的微生物組譜。在一些實施方式中，相較於正常存在於取自未患癌症的個體的在其他方面當量的組織或樣本的微生物組中的細菌，該癌症相關微生物組譜包含更大數量或量的癌症相關細菌。A "microbiome profile" or "microbiome signature" of a tissue or sample refers to at least a partial characterization of the bacterial composition of the microbiome. In some embodiments, the microbiome profile indicates whether at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more bacterial strains are present in the microbiome or absent in the microbiome. In some embodiments, the microbiome profile indicates whether at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 or more cancer-associated bacterial strains are present in the sample. In some embodiments, the microbiome profile is indicative of the relative or absolute amount of each bacterial strain detected in the sample. In some embodiments, the microbiome profile is a cancer-associated microbiome profile. Cancer-Associated Microbiome Profiles Microbiome profiles in subjects with cancer appear at a greater frequency than the general population. In some embodiments, the cancer-associated microbiome profile comprises a greater number or amount of cancer-associated microbiomes than bacteria normally present in the microbiome of an otherwise equivalent tissue or sample taken from an individual without cancer. bacteria.

關於細菌的「經修飾的」在廣義上指自野生型形式已經發生變化的細菌。細菌修飾可以產生自工程菌。細菌修飾的實例包括遺傳修飾、基因表現修飾、表型修飾、配製修飾、化學修飾及劑量或濃度。經改善的性質的實例描述於整個說明書中且包括（例如）減毒、營養缺陷、歸巢或抗原性。表型修飾可包括（以實例說明的）細菌在修飾細菌的表型的培養基中生長以便增加或降低毒力。"Modified" in reference to a bacterium refers broadly to a bacterium that has changed from its wild-type form. Bacterial modifications can be produced from engineered bacteria. Examples of bacterial modifications include genetic modification, gene expression modification, phenotypic modification, formulation modification, chemical modification and dosage or concentration. Examples of improved properties are described throughout the specification and include, for example, attenuation, auxotrophy, homing or antigenicity. Phenotype modification may include (by way of example) growing the bacteria in a medium that modifies the phenotype of the bacteria in order to increase or decrease virulence.

如本文所用的「腫瘤生物群系（oncobiome）」包含致腫瘤的和/或癌症相關的微生物群，其中該微生物群包含病毒、細菌、真菌、原生生物、寄生蟲或另一種微生物中的一種或多種。An "oncobiome" as used herein includes a tumorigenic and/or cancer-associated microbiome comprising one or more of a virus, bacteria, fungus, protozoa, parasite, or another microorganism Various.

「腫瘤營養性（Oncotrophic）」或「嗜腫瘤（oncophilic）」微生物及細菌係在癌症微環境中高度相關或存在的微生物。它們可被優先選擇用於該環境中，優先在癌症微環境中生長或適應所述環境。"Oncotrophic" or "oncophilic" microorganisms and bacteria are microorganisms that are highly associated or present in the cancer microenvironment. They can be preferentially selected for use in this environment, preferentially growing in or adapting to the cancer microenvironment.

「運算分類單元」及「OTU」係指系統發生樹中的末端葉且藉由核酸序列（例如整個基因組或特定基因序列及所有與此核酸序列在物種層面共用序列同一性的序列）來定義。在一些實施方式中，特定基因序列可為16S序列或16S序列的一部分。在其他實施方式中，對兩種實體的整個基因組進行定序並進行比較。在另一個實施方式中，可以基因方式比較所選區域（例如多基因座序列標籤（MLST）、特定基因或基因集）。對於16S而言，整個16S或一些16S可變區中共有≥ 97%平均核苷酸同一性的OTU可視為相同OTU。參見，例如Claesson MJ, Wang Q, O’Sullivan O, Greene-Diniz R, Cole JR, Ross RP, 和O’Toole PW. 2010. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions[使用串聯可變16S rRNA基因區解析高度複雜的微生物群組成的兩種下一代定序技術的比較].Nucleic Acids Res[核酸研究] 38: e200.Konstantinidis KT, Ramette A及Tiedje JM.2006.The bacterial species definition in the genomic era[基因組時代的細菌物種類定義].Philos Trans R Soc Lond B Biol Sci[倫敦皇家學會B輯：生物科學哲學學報] 361: 1929-1940。對於完整基因組、MLST、特定基因（除16S外）或基因集而言，共有≥ 95%平均核苷酸同一性的OTU可視為相同OTU。例如參見Achtman M及Wagner M. 2008.Microbial diversity and the genetic nature of microbial species[微生物多樣性和微生物物種的遺傳性質].Nat. Rev. Microbiol.[微生物自然評論] 6: 431–440.Konstantinidis KT, Ramette A及Tiedje JM.2006.The bacterial species definition in the genomic era[基因組時代的細菌物種類定義].Philos Trans R Soc Lond B Biol Sci[倫敦皇家學會B輯：生物科學哲學學報] 361: 1929-1940。通常藉由比較生物體之間的序列來定義OTU。通常，具有不超過95%序列同一性的序列並不視為形成相同OTU的一部分。還可藉由核苷酸標誌或基因、尤其高度保守基因（例如「管家」基因）或其組合的任一組合來表徵OTU。本文提供可分配（例如）屬、物種及系統發育進化枝的運算分類單元（OTU）。"Operational Taxonomic Unit" and "OTU" refer to terminal leaves in a phylogenetic tree and are defined by a nucleic acid sequence, such as an entire genome or a specific gene sequence and all sequences that share sequence identity with this nucleic acid sequence at the species level. In some embodiments, the specific gene sequence can be a 16S sequence or a part of a 16S sequence. In other embodiments, the entire genomes of the two entities are sequenced and compared. In another embodiment, selected regions (eg, multilocus sequence tags (MLST), specific genes or sets of genes) can be compared genetically. For 16S, OTUs that share ≥97% average nucleotide identity across the entire 16S or some 16S variable regions can be considered identical OTUs. See, for example, Claesson MJ, Wang Q, O'Sullivan O, Greene-Diniz R, Cole JR, Ross RP, and O'Toole PW. 2010. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions[Comparison of two next-generation sequencing techniques using tandem variable 16S rRNA gene regions to dissect the composition of highly complex microbiota].Nucleic Acids Res[Nucleic Acids Research] 38: e200. Tiedje JM.2006.The bacterial species definition in the genomic era[The definition of bacterial species in the genome era].Philos Trans R Soc Lond B Biol Sci[The Royal Society of London Series B: Philosophy of Biological Sciences] 361: 1929-1940. For the complete genome, MLST, specific genes (except 16S) or gene sets, OTUs sharing ≥95% average nucleotide identity can be considered identical OTUs. See eg Achtman M and Wagner M. 2008. Microbial diversity and the genetic nature of microbial species. Nat. Rev. Microbiol. 6: 431–440. Konstantinidis KT , Ramette A and Tiedje JM.2006.The bacterial species definition in the genomic era.Philos Trans R Soc Lond B Biol Sci[Royal Society of London Series B: Philosophical Journal of Biological Sciences] 361: 1929 -1940. OTUs are typically defined by comparing sequences between organisms. In general, sequences with no more than 95% sequence identity are not considered to form part of the same OTU. OTUs can also be characterized by any combination of nucleotide markers or genes, especially highly conserved genes (such as "housekeeping" genes), or combinations thereof. This article provides operational taxonomic units (OTUs) to which, for example, genera, species, and phylogenetic clades can be assigned.

如本文所用，如果基因在至少一些條件下在工程化細菌中的表現水平高於相同物種的野生型細菌在相同條件下的表現水平，則該基因在細菌中「過度表現」。類似地，如果基因在至少一些條件下在工程化細菌中的表現水平低於相同物種的野生型細菌在相同條件下的表現水平，則該基因在細菌中「表現不足」。As used herein, a gene is "over-represented" in a bacterium if, under at least some conditions, the gene is expressed at a higher level in the engineered bacterium than in a wild-type bacterium of the same species under the same conditions. Similarly, a gene is "underrepresented" in a bacterium if, under at least some conditions, the gene is expressed at a lower level in the engineered bacterium than in a wild-type bacterium of the same species under the same conditions.

術語「多核苷酸」及「核酸」可互換使用。它們係指任何長度的核苷酸的聚合形式（去氧核糖核苷酸或核糖核苷酸）或其類似物。多核苷酸可具有任何三維結構，且可實施任何功能。多核苷酸的非限制性實例如下：基因或基因片段的編碼或非編碼區域、定義自連鎖分析的多個基因座（loci）（基因座（locus））、外顯子、內含子、信使RNA（mRNA）、微小RNA（miRNA）、緘默RNA（siRNA）、轉移RNA、核糖體RNA、核糖酶、cDNA、重組多核苷酸、分支多核苷酸、質體、載體、任何序列的分離的DNA、任何序列的分離的RNA、核酸探針及引物。多核苷酸可包含經修飾的核苷酸，如甲基化核苷酸及核苷酸類似物。如果存在，則可在組裝聚合物之前或之後賦予對核苷酸結構的修飾。多核苷酸可藉由如與標記組分軛合而經進一步修飾。在本文提供的所有核酸序列中，U核苷酸可與T核苷酸互換。The terms "polynucleotide" and "nucleic acid" are used interchangeably. They refer to polymeric forms of nucleotides of any length (deoxyribonucleotides or ribonucleotides) or analogs thereof. A polynucleotide can have any three-dimensional structure, and can perform any function. Non-limiting examples of polynucleotides are the following: coding or non-coding regions of a gene or gene fragment, multiple loci (locus) defined from linkage analysis, exons, introns, messengers RNA (mRNA), microRNA (miRNA), silencing RNA (siRNA), transfer RNA, ribosomal RNA, ribozyme, cDNA, recombinant polynucleotides, branched polynucleotides, plastids, vectors, isolated DNA of any sequence , isolated RNA of any sequence, nucleic acid probes and primers. A polynucleotide may comprise modified nucleotides, such as methylated nucleotides and nucleotide analogs. Modifications to the nucleotide structure, if present, can be imparted either before or after assembly of the polymer. Polynucleotides can be further modified, eg, by conjugation with labeling components. In all nucleic acid sequences provided herein, U nucleotides are interchangeable with T nucleotides.

如本文所用，術語「預防」受試者中的疾病或病症係指對受試者施用藥劑治療，例如，施用一種或多種藥劑（例如，藥劑），使得疾病或病症的至少一個症狀的發作被延遲或預防。As used herein, the term "preventing" a disease or condition in a subject refers to administering an agent for treatment to the subject, e.g., administering one or more agents (e.g., agents) such that the onset of at least one symptom of the disease or condition is prevented delay or prevent.

如本文所用，物質基本上不含其他組分時係「純的」。術語「純化（purify）」或「進行純化（purifying）」及「純化的（purified）」係指mEV（例如smEV和/或pmEV）製劑或其他材料已與最初產生或形成（例如，無論在自然中或在實驗環境中）時或在初始產生後的任何時間期間與的相關聯的至少一些組分分離。若如果mEV（例如smEV和/或pmEV）製劑或組成物在產生時或產生後與（諸如）一種或多種其他細菌組分分離，則該mEV（例如smEV和/或pmEV）製劑或組成物可被視為純化的，並且純化的微生物或微生物群體可含有其他材料多達約10%、約20%、約30%、約40%、約50%、約60%、約70%、約80%、約90%或超過約90%且仍被視為「純化的」。在一些實施方式中，純化的mEV（例如smEV和/或pmEV）係超過約80%、約85%、約90%、約91%、約92%、約93%、約94%、約95%、約96%、約97%、約98%、約99%、或超過約99%純的。mEV（例如smEV和/或pmEV）組成物（或製劑）例如從殘餘生境產物純化。As used herein, a substance is "pure" when it is substantially free of other components. The terms "purify" or "purifying" and "purified" refer to mEV (such as smEV and/or pmEV) preparations or other materials that have been in or in an experimental setting) or during any time after initial production from at least some of the components associated with it. If an mEV (e.g. smEV and/or pmEV) preparation or composition is separated from, for example, one or more other bacterial components during or after production, the mEV (e.g. smEV and/or pmEV) preparation or composition may be Considered purified, and a purified microorganism or population of microorganisms may contain as much as about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80% of other materials , about 90%, or more than about 90% and still be considered "purified." In some embodiments, the purified mEV (e.g., smEV and/or pmEV) is greater than about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95% , about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. The mEV (eg smEV and/or pmEV) composition (or preparation) is eg purified from residual habitat products.

如本文所用，術語「經純化的mEV組成物」或「mEV組成物」係指如下的製劑：其包括已與源材料或在用以產生該製劑的任何方法中與mEV（如smEV和/或pmEV）締合的任何材料中發現的至少一種締合物質分離（例如，與至少一種其他細菌組分分離）的mEV（如smEV和/或pmEV）。它還指已經顯著富集或濃縮的組成物。在一些實施方式中，mEV（如smEV和/或pmEV）被濃縮2倍、3倍、4倍、5倍、10倍、100倍、1000倍、10,000倍或超過10,000倍。As used herein, the term "purified mEV composition" or "mEV composition" refers to a preparation comprising mEVs (such as smEV and/or mEV (such as smEV and/or pmEV) in which at least one associated species is isolated (eg, from at least one other bacterial component) found in any material associated with pmEV). It also refers to a composition that has been significantly enriched or concentrated. In some embodiments, mEVs (such as smEVs and/or pmEVs) are enriched 2-fold, 3-fold, 4-fold, 5-fold, 10-fold, 100-fold, 1000-fold, 10,000-fold, or more than 10,000-fold.

「殘餘生境產物」係指自受試者內或受試者上的微生物群生境衍生的材料。例如，微生物的發酵培養物可以含有污染物，例如其他微生物菌株或形式（例如細菌、病毒、支原體和/或真菌）。例如，微生物生存於胃腸道的糞便中、皮膚本身上、唾液中、呼吸道的黏液中或泌尿生殖道的分泌物中（即，與微生物群落相關聯的生物物質）。基本上不含殘餘生境產物意指該微生物組成物不再含有與人或動物受試者上或培養物中或人或動物受試者中的微生物環境相關聯的生物物質且是100%不含、99%不含、98%不含、97%不含、96%不含或95%不含與該微生物群落相關聯的任何污染生物物質。殘餘生境產物可包括非生物材料（包括未經消化的食物）或其可包括非所需的微生物。基本上不含殘餘生境產物亦可意指該微生物組成物不含有來自培養物污染物或人或動物的可檢測細胞且意指僅微生物細胞係可檢測的。在一項實施方式中，大體上不含殘餘生境產物亦可意指該微生物組成物不含有可檢測的病毒（包括細菌、病毒（例如，噬菌體））、真菌、支原體污染物。在另一個實施方式中，這意味著與微生物細胞相比，該微生物組成物中少於1 x 10 -2%、1 x 10 -3%、1 x 10 -4%、1 x 10 -5%、1 x 10 -6%、1 x 10 -7%、1 x 10 -8%的有活力細胞係人或動物細胞。達到此純度之方法有很多，該等方法中無任何一者係限制性的。因此，污染物可經由藉由在固體培養基上對單菌落進行多個畫線步驟，直至來自系列性單菌落的複製（例如但不限於兩個）畫線已顯示僅單一菌落形態來分離所需成分而減少。可替代地，污染物的減少可藉由多輪連續稀釋至單一所需細胞（例如，10 -8或10 -9的稀釋），諸如藉由多個10倍連續稀釋完成。此可藉由顯示多個經分離的菌落具有相似細胞形狀及革蘭氏染色行為進一步證實。用於證實足夠的純度的其他方法包括遺傳分析（例如，PCR、DNA定序）、血清學及抗原分析、酶及代謝分析及使用儀器之方法，諸如使用自污染物區分所需成分的試劑的流動式細胞測量術。 "Residual habitat product" means material derived from the habitat of microbiota in or on a subject. For example, a fermentation culture of microorganisms may contain contaminants, such as other strains or forms of microorganisms (eg, bacteria, viruses, mycoplasma, and/or fungi). For example, microorganisms live in the feces of the gastrointestinal tract, on the skin itself, in saliva, in the mucus of the respiratory tract or in secretions of the urogenital tract (ie, biological matter associated with the microbiome). Substantially free of residual habitat products means that the microbial composition no longer contains biological material associated with the microbial environment on or in culture on or in a human or animal subject and is 100% free , 99% free, 98% free, 97% free, 96% free, or 95% free of any contaminating biological material associated with the microbial community. Residual habitat products may include non-living material (including undigested food) or it may include undesirable microorganisms. Substantially free of residual habitat products can also mean that the microbial composition contains no detectable cells from culture contaminants or humans or animals and means that only microbial cell lines are detectable. In one embodiment, substantially free of residual habitat products can also mean that the microbial composition is free of detectable viral (including bacteria, viral (eg, phage)), fungal, mycoplasma contaminants. In another embodiment, this means less than 1 x 10 -2 %, 1 x 10 -3 %, 1 x 10 -4 %, 1 x 10 -5 % in the microbial composition compared to microbial cells , 1 x 10 -6 %, 1 x 10 -7 %, 1 x 10 -8 % viable cell line human or animal cells. There are many ways to achieve this purity, none of which are limiting. Thus, contaminants can be isolated by performing multiple streaking steps on a single colony on solid medium until streaking from replicates (such as but not limited to two) of a serial single colony has shown only a single colony morphology. components are reduced. Alternatively, reduction of contaminants can be accomplished by multiple rounds of serial dilutions to a single desired cell (eg, 10 −8 or 10 −9 dilutions), such as by multiple 10-fold serial dilutions. This was further confirmed by showing that multiple isolated colonies had similar cell shape and Gram stain behavior. Other methods used to demonstrate adequate purity include genetic analysis (e.g., PCR, DNA sequencing), serological and antigenic analysis, enzymatic and metabolic analysis, and instrumental methods such as those using reagents to distinguish desired components from contaminants. Flow Cytometry.

如本文所用，「特異性結合」係指抗體能夠結合至預定抗原或多肽能夠結合至其預定結合配偶體。通常，抗體或多肽以對應於約10 -7M或更小K D的親和力特異性結合至其預定抗原或結合配偶體，且以相對於結合至非特異性及不相關抗原/結合配偶體（例如BSA、酪蛋白）小至少10倍、小至少100倍或不超過至少1000倍的其親和力的親和力（如藉由K D所表示）結合至預定抗原/結合配偶體。可替代地，特異性結合在廣義上更適用於二組分系統，其中一種組分係蛋白質、脂質或碳水化合物或其組合且與係蛋白質、脂質、碳水化合物或其組合的第二組分以特定方式接合。 As used herein, "specifically binds" means that an antibody is capable of binding to a predetermined antigen or a polypeptide is capable of binding to its predetermined binding partner. Typically, an antibody or polypeptide binds specifically to its intended antigen or binding partner with an affinity corresponding to a KD of about 10 −7 M or less, and with relative binding to a nonspecific and irrelevant antigen/binding partner ( For example BSA, casein) binds to the intended antigen/binding partner with an affinity (as expressed by KD ) that is at least 10 times less, at least 100 times less or no more than at least 1000 times less than its affinity. Alternatively, specific binding is more broadly applicable to two-component systems, where one component is a protein, lipid, or carbohydrate, or a combination thereof, and a second component is a protein, lipid, carbohydrate, or combination thereof. joint in a certain way.

「菌株」係指具有基因特徵的細菌物種的成員，該特徵使該成員可與相同細菌物種的密切相關成員區分開來。基因特徵可為不存在至少一種基因的全部或一部分、不存在至少一個調控區（例如啟動子、終止子、核糖開關、核糖體結合位點）的全部或一部分、不存在（「消除」）至少一種天然質體、存在至少一種重組基因、存在至少一種突變基因、存在至少一種外來基因（衍生自另一物種的基因）、存在至少一種突變調控區（例如啟動子、終止子、核糖開關、核糖體結合位點）、存在至少一種非天然質體、存在至少一種抗生素抗性盒或其組合。可藉由PCR擴增且視需要隨後進行一個或多個目的基因組區域或全基因組的DNA定序來鑒別不同菌株之間的基因簽名。如果一種菌株（與相同物種的另一種菌株相比）已獲得或失去抗生素抗性或獲得或失去生物合成能力（例如營養缺陷型菌株），則可藉由選擇或反選擇分別使用抗生素或營養物/代謝物來區分菌株。"Strain" means a member of a bacterial species having a genetic characteristic that distinguishes that member from closely related members of the same bacterial species. Genetic features can be the absence of all or a portion of at least one gene, the absence of all or a portion of at least one regulatory region (e.g., promoter, terminator, riboswitch, ribosome binding site), the absence ("elimination") of at least A native plastid, presence of at least one recombinant gene, presence of at least one mutated gene, presence of at least one foreign gene (gene derived from another species), presence of at least one mutated regulatory region (e.g. promoter, terminator, riboswitch, ribose plastid binding site), the presence of at least one non-native plastid, the presence of at least one antibiotic resistance cassette, or a combination thereof. Gene signatures between different strains can be identified by PCR amplification followed by DNA sequencing of one or more genomic regions of interest or the whole genome, if desired. If a strain (compared to another strain of the same species) has acquired or lost antibiotic resistance or acquired or lost biosynthetic capacity (e.g. auxotrophic strains), antibiotics or nutrients, respectively, can be used by selection or counter-selection /metabolites to differentiate strains.

術語「受試者」或「患者」係指任何哺乳動物。描述為「有需要」的受試者或患者係指需要治療（或預防）疾病的人。哺乳動物（即哺乳類動物）包括人、實驗室動物（例如靈長類動物、大鼠、小鼠）、家畜（例如牛、綿羊、山羊、豬）及家庭寵物（例如狗、貓、齧齒類動物）。受試者可以是人。受試者可以是非人哺乳動物，包括但不限於：狗、貓、牛、馬、豬、驢、山羊、駱駝、小鼠、大鼠、天竺鼠、綿羊、美洲駝、猴、大猩猩或黑猩猩。受試者可以是健康的，或可患有任一發展階段的癌症，其中任一階段由癌症相關或致病病原體引起或伺機性地支持該病原體，或受試者可能處於發生癌症或向其他受試者傳播癌症相關或癌症致病病原體的風險中。在一些實施方式中，受試者患有肺癌、膀胱癌、前列腺癌、漿細胞瘤、結直腸癌、直腸癌、梅克爾細胞癌、唾液腺癌、卵巢癌和/或黑色素瘤。受試者可以具有腫瘤。受試者可以具有展示增強的大型胞飲作用的腫瘤，其中該過程的潛在基因組學包括Ras活化。在其他實施方式中，受試者患有另一種癌症。在一些實施方式中，受試者已經接受癌症療法。The term "subject" or "patient" refers to any mammal. A subject or patient described as "in need thereof" is a human in need of treatment (or prevention) of a disease. Mammals (i.e., mammals) include humans, laboratory animals (e.g., primates, rats, mice), livestock (e.g., cattle, sheep, goats, pigs), and household pets (e.g., dogs, cats, rodents ). A subject can be a human. The subject can be a non-human mammal including, but not limited to, a dog, cat, cow, horse, pig, donkey, goat, camel, mouse, rat, guinea pig, sheep, llama, monkey, gorilla, or chimpanzee. The subject may be healthy, or may have cancer at any stage of development, either of which is caused by or opportunistically supported by a cancer-associated or causative pathogen, or the subject may be at risk of developing cancer or contributing to other The subject is at risk of transmitting cancer-related or cancer-causing pathogens. In some embodiments, the subject has lung cancer, bladder cancer, prostate cancer, plasmacytoma, colorectal cancer, rectal cancer, Merkel cell carcinoma, salivary gland cancer, ovarian cancer, and/or melanoma. The subject can have a tumor. The subject may have a tumor exhibiting enhanced macropinocytosis, where the underlying genomics of this process includes Ras activation. In other embodiments, the subject has another cancer. In some embodiments, the subject has received cancer therapy.

如本文所用，在用包含本文所述之細菌或mEV的藥劑（例如，包含細菌或mEV的藥劑）治療的受試者中的「系統性作用」係指在胃腸道外的一個或多個部位發生的生理作用。一種或多種系統性作用可以由免疫調節（例如，藉由增加和/或減少一種或多種免疫細胞類型或亞型（例如，CD8+ T細胞）和/或一種或多種細胞介素）產生。此類一種或多種系統性作用可能是由本文所述之細菌或mEV對胃腸道中的免疫細胞或其他細胞（例如上皮細胞）調節的結果，然後這直接地或間接地導致胃腸道外的一個或多個生物化學途徑的活性改變（活化和/或失活）。系統性作用可包括治療或預防受試者的疾病或病症。As used herein, a "systemic effect" in a subject treated with an agent comprising a bacterium or mEV described herein (e.g., an agent comprising a bacterium or mEV) means occurring at one or more sites outside the gastrointestinal tract physiological effects. One or more systemic effects can result from immune modulation (eg, by increasing and/or decreasing one or more immune cell types or subtypes (eg, CD8+ T cells) and/or one or more cytokines). Such one or more systemic effects may be the result of modulation of immune cells or other cells (such as epithelial cells) in the gastrointestinal tract by the bacteria or mEVs described herein, which then directly or indirectly lead to one or more outside the gastrointestinal tract. Altered activity (activation and/or inactivation) of a biochemical pathway. Systemic effects can include treating or preventing a disease or condition in a subject.

如本文所用，術語「治療」受試者疾病或「治療」患有或懷疑患有疾病的受試者係指向受試者施用藥物治療（例如施用一種或多種藥劑），從而降低至少一種疾病症狀或預防其惡化。因此，在一個實施方式中，「治療」尤其是指延遲進展、促進緩解、誘導緩解、增大緩解、加速恢復、增加功效或降低替代治療的抗性，或其組合。As used herein, the term "treating" a disease in a subject or "treating" a subject having or suspected of having a disease means administering to the subject a pharmaceutical treatment (e.g., administering one or more agents) such that at least one symptom of the disease is reduced or prevent its deterioration. Thus, in one embodiment "treating" refers inter alia to delaying progression, promoting remission, inducing remission, increasing remission, accelerating recovery, increasing efficacy or reducing resistance to alternative treatments, or a combination thereof.

如本文所使用的，如果一個值高出任何數量，則該值「大於」另一個值（例如，100、50、20、12、11、10.6、10.1、10.01和10.001中的每一個係至少10）。類似地，如本文所使用的，如果一個值低出任何數量，則該值「小於」另一個值（例如，1、2、4、6、8、9、9.2、9.4、9.6、9.8、9.9、9.99、9.999中的每一個係不超過10）。相反，如本文所使用的，當測試值四捨五入到錨定值時，測試值「係」錨定值（例如，如果「成分質量係總質量的10%」（在這種情況下，錨定值係10%），則測試值9.5、9.6、9.7、9.8、9.9、10、10.1、10.2、10.3和10.4也將滿足「成分質量係總質量的10%」特徵。 細菌 As used herein, a value is "greater than" another value if the value is higher by any amount (for example, each of 100, 50, 20, 12, 11, 10.6, 10.1, 10.01, and 10.001 is at least 10 ). Similarly, as used herein, a value is "less than" another value if it is lower by any amount (eg, 1, 2, 4, 6, 8, 9, 9.2, 9.4, 9.6, 9.8, 9.9 , 9.99, and 9.999 each of which shall not exceed 10). Conversely, as used herein, when a test value is rounded to an anchor value, the test value "relates to" the anchor value (for example, if "the mass of an ingredient is 10% of the total mass" (in which case the anchor value is 10%), then the test values 9.5, 9.6, 9.7, 9.8, 9.9, 10, 10.1, 10.2, 10.3 and 10.4 will also satisfy the feature of "component mass is 10% of the total mass". bacteria

本文公開的藥物組成物的藥劑可以包含細菌和/或微生物胞外囊泡（mEV）（例如smEV和/或pmEV）。例如，本文公開的藥物組成物的藥劑可以包含粉末，該粉末包含細菌和/或微生物胞外囊泡（mEV）（例如smEV和/或pmEV）。在包含細菌和mEV的藥劑中，mEV可以與藥劑的細菌來自相同的細菌起源（例如，相同的菌株）。藥劑可以包含來自一個或多個菌株的細菌和/或mEV。The agents of the pharmaceutical compositions disclosed herein may comprise bacterial and/or microbial extracellular vesicles (mEVs) (eg smEVs and/or pmEVs). For example, a dose of a pharmaceutical composition disclosed herein may comprise a powder comprising bacterial and/or microbial extracellular vesicles (mEVs) (eg, smEVs and/or pmEVs). In an agent comprising bacteria and mEV, the mEV may be from the same bacterial origin (eg, the same strain) as the bacteria of the agent. A medicament may comprise bacteria and/or mEV from one or more strains.

在一些實施方式中，對藥劑的細菌或藥劑的mEV自其獲得的細菌進行修飾以降低毒性或其他不利影響；提高遞送（例如口服遞送）（例如，藉由改良耐酸性、黏液黏著性和/或滲透性和/或對膽汁酸的抗性、消化酶、對抗微生物肽的抗性和/或抗體中和）；靶向所需細胞類型（例如，M細胞、杯狀細胞、腸上皮細胞、樹突細胞、巨噬細胞）；增強細菌和/或mEV的免疫調節和/或治療效果（例如單獨或與另一治療劑組合）；和/或藉由細菌和/或mEV（如smEV和/或pmEV）（例如藉由修飾地產生多糖、纖毛、傘毛、黏附素）增強免疫活化或抑制。在一些實施方式中，本文描述的工程改造的細菌被修飾以改善細菌和/或mEV（例如smEV和/或pmEV）製造（例如，更高的耐氧性、穩定性、改善的凍融耐受性、較短的產生時間）。例如，在一些實施方式中，本文描述的工程改造的細菌包括具有一種或多種遺傳改變的細菌，此改變包含於細菌染色體或內源性質體和/或一或多個外源性質體上的一或多個核苷酸的插入、刪除、易位或取代，或其任何組合，其中該遺傳改變可導致一或多個基因的過表現和/或低表現。工程改造的細菌可使用本領域中已知的任何技術產生，包括（但不限於）定點誘變、轉座子誘變、敲除、敲入、聚合酶鏈反應誘變、化學誘變、紫外線誘變、轉形（化學或藉由電穿孔）、噬菌體轉導、定向演化或其任何組合。In some embodiments, the bacteria of the agent, or the bacteria from which the mEVs of the agent were obtained, are modified to reduce toxicity or other adverse effects; to improve delivery (e.g., oral delivery) (e.g., by improving acid resistance, mucoadhesion, and/or or permeability and/or resistance to bile acids, digestive enzymes, resistance to antimicrobial peptides and/or antibody neutralization); targeting desired cell types (e.g., M cells, goblet cells, intestinal epithelial cells, dendritic cells, macrophages); enhance the immunomodulatory and/or therapeutic effect of bacteria and/or mEV (e.g. alone or in combination with another therapeutic agent); and/or or pmEV) (eg, by modified production of polysaccharides, cilia, fimbriae, adhesins) to enhance immune activation or suppression. In some embodiments, the engineered bacteria described herein are modified to improve bacterial and/or mEV (e.g., smEV and/or pmEV) production (e.g., higher oxygen tolerance, stability, improved freeze-thaw tolerance nature, shorter generation time). For example, in some embodiments, the engineered bacteria described herein include bacteria with one or more genetic alterations contained on the bacterial chromosome or on an endogenous plastid and/or on one or more exogenous plastids. Insertion, deletion, translocation or substitution of one or more nucleotides, or any combination thereof, wherein the genetic alteration can result in over- and/or under-expression of one or more genes. Engineered bacteria can be generated using any technique known in the art, including but not limited to site-directed mutagenesis, transposon mutagenesis, knockout, knockin, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet light Mutagenesis, transformation (chemical or by electroporation), phage transduction, directed evolution, or any combination thereof.

可用作本文描述的藥劑的細菌和/或mEV（例如smEV和/或pmEV）來源的細菌的分類學組（例如，綱、目、科、屬、種或菌株）的實例係本文提供的術語（例如，表1、表2、表3和/或表4和/或說明書中其他地方（例如，表J）列舉的）。在一些實施方式中，細菌菌株係具有與本文列舉的菌株有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%或99.9%序列同一性的基因組的細菌菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係腫瘤營養性細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係免疫調節細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係免疫刺激細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係免疫抑制細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係免疫調節細菌。在某些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係從本文提供的細菌菌株的組合產生的。在一些實施方式中，該組合係至少2、3、4、5、6、7、8、9、10、11、12、13、14、15、20、25、30、35、40、45或50個細菌菌株的組合。在一些實施方式中，組合包括藥劑的細菌或藥劑的mEV自其獲得的細菌，該細菌來自本文列舉的細菌菌株和/或具有與本文列舉的（例如，表1、表2、表3和/或表4中列舉的和/或說明書中其他地方（例如，表J）列舉的）菌株有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%或99.9%序列同一性的基因組的細菌菌株。在某些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係從本文提供的細菌菌株產生的。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌來自本文列舉的（例如，表1、表2、表3和/或表4中列舉的和/或說明書中其他地方（例如，表J）列舉的）細菌菌株和/或具有與本文列舉的（例如，表1、表2、表3和/或表4中列舉的和/或說明書中其他地方（例如，表J）列舉的）菌株有至少80%、85%、90%、91%、92%、93%、94%、95%、96%、97%、98%、99%、99.1%、99.2%、99.3%、99.4%、99.5%、99.6%、99.7%、99.8%或99.9%序列同一性的基因組的細菌菌株。Examples of taxonomic groups (e.g., classes, orders, families, genus, species, or strains) of bacteria and/or mEV (e.g., smEV and/or pmEV)-derived bacteria useful as agents described herein are the terms provided herein (eg, listed in Table 1, Table 2, Table 3, and/or Table 4 and/or elsewhere in the specification (eg, Table J)). In some embodiments, the bacterial strain has at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, Bacterial strains with genomes of 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an oncotrophic bacterium. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an immunomodulatory bacterium. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an immunostimulatory bacterium. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an immunosuppressive bacterium. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an immunomodulatory bacterium. In certain embodiments, the bacterium of the medicament, or the bacterium from which the mEV of the medicament was obtained, is produced from a combination of bacterial strains provided herein. In some embodiments, the combination is at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, 30, 35, 40, 45 or Combination of 50 bacterial strains. In some embodiments, the combination comprises a bacterium of the medicament or a bacterium from which the mEV of the medicament was obtained, which is from a bacterial strain listed herein and/or has a bacterial strain similar to that listed herein (e.g., Table 1, Table 2, Table 3, and/or or those listed in Table 4 and/or listed elsewhere in the specification (e.g., Table J)) have at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96 %, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity of the bacterial strain genome. In certain embodiments, the bacterium of the medicament, or the bacterium from which the mEV of the medicament was obtained, is produced from a bacterial strain provided herein. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is from a bacterium listed herein (e.g., listed in Table 1, Table 2, Table 3, and/or Table 4 and/or elsewhere in the specification (e.g., , Table J) bacterial strains and/or have a ) strains with at least 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.1%, 99.2%, 99.3%, Bacterial strains with genomes of 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, or 99.9% sequence identity.

在一些實施方式中，藥劑包含分離的小韋榮氏球菌細菌（例如，來自一種或多種細菌菌株（例如，目的細菌）（例如，其治療有效量））。例如，其中藥劑的至少50%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%的含量係分離的小韋榮氏球菌細菌（例如目的細菌）。In some embodiments, the medicament comprises an isolated Veillonella parvum bacterium (eg, from one or more bacterial strains (eg, the bacterium of interest) (eg, a therapeutically effective amount thereof)). For example, wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the agent is isolated Veillonella parvum bacteria (eg, the bacterium of interest).

在一些實施方式中，藥劑包含分離的小韋榮氏球菌細菌（例如，來自一種或多種細菌菌株（例如，目的細菌）（例如，其治療有效量））。例如，其中藥劑的至少50%、至少75%、至少80%、至少85%、至少90%、至少95%或至少99%的含量係分離的小韋榮氏球菌細菌（例如目的細菌）。In some embodiments, the medicament comprises an isolated Veillonella parvum bacterium (eg, from one or more bacterial strains (eg, the bacterium of interest) (eg, a therapeutically effective amount thereof)). For example, wherein at least 50%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% of the agent is isolated Veillonella parvum bacteria (eg, the bacterium of interest).

在一些實施方式中，小韋榮氏球菌細菌來自與小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）的核苷酸序列具有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，小韋榮氏球菌細菌來自與小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）的核苷酸序列具有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，普雷沃菌屬細菌來自小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）。In some embodiments, the Veillonella parvum bacterium is from a nucleotide sequence having at least 90% (or at least 97%) of the genome, 16S and/or Strains with CRISPR sequence identity. In some embodiments, the Veillonella parvum bacterium is from a strain that has at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of Veillonella parvum strain A (ATCC Accession No. PTA-125691) . In some embodiments, the Prevotella bacterium is from Veillonella parvum strain A (ATCC Accession No. PTA-125691).

在一些實施方式中，藥物組成物中至少50%、60%、70%、80%或90%的細菌係小韋榮氏球菌菌株A。In some embodiments, at least 50%, 60%, 70%, 80%, or 90% of the bacteria in the pharmaceutical composition are Veillonella parvum strain A.

在一些實施方式中，藥劑包含至少1 x 10 5、5 x 10 5、1 x 10 6、2 x 10 6、3 x 10 6、4 x 10 6、5 x 10 6、6 x 10 6、7 x 10 6、8 x 10 6、9 x 10 6、1 x 10 7、2 x 10 7、3 x 10 7、4 x 10 7、5 x 10 7、6 x 10 7、7 x 10 7、8 x 10 7、9 x 10 7、1 x 10 8、2 x 10 8、3 x 10 8、4 x 10 8、5 x 10 8、6 x 10 8、7 x 10 8、8 x 10 8、9 x 10 8或1 x 10 9個本文所述韋榮氏球菌屬細菌（例如，小韋榮氏球菌菌株A（ATCC保藏號PTA-125691））的菌落形成單位。 In some embodiments, the medicament comprises at least 1 x 10 5 , 5 x 10 5 , 1 x 10 6 , 2 x 10 6 , 3 x 10 6 , 4 x 10 6 , 5 x 10 6 , 6 x 10 6 , 7 x 10 6 , 8 x 10 6 , 9 x 10 6 , 1 x 10 7 , 2 x 10 7 , 3 x 10 7 , 4 x 10 7 , 5 x 10 7 , 6 x 10 7 , 7 x 10 7 , 8 x 10 7 , 9 x 10 7 , 1 x 10 8 , 2 x 10 8 , 3 x 10 8 , 4 x 10 8 , 5 x 10 8 , 6 x 10 8 , 7 x 10 8 , 8 x 10 8 , 9 x 108 or 1 x 109 colony-forming units of Veillonella bacteria described herein (eg, Veillonella parvum strain A (ATCC Accession No. PTA-125691 )).

在一些實施方式中，藥劑包含至少1 x 10 5、5 x 10 5、1 x 10 6、2 x 10 6、3 x 10 6、4 x 10 6、5 x 10 6、6 x 10 6、7 x 10 6、8 x 10 6、9 x 10 6、1 x 10 7、2 x 10 7、3 x 10 7、4 x 10 7、5 x 10 7、6 x 10 7、7 x 10 7、8 x 10 7、9 x 10 7、1 x 10 8、2 x 10 8、3 x 10 8、4 x 10 8、5 x 10 8、6 x 10 8、7 x 10 8、8 x 10 8、9 x 10 8或1 x 10 9個本文所述韋榮氏球菌屬細菌（例如，小韋榮氏球菌菌株A（ATCC保藏號PTA-125691））的總細胞（例如，其中細胞數目由總細胞計數確定（例如，由庫爾特計數器確定）。 In some embodiments, the medicament comprises at least 1 x 10 5 , 5 x 10 5 , 1 x 10 6 , 2 x 10 6 , 3 x 10 6 , 4 x 10 6 , 5 x 10 6 , 6 x 10 6 , 7 x 10 6 , 8 x 10 6 , 9 x 10 6 , 1 x 10 7 , 2 x 10 7 , 3 x 10 7 , 4 x 10 7 , 5 x 10 7 , 6 x 10 7 , 7 x 10 7 , 8 x 10 7 , 9 x 10 7 , 1 x 10 8 , 2 x 10 8 , 3 x 10 8 , 4 x 10 8 , 5 x 10 8 , 6 x 10 8 , 7 x 10 8 , 8 x 10 8 , 9 x 108 or 1 x 109 total cells of Veillonella bacteria described herein (e.g., Veillonella parvum strain A (ATCC Accession No. PTA-125691)) (e.g., where the number of cells is counted by total cells Determined (for example, by a Coulter counter).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係革蘭氏陰性細菌。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is a Gram-negative bacterium.

在一些實施方式中，革蘭氏陰性細菌屬於 Negativicutes綱。 Negativicutes代表微生物的一個獨特綱，因為它們係厚壁菌門中唯一的雙層成員。該等厭氧生物可以在環境中發現，並且是人口腔和胃腸道的正常共生體。由於該等生物體具有外膜，因此對該綱的EV產率進行了研究。發現在以每個細胞為基礎，該等細菌產生大量的囊泡（10-150 EV/細胞）。來自該等生物的EV在體外測定中具有廣泛的刺激性和高效力。對其在幾種腫瘤學和炎症體內模型中治療性應用的研究顯示了其治療性潛力。 Negativicutes綱包括以下科：韋榮氏球菌科、月形單胞菌科、胺基酸球菌科和 Sporomusaceae科。 Negativicutes綱包括巨型球菌屬、月形單胞菌科屬 、 Propionospora屬和胺基酸球菌屬。示例性Negativicutes物種包括但不限於巨型球菌屬物種、菲利克斯月形單胞菌、腸胺基酸球菌、和 Propionospora屬物種。 In some embodiments, the Gram-negative bacteria belong to the class Negativicutes . Negativicutes represent a unique class of microorganisms, as they are the only bilayer members of the Firmicutes phylum. These anaerobic organisms can be found in the environment and are normal commensals of the human oral cavity and gastrointestinal tract. Since these organisms have an outer membrane, the EV yield of this class was investigated. These bacteria were found to produce large numbers of vesicles (10-150 EV/cell) on a per cell basis. EVs from these organisms are broadly stimulatory and highly potent in in vitro assays. Studies of its therapeutic application in several in vivo models of oncology and inflammation have shown its therapeutic potential. The class Negativicutes includes the following families: Veillonellaceae, Luneomonaceae, Aminococcaceae, and Sporomusaceae . The class Negativicutes includes the genera Megasococcus, Seuromonadaceae , Propionospora , and Aminococcus. Exemplary Negativicutes species include, but are not limited to, Megacoccus species, Lueromonas Felix, Aminococcus enterica, and Propionospora species.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係革蘭氏陽性細菌。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is a Gram-positive bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係需氧細菌。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an aerobic bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係厭氧細菌。在一些實施方式中，厭氧細菌包含專性厭氧菌。在一些實施方式中，厭氧細菌包含兼性厭氧菌。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an anaerobic bacterium. In some embodiments, the anaerobic bacteria comprise obligate anaerobes. In some embodiments, the anaerobic bacteria comprise facultative anaerobes.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係嗜酸細菌。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an acidophilic bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係嗜鹼細菌。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an alkaliphilic bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係嗜中性細菌。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is a neutrophil.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係難養細菌。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is a fastidious bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係非難養細菌。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a non-fastidious bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌或mEV自身係經凍乾的。In some embodiments, the bacterium or mEV of the medicament or the bacterium or mEV from which the mEV of the medicament was obtained is itself lyophilized.

在一些實施方式中，將藥劑的細菌或藥劑的mEV自其獲得的細菌或mEV自身經γ照射（例如，以17.5或25 kGy）。In some embodiments, the bacteria of the agent or the bacteria or mEVs from which the mEVs of the agent were obtained are themselves gamma-irradiated (eg, at 17.5 or 25 kGy).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌或mEV自身係經UV照射的。In some embodiments, the bacterium of the medicament or the bacterium or mEV from which the mEV of the medicament was obtained is itself UV-irradiated.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌或mEV自身係經熱滅活的（例如，在50°C下持續兩小時或在90°C下持續兩小時）。In some embodiments, the bacteria of the agent or the mEVs of the agent from which the mEVs were obtained are themselves heat-inactivated (eg, at 50°C for two hours or at 90°C for two hours).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌或mEV自身係經酸處理的。In some embodiments, the bacterium of the medicament or the bacterium or mEV from which the mEV of the medicament was obtained is itself acid-treated.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌或mEV自身係經氧噴射的（例如，以0.1 vvm進行兩小時）。In some embodiments, the bacteria of the agent or the bacteria or mEVs of the agent from which the mEVs were obtained are themselves oxygen sparged (eg, at 0.1 vvm for two hours).

生長階段會影響細菌和/或細菌產生的mEV的數量或性質。例如，在本文提供的mEV製備方法中，可以例如在對數生長期開始時、在對數生長期的中間時、和/或一旦達到穩定生長期時從培養物中分離mEV。The growth stage can affect the amount or nature of the bacteria and/or the mEVs produced by the bacteria. For example, in the mEV production methods provided herein, mEVs can be isolated from the culture, eg, at the beginning of the logarithmic growth phase, in the middle of the logarithmic growth phase, and/or once the stationary growth phase has been reached.

在某些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌獲得自專性厭氧細菌。專性厭氧細菌的實例包括革蘭氏陰性桿菌（包括擬桿菌、普雷沃菌、卟啉單胞菌、梭桿菌、嗜膽菌及薩特氏菌屬物種的屬）、革蘭氏陽性球菌（主要為消化鏈球菌屬）、革蘭氏陽性孢子形成菌（梭菌屬）、非孢子形成桿菌（放線菌、丙酸桿菌、真桿菌、乳桿菌及雙歧桿菌屬）及革蘭氏陰性球菌（主要為韋榮氏球菌屬）。在一些實施方式中，專性厭氧細菌係選自由以下組成之群組的屬的細菌：阿加薩桿菌屬、奇異菌屬（Atopobium）、布勞特氏菌屬（Blautia）、伯克霍爾德菌屬（Burkholderia）、迪爾莫菌屬（Dielma）、長鏈菌屬（Longicatena）、副梭菌屬（Paraclostridium）、蘇黎世桿菌屬（Turicibacter）及泰澤菌屬（Tyzzerella）。In certain embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is obtained from an obligate anaerobic bacterium. Examples of obligate anaerobic bacteria include Gram-negative bacilli (genus including Bacteroides, Prevotella, Porphyromonas, Fusobacterium, Biliophilus, and Sartreia species), Gram-positive Cocci (mainly Peptostreptococci), Gram-positive spore-forming bacteria (Clostridium), non-spore-forming bacilli (Actinomycetes, Propionibacterium, Eubacterium, Lactobacillus, and Bifidobacterium) and Gram Negative cocci (mainly Veillonella spp.). In some embodiments, the obligate anaerobic bacterium is a bacterium of a genus selected from the group consisting of: Agassia, Atopobium, Blautia, Burkeholm Burkholderia, Dielma, Longicatena, Paraclostridium, Turicibacter and Tyzzerella.

Negativicutes綱包括以下科：韋榮氏球菌科、月形單胞菌科、胺基酸球菌科和 Sporomusaceae科。 Negativicutes綱包括巨型球菌屬、月形單胞菌科屬 、 Propionospora屬和胺基酸球菌屬。示例性Negativicutes物種包括但不限於巨型球菌屬物種、菲利克斯月形單胞菌、腸胺基酸球菌、和 Propionospora屬物種。 The class Negativicutes includes the following families: Veillonellaceae, Luneomonaceae, Aminococcaceae, and Sporomusaceae . The class Negativicutes includes the genera Megasococcus, Seuromonadaceae , Propionospora , and Aminococcus. Exemplary Negativicutes species include, but are not limited to, Megacoccus species, Lueromonas Felix, Aminococcus enterica, and Propionospora species.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Negativicutes綱。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the class Negativicutes .

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於韋榮氏球菌科。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Veillonellaceae.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於月形單胞菌科。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Seuromonaceae.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於胺基酸球菌科。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Aminococcus.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Sporomusaceae科。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Sporomusaceae .

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於巨型球菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Megasphaera.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於月形單胞菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Seuromonas.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Propionospora屬。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Propionospora .

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於胺基酸球菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Aminococcus.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係巨型球菌屬物種細菌。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Megasphaera sp. bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係菲利克斯月形單胞菌細菌。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Lueromonas bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係腸胺基酸球菌細菌。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an Aminococcus enterica bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係 Propionospora屬物種細菌。 In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a bacterium of the genus Propionospora .

微生物梭菌綱中的顫螺旋菌科係脊椎動物的常見共生生物。Microbial Clostridiaceae Vibrating spirochetes are common symbionts of vertebrates.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the class Clostridium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於顫螺旋菌科。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained belongs to the family of Cyclospiraceae.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於糞桿菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Faecalibacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Fournierella屬。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Fournierella .

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Harryflintia屬。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Harryflintia .

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於阿加薩桿菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Agartsia.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普氏棲糞桿菌（普氏棲糞桿菌菌株A）細菌。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Faecalibacterium prausnitzii (F. prauszizii strain A) bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係 Fournierella massiliensis（例如， Fournierella massiliensis菌株A）細菌。 In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Fournierella massiliensis (eg, Fournierella massiliensis strain A) bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係 Harryflintia acetispora（例如， Harryflintia acetispora菌株A）細菌。 In some embodiments, the bacterium of the agent or the mEV of the agent is obtained from a bacterium of the strain Harryflintia acetispora (eg, Harryflintia acetispora strain A).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係阿加薩桿菌屬物種（例如，阿加薩桿菌屬物種菌株A）細菌。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an Agartsia sp. (eg, Agartsia sp. strain A) bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係選自由以下組成之群組的屬的細菌：大腸桿菌屬、克雷伯氏菌屬、乳桿菌屬、志賀氏菌屬和葡萄球菌屬。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament is obtained is a bacterium of a genus selected from the group consisting of: Escherichia coli, Klebsiella, Lactobacillus, Shigella and Staphylococcus species.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係選自由以下組成之群組的物種：馬賽布勞特氏菌（ Blautia massiliensis）、解苯副梭菌（ Paraclostridium benzoelyticum）、 Dielma fastidiosa、 Longicatena caecimuris、乳酸乳球菌乳脂亞種、納西利斯泰澤菌（ Tyzzerella nexilis）、 Hungatella effluvia、類肺炎克雷伯氏菌擬肺炎亞種（ Klebsiella quasipneumoniae subsp. Similipneumoniae）、產酸克雷伯菌（ Klebsiella oxytoca）、和當別町韋榮氏球菌（ Veillonella tobetsuensis）。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent is obtained is a species selected from the group consisting of: Blautia massiliensis , Paraclostridium benzoelyticum , Dielma fastidiosa , Longicatena caecimuris , Lactococcus lactis subsp. cremoris, Tyzzerella nexilis , Hungatella efffluvia , Klebsiella quasipneumoniae subsp. Klebsiella oxytoca , and Veillonella tobetsuensis .

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普雷沃菌屬細菌，該普雷沃菌屬細菌選自由以下組成之群組：阿爾伯普雷沃菌、羊水普雷沃菌、貝根普雷沃菌、二路普雷沃菌、短普雷沃菌、布氏普雷沃菌、頰普雷沃菌、口頰普雷沃菌、糞便普雷沃菌、牙普雷沃菌、棲牙普雷沃菌、解糖腖普雷沃菌、棲組織普雷沃菌、中間普雷沃菌、小斑點普雷沃菌、馬斯普雷沃菌、產黑普雷沃菌、彩虹普雷沃菌、多形普雷沃菌、變黑普雷沃菌、口腔普雷沃菌、口普雷沃菌、齦炎普雷沃菌、蒼白普雷沃菌、唾液普雷沃菌、斯特塞拉普雷沃菌、坦納普雷沃菌、蒂莫普雷沃菌、空腸普雷沃菌、橙色普雷沃菌、保氏普雷沃菌、著色普雷沃菌、人體普雷沃菌、丹塔普雷沃菌、棲居普雷沃菌、斐氏普雷沃菌、深黑色普雷沃菌、解肝素普雷沃菌、洛氏普雷沃菌、嗜糖普雷沃菌、南錫普雷沃菌、稻普雷沃菌、沼澤普雷沃菌、胸膜炎普雷沃菌、棲瘤胃普雷沃菌、解糖普雷沃菌、靶心普雷沃菌、賽赫普雷沃菌、動膠普雷沃菌和真空腔普雷沃菌。 In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament is obtained is a Prevotella bacterium selected from the group consisting of: Revotella, Prevotella bergen, Prevotella erus, Prevotella brevis, Prevotella brucei, Prevotella buccal, Prevotella buccal, Prevotella faecalis, Prevotella dentition, Prevotella dentatus, Prevotella saccharolyticus, Prevotella tissue, Prevotella intermedium, Prevotella minor spot, Prevotella maspartum, Black-producing Prevotella, Prevotella rainbow, Prevotella polymorpha, Prevotella black, Prevotella oral, Prevotella oral, Prevotti gingivitidis, Prevotella pallidum, Prevotella salivarius, Prevotella stercella, Prevotella tanneri, Prevotella timo, Prevotella jejuni, Prevotella aurantia, Prevotti spp. Revolutella, Prevotella human, Prevotella danta, Prevotella inhabitant, Prevotella fischeri, Prevotella dark black, Prevotella heparinica, Prevotella loci Bacteria, Prevotella saccharophila, Prevotella Nancy, Prevotella rice, Prevotella marsh, Prevotella pleurisy, Prevotella rumen-dwelling, Prevotella saccharolyticum, Bullseye Prevotella syringae, Prevotella syringae, Prevotella kinesiella, and Prevotella vacuum chambers.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係如下細菌菌株，該細菌菌株包含如下基因組序列，該基因組序列與表3中提供的以ATCC保藏號保藏的細菌菌株的基因組序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係如下細菌菌株，該細菌菌株包含如下16S序列，該16S序列與表3中提供的以ATCC保藏號保藏的細菌菌株的16S序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament is obtained is a bacterial strain comprising a genome sequence that is identical to the genome of the bacterial strain deposited with the ATCC accession number provided in Table 3 The sequences have at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity). In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament is obtained is a bacterial strain comprising a 16S sequence that is identical to the 16S sequence of the bacterial strain deposited with the ATCC accession number provided in Table 3 The sequences have at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係如下細菌菌株，該細菌菌株包含如下基因組序列，該基因組序列與表4中提供的以保藏號保藏的細菌菌株的基因組序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係如下細菌菌株，該細菌菌株包含如下16S序列，該16S序列與表4中提供的以保藏號保藏的細菌菌株的16S序列具有至少90%、至少91%、至少92%、至少93%、至少94%、至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament is obtained is a bacterial strain comprising a genome sequence that is identical to the genome sequence of the bacterial strain deposited with the accession number provided in Table 4 have at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity). In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament is obtained is a bacterial strain comprising a 16S sequence that is identical to the 16S sequence of the bacterial strain deposited with the accession number provided in Table 4 have at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity).

Negativicutes綱包括以下科：韋榮氏球菌科、月形單胞菌科、胺基酸球菌科和 Sporomusaceae科。 Negativicutes綱包括巨型球菌屬、月形單胞菌科屬 、 Propionospora屬和胺基酸球菌屬。示例性Negativicutes物種包括但不限於巨型球菌屬物種、菲利克斯月形單胞菌、腸胺基酸球菌、和 Propionospora屬物種。 The class Negativicutes includes the following families: Veillonellaceae, Luneomonaceae, Aminococcaceae, and Sporomusaceae . The class Negativicutes includes the genera Megasococcus, Seuromonadaceae , Propionospora , and Aminococcus. Exemplary Negativicutes species include, but are not limited to, Megacoccus species, Lueromonas Felix, Aminococcus enterica, and Propionospora species.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Negativicutes綱。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the class Negativicutes .

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於韋榮氏球菌科。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Veillonellaceae.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於月形單胞菌科。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Seuromonaceae.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於胺基酸球菌科。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Aminococcus.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Sporomusaceae科。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Sporomusaceae .

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於巨型球菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Megasphaera.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於月形單胞菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Seuromonas.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Propionospora屬。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Propionospora .

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於胺基酸球菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Aminococcus.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係巨型球菌屬物種細菌。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Megasphaera sp. bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係菲利克斯月形單胞菌細菌。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Lueromonas bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係腸胺基酸球菌細菌。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an Aminococcus enterica bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係 Propionospora屬物種細菌。 In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a bacterium of the genus Propionospora .

微生物梭菌綱中的顫螺旋菌科係脊椎動物的常見共生生物。Microbial Clostridiaceae Vibrating spirochetes are common symbionts of vertebrates.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the class Clostridium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於顫螺旋菌科。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained belongs to the family of Cyclospiraceae.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於糞桿菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Faecalibacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Fournierella屬。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Fournierella .

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Harryflintia屬。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Harryflintia .

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於阿加薩桿菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Agartsia.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普氏棲糞桿菌（普氏棲糞桿菌菌株A）細菌。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Faecalibacterium prausnitzii (F. prauszizii strain A) bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係 Fournierella massiliensis（例如， Fournierella massiliensis菌株A）細菌。 In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Fournierella massiliensis (eg, Fournierella massiliensis strain A) bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係 Harryflintia acetispora（例如， Harryflintia acetispora菌株A）細菌。 In some embodiments, the bacterium of the agent or the mEV of the agent is obtained from a bacterium of the strain Harryflintia acetispora (eg, Harryflintia acetispora strain A).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係阿加薩桿菌屬物種（例如，阿加薩桿菌屬物種菌株A）細菌。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is an Agartsia sp. (eg, Agartsia sp. strain A) bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係阿加薩桿菌屬物種的菌株。在一些實施方式中，阿加薩桿菌屬物種菌株係與阿加薩桿菌屬物種菌株A（ATCC保藏號PTA-125892）的核苷酸序列（例如，基因組序列、16S序列、CRISPR序列）具有至少95%、至少96%、至少97%、至少98%或至少99%序列同一性（例如，至少99.5%序列同一性、至少99.6%序列同一性、至少99.7%序列同一性、至少99.8%序列同一性、至少99.9%序列同一性）的菌株。在一些實施方式中，阿加薩桿菌屬物種菌株係阿加薩桿菌屬物種菌株A（ATCC保藏號PTA- 125892）細菌。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a strain of the genus Agartsia spp. In some embodiments, the nucleotide sequence (eg, genomic sequence, 16S sequence, CRISPR sequence) of Agartsia sp. strain A (ATCC Deposit No. PTA-125892) has at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity sex, at least 99.9% sequence identity). In some embodiments, the Agartsia sp. strain is Agartsia sp. strain A (ATCC Accession No. PTA-125892) bacterium.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於擬桿菌綱[擬桿菌門]。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係擬桿菌目的細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於紫單胞菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於普雷沃菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係擬桿菌綱的細菌，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係擬桿菌綱、革蘭氏陰性染色的細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係擬桿菌綱的細菌，其中細菌係雙層的並且該細菌係革蘭氏陰性染色。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained belongs to the class Bacteroidetes [phylum Bacteroidetes]. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a bacterium of the order Bacteroidetes. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Porphyromonadaceae. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained belongs to the Prevotaceae family. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament is obtained is a bacterium of the class Bacteroides, wherein the cell envelope structure of the bacterium is bilayer. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Bacteroidetes, Gram-negative staining bacterium. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a bacterium of the class Bacteroidetes, wherein the bacterium is bilayered and the bacterium is Gram-negative staining.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係梭菌綱[厚壁菌門]的細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於真細菌目。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於顫螺旋菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於毛螺菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於消化鏈球菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌目XIII科/地位未定41。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱，其中細菌的細胞被膜結構係單層的。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱、革蘭氏陰性染色。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱、革蘭氏陽性染色。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱，其中細菌的細胞被膜結構係單層的並且該細菌係革蘭氏陰性染色。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於梭菌綱，其中細菌的細胞被膜結構係單層的並且該細菌係革蘭氏陽性染色。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a bacterium of the class Clostridium [Firmicutes]. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the order Eubacteria. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained belongs to the family of Cyclospiraceae. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Lachnospiraceae. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Peptostreptococcus. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained belongs to the Clostridiaceae family XIII/status indeterminate 41 . In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained belongs to the class Clostridium, wherein the cell envelope structure of the bacterium is monolayer. In some embodiments, the bacterium of the agent, or the bacterium from which the mEV of the agent was obtained, is of the class Clostridium, Gram-negative staining. In some embodiments, the bacterium of the agent, or the bacterium from which the mEV of the agent was obtained, is of the class Clostridium, Gram-positive staining. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is of the class Clostridium, wherein the cell envelope of the bacterium is monolayer and the bacterium stains Gram-negative. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is of the class Clostridium, wherein the cell envelope of the bacterium is monolayer and the bacterium stains Gram-positive.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Negativicutes綱[厚壁菌門]。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於韋榮氏球菌目。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於韋榮氏球菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於月形單胞菌目。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係月形單胞菌科的細菌。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Sporomusaceae科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Negativicutes綱，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於藥劑的細菌或藥劑的mEV自其獲得的細菌係來自 Negativicutes綱的細菌的EV，其中細菌的細胞被膜結構係雙層的並且該細菌係革蘭氏陰性染色。 In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained belongs to the class Negativicutes [Firmicutes]. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is of the order Veillonellales. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Veillonellaceae. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the order Seuromonas. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a bacterium of the family Seuromonaceae. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Sporomusaceae . In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained belongs to the class Negativicutes , wherein the cell envelope structure of the bacterium is bilayer. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained belongs to the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is an EV from a bacterium of the class Negativicutes , wherein the cell envelope structure of the bacterium is bilayer And the bacteria stained Gram-negative.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於互養菌綱[互養菌門]。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於互養菌目。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於互養菌科。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於互養菌綱，其中細菌的細胞被膜結構係雙層的。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於互養菌綱、革蘭氏陰性染色。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於互養菌綱，其中細菌的細胞被膜結構係雙層的並且該細菌係革蘭氏陰性染色。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained belongs to the class Syntrophyta [phylum Syntrophyta]. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the order Syntrophyles. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the family Syntrophyceae. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is of the class Syntrophyles, wherein the cell envelope structure of the bacterium is bilayer. In some embodiments, the bacterium of the agent, or the bacterium from which the mEV of the agent was obtained, is of the class Syntrophycetes, Gram-negative staining. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is of the class Syntrophycetes, wherein the cell envelope of the bacterium is bilayered and the bacterium stains Gram-negative.

在某些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌來自一種細菌菌株，例如本文提供的一種菌株。In certain embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is from a bacterial strain, such as a strain provided herein.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌來自一種細菌菌株（例如本文提供的一種菌株）或來自本文提供的一種以上的菌株。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is from one bacterial strain (eg, one strain provided herein) or from more than one strain provided herein.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係乳酸乳球菌乳脂亞種細菌，例如與乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）的核苷酸序列有至少90%或至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係乳球菌屬細菌，例如乳酸乳球菌乳脂亞種菌株A（ATCC指定編號PTA-125368）。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament is obtained is a Lactococcus lactis subsp. cremoris bacterium, for example with the nucleotide sequence of Lactococcus lactis subsp. cremoris strain A (ATCC designation number PTA-125368) Strains with at least 90% or at least 99% genomic, 16S and/or CRISPR sequence identity. In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent is obtained is a bacterium of the genus Lactococcus, eg, Lactococcus lactis subsp. cremoris strain A (ATCC designation number PTA-125368).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普雷沃菌屬細菌，例如包含與普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）的核苷酸序列具有至少90%或至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普雷沃菌屬細菌，例如普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）。In some embodiments, the bacterium of the medicament or the mEV of the medicament is obtained from a bacterium of the genus Prevotella, for example comprising a nucleotide sequence having the same Strains with at least 90% or at least 99% genomic, 16S and/or CRISPR sequence identity. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Prevotella bacterium, eg, Prevotella strain B 50329 (NRRL Deposit No. B 50329).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普雷沃菌屬細菌，例如包含與普雷沃菌屬菌株C（ATCC保藏號PTA-126140）的核苷酸序列具有至少90%或至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係普雷沃菌屬細菌，例如普雷沃菌屬菌株C（ATCC保藏號PTA-126140）。In some embodiments, the bacterium of the medicament or the mEV of the medicament is obtained from a bacterium of the genus Prevotella, for example comprising a nucleotide sequence having the same Strains with at least 90% or at least 99% genomic, 16S and/or CRISPR sequence identity. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Prevotella bacterium, eg, Prevotella strain C (ATCC Accession No. PTA-126140).

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係雙歧桿菌屬細菌，例如與以ATCC指定編號PTA-125097保藏的雙歧桿菌屬細菌的核苷酸序列有至少90%或至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係雙歧桿菌屬細菌，例如以ATCC指定編號PTA-125097保藏的雙歧桿菌屬細菌。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Bifidobacterium bacterium, for example at least 90% identical to the nucleotide sequence of the Bifidobacterium bacterium deposited under ATCC designation number PTA-125097 Or strains with at least 99% genome, 16S and/or CRISPR sequence identity. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a bacterium of the genus Bifidobacterium, eg, a bacterium of the genus Bifidobacterium deposited under ATCC Designation No. PTA-125097.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係韋榮球氏菌屬細菌，例如與以ATCC指定編號PTA-125691保藏的韋榮球氏菌屬細菌的核苷酸序列有至少90%或至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係韋榮球氏菌屬細菌，例如以ATCC指定編號PTA-125691保藏的韋榮球氏菌屬細菌。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Veillonella bacterium, e.g., at least 90% identical in nucleotide sequence to the Veillonella bacterium deposited under ATCC Designation No. PTA-125691 Or strains with at least 99% genome, 16S and/or CRISPR sequence identity. In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament is obtained is a Veillonella bacterium, eg, a Veillonella bacterium deposited under ATCC Designation No. PTA-125691.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係活潑瘤胃球菌。在一些實施方式中，活潑瘤胃球菌細菌係與以ATCC指定編號PTA-126695保藏的活潑瘤胃球菌細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，活潑瘤胃球菌細菌係與以ATCC指定編號PTA-126695保藏的活潑瘤胃球菌細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，活潑瘤胃球菌細菌係以ATCC指定編號PTA-126695保藏的活潑瘤胃球菌細菌。In some embodiments, the bacterium of the agent, or the bacterium from which the mEV of the agent was obtained, is Ruminococcus vivabilis. In some embodiments, the Ruminococcus mobilis bacterial strain has at least 90% (or at least 97%) genomic, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus mobilis bacterium deposited under ATCC designation number PTA-126695 strains. In some embodiments, the Ruminococcus mobilis bacterium is a strain that has at least 99% genomic, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Ruminococcus mobilis bacterium deposited under ATCC designation number PTA-126695. In some embodiments, the Ruminococcus mobilis bacterium is the Ruminococcus mobilis bacterium deposited under ATCC designation number PTA-126695.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係巨型球菌屬物種細菌。在一些實施方式中，巨型球菌屬物種細菌係與以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，巨型球菌屬物種細菌係與以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中，巨型球菌屬物種細菌係以ATCC指定編號PTA-126770保藏的巨型球菌屬物種細菌。In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Megasphaera sp. bacterium. In some embodiments, the Megastococcus sp. bacterial strain has at least 90% (or at least 97%) genomic, 16S, and/or CRISPR sequences with the nucleotide sequence of the Megastococcus sp. bacterium deposited under ATCC designation number PTA-126770 identical strains. In some embodiments, the Megastococcus sp. bacterium is a strain that has at least 99% genomic, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Megastococcus sp. bacterium deposited under ATCC designation number PTA-126770. In some embodiments, the Megastococcus sp. bacterium is a Megastococcus sp. bacterium deposited under ATCC Designation No. PTA-126770.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係 Fournierella massiliensis細菌。在一些實施方式中， Fournierella massiliensis細菌係與以ATCC指定編號PTA-126696保藏的 Fournierella massiliensis細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中， Fournierella massiliensis細菌係與以ATCC指定編號PTA-126696保藏的 Fournierella massiliensis細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中， Fournierella massiliensis細菌係以ATCC指定編號PTA-126696保藏的 Fournierella massiliensis細菌。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is a Fournierella massiliensis bacterium. In some embodiments, the Fournierella massiliensis strain has at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited under ATCC designation number PTA-126696 . In some embodiments, the Fournierella massiliensis strain is a strain that has at least 99% genomic, 16S, and/or CRISPR sequence identity to the nucleotide sequence of the Fournierella massiliensis bacteria deposited under ATCC designation number PTA-126696. In some embodiments, the Fournierella massiliensis bacterium is the Fournierella massiliensis bacterium deposited under ATCC Designation Number PTA-126696.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係 Harryflintia acetispora細菌。在一些實施方式中， Harryflintia acetispora細菌係與以ATCC指定編號PTA-126694保藏的 Harryflintia acetispora細菌的核苷酸序列有至少90%（或至少97%）基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中， Harryflintia acetispora細菌係與以ATCC指定編號PTA-126694保藏的 Harryflintia acetispora細菌的核苷酸序列有至少99%基因組、16S和/或CRISPR序列同一性的菌株。在一些實施方式中， Harryflintia acetispora細菌係以ATCC指定編號PTA-126694保藏的 Harryflintia acetispora細菌。 In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Harryflintia acetispora bacterium. In some embodiments, the Harryflintia acetispora bacterial strain is a strain having at least 90% (or at least 97%) genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacteria deposited under ATCC designation number PTA-126694 . In some embodiments, the Harryflintia acetispora bacterium is a strain that has at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Harryflintia acetispora bacterium deposited under ATCC designation number PTA-126694. In some embodiments, the Harryflintia acetispora bacterium is the Harryflintia acetispora bacterium deposited under ATCC designation number PTA-126694.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係產生代謝產物的細菌，例如，細菌產生丁酸、肌苷、丙酸、或色胺酸代謝產物。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent is obtained is a bacterium that produces a metabolite, eg, a bacterium that produces a butyrate, inosine, propionate, or tryptophan metabolite.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌產生丁酸鹽。在一些實施方式中，細菌來自布勞特氏菌屬 ；克裡斯滕森菌屬；糞球菌屬；真桿菌屬； Lachnosperacea ；巨型球菌屬；或羅斯氏菌屬。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained produces butyrate. In some embodiments, the bacterium is from the genus Blautia; Christensen; Coprococcus ; Eubacterium;

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌產生肌苷。在一些實施方式中，細菌來自雙歧桿菌屬；乳桿菌屬；或歐陸森氏菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained produces inosine. In some embodiments, the bacterium is from the genus Bifidobacterium; Lactobacillus; or Eugenia.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌產生丙酸鹽。在一些實施方式中，細菌來自阿克曼氏菌屬；擬桿菌屬；戴阿利斯特菌屬；真桿菌屬；巨型球菌屬；副擬桿菌屬；普雷沃菌屬；瘤胃球菌屬；或韋榮氏球菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained produces propionate. In some embodiments, the bacterium is from the genus Akkermansia; Bacteroides; Dialisteria; Eubacterium; Veillonella spp.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌產生色胺酸代謝物。在一些實施方式中，細菌來自乳桿菌屬或消化鏈球菌屬。In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained produces a tryptophan metabolite. In some embodiments, the bacteria are from the genus Lactobacillus or Peptostreptococcus.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係產生組蛋白脫乙醯基酶3（HDAC3）的抑制劑的細菌。在一些實施方式中，細菌來自物種 Bariatricus massiliensis、普氏棲糞桿菌、馬賽巨型球菌或腸羅斯氏菌。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained is a bacterium that produces an inhibitor of histone deacetylase 3 (HDAC3). In some embodiments, the bacterium is from the species Bariatricus massiliensis , Faecalibacterium prausnitzii, M. marseilles, or Rothia enterica.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於差異球菌屬； 芽孢桿菌屬；鏈型桿菌屬；棒狀桿菌屬；貪銅菌屬；水棲菌屬；微小桿菌屬；糞桿菌屬； 土芽孢桿菌屬；甲基桿菌屬；微球菌屬；摩根氏菌屬；變形桿菌屬；假單胞菌屬；根瘤菌屬；或鞘胺醇單胞菌屬。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Differococcus; Bacillus; Streptobacter; Corynebacterium; Faecalibacterium; Geobacillus; Methylobacterium; Micrococcus; Morganella; Proteus; Pseudomonas; Rhizobium; or Sphingomonas.

在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌屬於 Cutibacterium屬。在一些實施方式中，藥劑的細菌或藥劑的mEV自其獲得的細菌係 Cutibacterium avidum細菌。 In some embodiments, the bacterium of the agent or the bacterium from which the mEV of the agent was obtained belongs to the genus Cutibacterium . In some embodiments, the bacterium of the medicament or the bacterium from which the mEV of the medicament was obtained is a Cutibacterium avidum bacterium.

在一些實施方式中，細菌來自乳桿菌屬。在一些實施方式中，細菌來自物種加氏乳桿菌。在一些實施方式中，細菌來自 Dysosmobacter屬。在一些實施方式中，細菌來自物種 Dysosmobacter welbionis。 [ 表 1] ：細菌，按綱分 綱 目 科 屬 物種 放線菌綱 放線菌屬 分枝桿菌科 分枝桿菌屬 鏈黴菌科 鏈黴菌屬 變鉛青鏈黴菌、天藍色鏈黴菌、蘇丹鏈黴菌（ Streptomyces sudanesis ）、索馬里鏈黴菌 雙歧桿菌目 雙歧桿菌科 雙歧桿菌屬 青春雙歧桿菌、動物雙歧桿菌、兩歧雙歧桿菌、短雙歧桿菌、乳酸雙歧桿菌、長雙歧桿菌、假雙歧桿菌 紅蝽桿菌目 紅蝽菌科 柯林斯氏菌屬 產氣柯林斯菌 歐陸森氏菌屬 糞歐陸森氏菌 丙酸桿菌目 丙酸桿菌科 丙酸桿菌 芽孢桿菌綱（ Bacilli ） 芽孢桿菌目 芽孢桿菌目地位未定 XI 科 孿生球菌 溶血孿生球菌、麻疹孿生球菌 李斯特菌科 李斯特氏菌 單核細胞增多性李斯特氏菌、威氏李斯特氏菌 乳桿菌目 腸球菌科 腸球菌屬 耐久腸球菌、糞腸球菌、糞腸球菌、鶉雞腸球菌、絨毛腸球菌 乳桿菌屬 乾酪乳桿菌、發酵乳桿菌、乳酸乳球菌乳脂亞種、黏膜乳桿菌、植物乳桿菌、羅伊氏乳桿菌、鼠李糖乳桿菌、唾液乳桿菌、格氏乳桿菌 鏈球菌科 乳球菌屬 乳酸乳球菌乳脂亞種 葡萄球菌 金黃色葡萄球菌 鏈球菌 無乳鏈球菌，金黃色鏈球菌，澳式鏈球菌，變形鏈球菌，副血鏈球菌，肺炎鏈球菌，化膿性鏈球菌，唾液鏈球菌 擬桿菌屬 擬桿菌目 擬桿菌科 擬桿菌屬 糞便擬桿菌、纖維素分解擬桿菌、糞居擬桿菌、多裡氏擬桿菌、脆弱擬桿菌、卵形擬桿菌、腐敗擬桿菌、薩氏擬桿菌、多形擬桿菌、普通擬桿菌 臭桿菌科 臭桿菌屬 內臟臭桿菌 卟啉單胞菌科 副擬桿菌屬 狄氏副擬桿菌、古氏副擬桿菌、屎副擬桿菌 卟啉單胞菌屬 牙齦卟啉單胞菌 普雷沃菌科 普雷沃菌屬 阿爾伯斯普雷沃菌、羊水普雷沃菌、橙色普雷沃菌、保氏普雷沃菌、貝根普雷沃菌、二路普雷沃菌、短普雷沃菌、布氏普雷沃菌、頰普雷沃菌、口頰普雷沃菌、著色普雷沃菌、人體普雷沃菌、糞便普雷沃菌、牙普雷沃菌、丹塔普雷沃菌、棲牙普雷沃菌、解糖腖普雷沃菌、棲居普雷沃菌、斐氏普雷沃菌、深黑色普雷沃菌、解肝素普雷沃菌、棲組織普雷沃菌、中間普雷沃菌、空腸普雷沃菌、洛氏普雷沃菌、小斑點普雷沃菌、馬斯普雷沃菌、產黑普雷沃菌、彩虹普雷沃菌、多形普雷沃菌、嗜糖普雷沃菌、南錫普雷沃菌、變黑普雷沃菌、口腔普雷沃菌、口普雷沃菌、稻普雷沃菌、齦炎普雷沃菌、蒼白普雷沃菌、沼澤普雷沃菌、胸膜炎普雷沃菌、棲瘤胃普雷沃菌、解糖普雷沃菌、唾液普雷沃菌、靶心普雷沃菌、賽赫普雷沃菌、 斯特塞拉普雷沃菌、坦納普雷沃菌、蒂莫普雷沃菌、真空腔普雷沃菌、動膠普雷沃菌 理研菌科 另枝菌屬（ Alstipes ） 普通另枝菌、殊異另枝菌、芬戈爾德氏另枝菌、不明顯另枝菌、 Alistipes ihumii 、 Alistipes inops 、馬賽另枝菌、 Alistipes megaguti 、 Alistipes obesi 、奧登多克氏另枝菌、 Alistipes provencensis 、腐敗另枝菌、塞內加爾另枝菌（ Alistipes senegalensis ）、賽赫另枝菌、蒂莫另枝菌 β 變形桿菌綱（ Betaproteobacteria ） 霍爾德菌目 產鹼桿菌科 產鹼菌屬（ Paenalcaligenes ） 人類產鹼菌 鮑特氏菌屬（ Bordella ） 百日咳桿菌 伯克霍爾德菌科 伯克霍爾德菌屬 鼻疽伯克霍爾德菌、假伯克霍爾德菌 羅爾斯通菌屬（ Ralstonia ） 青枯羅爾斯通菌（ Ralstonia solanacearum ） 奈瑟菌科 奈瑟菌屬 腦膜炎奈瑟菌 薩特氏菌科 薩特氏菌屬 Sutterella parvirubra 、 Sutterella stercoricanis 、 Sutterella wadsworthensis 梭菌綱 梭菌目 Catabacteriaceae 海鷗菌屬（ Catabacter ） 香港海鷗菌 梭菌科 Aminiphila Anaerosphaera aminiphila 克裡斯滕森菌科（ Christensenellaceae） 馬氏克裡斯滕森菌、蒂莫克裡斯滕森菌 Hungatella Hungatella effluvia 真桿菌科 真桿菌屬 扭曲真桿菌、挑剔真桿菌、糞真桿菌、龐大真桿菌、霍氏真桿菌、黏液真桿菌、細枝真桿菌、直腸真桿菌 毛螺菌科 厭氧棒狀菌屬 （ Anaerostipes ） 糞厭氧棒狀菌、哈氏厭氧棒狀菌（ Anaerostipes hadrus ） 布勞特氏菌屬 產氫營養型布勞特氏菌、馬賽布勞特氏菌 、排泄物布勞特氏菌、韋氏布勞特氏菌 卡托氏菌屬 痰卡托氏菌 糞球菌屬 靈巧糞球菌、陪伴糞球菌、一致糞球菌 戴阿利斯特菌屬 渾濁戴阿利斯特菌（ Dialister invisus）、微好氣戴阿利斯特菌（ Dialister micraeophilus）、嗜琥珀酸戴阿利斯特菌（ Dialister succinatiphilus） 多爾氏菌屬 產甲酸多爾氏菌、長鏈多爾氏菌、 Johnsonella 懶惰約翰森菌（ Johnsonella ignava ） 口腔桿菌屬 微小口腔桿菌（ Oribacterium parvum ）、竇菌口腔桿菌（ Oribacterium sinus ） 毛形桿菌屬（ Lachnobacterium ） Lachnoclostridium Lacrimispora Lacrimispora sacchaarolytica 羅斯氏菌屬 人羅斯氏菌、腸羅斯氏菌 泰澤菌屬 納西利斯泰澤菌 顫螺旋菌科 顫桿菌屬 產戊酸顫桿菌 Harryflintia屬 Harryflinta acetispora 消化球菌科 消化鏈球菌科 副梭菌屬 解苯副梭菌 消化鏈球菌屬 羅氏消化鏈球菌 瘤胃球菌科 阿加薩桿菌屬物種 Fournierella屬 Fournierella masssiliensis 瘤胃球菌屬 白色瘤胃球菌、布氏瘤胃球菌、伶俐瘤胃球菌、活潑瘤胃球菌、食菊糖瘤胃球菌（ Ruminococcus inulinivorans ）、卵瘤胃球菌、扭鏈瘤胃球菌 糞桿菌屬 普氏棲糞桿菌 梭菌目XIII科/地位未定 Intestimonas butyriciproducens 梭桿菌門 梭桿菌目 梭桿菌科 梭桿菌屬 核粒梭桿菌、舟形梭桿菌 纖毛菌科 （ Leptotrichiaceae ） 纖發菌屬 纖毛菌屬 丙型變形菌綱 腸桿菌目（ Enterobacterales ） 腸桿菌科 克雷伯氏菌屬 產酸克雷伯菌、肺炎克雷伯菌、類肺炎克雷伯氏菌擬肺炎亞種、 埃希氏桿菌屬 大腸桿菌菌株 Nissle 1917 （ EcN ） 大腸桿菌菌株 ECOR12 大腸桿菌菌株 ECOR63 志賀氏菌屬 Negativicutes 胺基酸球菌科（ Acidaminococcaceae ） 胺基酸球菌屬 發酵胺基酸球菌、腸胺基酸球菌 考拉桿菌屬（ Phascolarctobacterium ） 糞考拉桿菌、琥珀考拉桿菌 月形單胞菌科 月形單胞菌屬 菲利克斯月形單胞菌、地位未定月形單胞菌、生痰月形單胞菌 Sporomusaceae 月形單胞菌目 韋榮氏球菌科 阿裡松氏菌屬（ Allisonella ） 厭氧球形菌屬 Anaeroglobus germinatus Caecibacter Colibacter 巨型球菌屬 埃氏巨型球菌（ Megasphera elsedenii）、馬賽巨型球菌、微核巨型球菌（ Megasphera micronuciformis） 巨型球菌屬物種 擬芽孢桿菌屬 （ Massilibacillus ） 馬賽擬芽孢桿菌（ Massilibacillus massiliensis ） 丙酸螺菌屬 （ Propionispira ） Negativicoccus Negativicoccus succinicivornas 韋榮氏球菌屬 殊異韋榮氏球菌、小韋榮氏球菌、鼠韋榮氏球菌（ Veillonella ratti ）、當別町韋榮氏球菌 互養菌目 互養菌科 胺基桿菌屬 移動胺基桿菌 氯酸桿菌屬 （ Cloacibacillus ） 埃夫裡桿菌 Rarimicrobium Rarimicrobium hominis 疣微菌綱 疣微菌目 阿克曼氏菌科 阿克曼氏菌屬 Akkermansia mucinophila [ 表 2] ：示例性細菌菌株 OTU 公開 DB 登錄號 OTU 公開 DB 登錄號 伴放線放線桿菌 AY362885 鼠乳桿菌 NR_042231 小放線桿菌 ACFT01000025 諾登西絲乳桿菌 NR_041629 胸膜肺炎放線桿菌 NR_074857 酒類乳桿菌 NR_043095 產琥珀酸放線桿菌 CP000746 口乳桿菌 AEKL01000077 脲放線桿菌 AEVG01000167 類短乳桿菌 NR_042456 馬西裡氏放線棒菌 AF487679 類布氏乳桿菌 NR_041294 夏氏放線棒菌 AY957507 副乾酪乳桿菌 ABQV01000067 放線棒菌屬 BM#101342 AY282578 類高加索乳桿菌 NR_029039 放線棒菌屬 P2P_19 P1 AY207066 戊糖乳桿菌 JN813103 嗜黏蛋白阿克曼氏菌 CP001071 惡味乳桿菌 NR_029360 芬戈爾德氏另枝菌 NR_043064 植物乳桿菌 ACGZ02000033 不明顯另枝菌 AB490804 腦橋乳桿菌 HM218420 奧登多克氏另枝菌 NR_043318 羅伊乳桿菌 ACGW02000012 腐敗另枝菌 ABFK02000017 鼠李糖乳桿菌 ABWJ01000068 沙氏另枝菌 FP929032 羅氏乳桿菌 GU269544 另枝菌屬 HGB5 AENZ01000082 瘤胃乳桿菌 ACGS02000043 另枝菌屬物種 JC50 JF824804 清酒乳桿菌 DQ989236 另枝菌屬 RMA 9912 GQ140629 唾液乳桿菌 AEBA01000145 糞厭氧棒狀菌 ABAX03000023 健男乳桿菌（ Lactobacillus saniviri ） AB602569 厭氧棒狀菌屬 3_2_56FAA ACWB01000002 老年乳桿菌 AB602570 風化芽孢桿菌 NR_025557 乳桿菌屬 66c FR681900 嗜氣芽孢桿菌 NR_042339 乳桿菌屬物種 BT6 HQ616370 艾氏芽孢桿菌 GQ980243 乳桿菌屬物種 KLDS 1.0701 EU600905 嗜鹼芽孢桿菌 X76436 乳桿菌屬物種 KLDS 1.0702 EU600906 解澱粉芽孢桿菌 NR_075005 乳桿菌屬物種 KLDS 1.0703 EU600907 炭疽芽孢桿菌 AAEN01000020 乳桿菌屬物種 KLDS 1.0704 EU600908 萎縮芽孢桿菌 NR_075016 乳桿菌屬物種 KLDS 1.0705 EU600909 栗褐芽孢桿菌 NR_036893 乳桿菌屬物種 KLDS 1.0707 EU600911 蠟樣芽孢桿菌 ABDJ01000015 乳桿菌屬物種 KLDS 1.0709 EU600913 環狀芽孢桿菌 AB271747 乳桿菌屬物種 KLDS 1.0711 EU600915 克勞氏芽孢桿菌 FN397477 乳桿菌屬物種 KLDS 1.0712 EU600916 凝結芽孢桿菌 DQ297928 乳桿菌屬物種 KLDS 1.0713 EU600917 堅韌芽孢桿菌 NR_025842 乳桿菌屬物種 KLDS 1.0716 EU600921 彎曲芽孢桿菌 NR_024691 乳桿菌屬物種 KLDS 1.0718 EU600922 福氏芽孢桿菌 NR_025786 乳桿菌屬物種 KLDS 1.0719 EU600923 明膠芽孢桿菌 NR_025595 乳桿菌屬口腔植株 HT002 AY349382 鹽沼芽孢桿菌 NR_026144 乳桿菌屬物種口腔植株 HT070 AY349383 耐鹽芽孢桿菌 AY144582 乳桿菌屬口腔分類群 052 GQ422710 黑佈施泰因芽孢桿菌 NR_042286 臘腸乳桿菌 NR_042194 霍爾氏芽孢桿菌 NR_036860 烏蘭乳桿菌 ACGU01000081 病研所芽孢桿菌 NR_043268 陰道乳桿菌 ACGV01000168 遲緩芽孢桿菌 NR_040792 酒乳桿菌 NR_042196 地衣芽孢桿菌 NC_006270 犢乳桿菌 NR_041305 巨大芽孢桿菌 GU252124 玉米乳桿菌 NR_037122 尼氏芽孢桿菌 NR_044546 格氏乳球菌 AF061005 農研所芽孢桿菌 NR_043334 乳酸乳球菌 CP002365 菸酸芽孢桿菌 NR_024695 棉子糖乳球菌 NR_044359 抱川芽孢桿菌 NR_041377 格雷氏李斯特氏菌 ACCR02000003 短小芽孢桿菌 NR_074977 無毒李斯特氏菌 JF967625 沙福芽孢桿菌 JQ624766 伊氏李斯特氏菌 X56151 單純芽孢桿菌 NR_042136 單核球增多性李斯特氏菌 CP002003 索諾氏芽孢桿菌 NR_025130 威氏李斯特氏菌 AM263198 芽孢桿菌屬 10403023 MM10403188 CAET01000089 埃氏巨型球菌 AY038996 芽孢桿菌屬 2_A_57_CT2 ACWD01000095 巨型球菌屬複合群 C1 AY278622 芽孢桿菌屬物種 2008724126 GU252108 巨型球菌屬複合群類型 _1 ADGP01000010 芽孢桿菌屬物種 2008724139 GU252111 微核巨型球菌 AECS01000020 芽孢桿菌屬物種 7_16AIA FN397518 巨型球菌屬 BLPYG_07 HM990964 芽孢桿菌屬物種 9_3AIA FN397519 巨型球菌屬 UPII 199_6 AFIJ01000040 芽孢桿菌屬物種 AP8 JX101689 古本微桿菌 NR_025098 芽孢桿菌屬 B27 （ 2008 ） EU362173 乳酸微桿菌 EU714351 芽孢桿菌屬物種 BT1B_CT2 ACWC01000034 賈氏光岡菌 NR_028840 芽孢桿菌屬物種 GB1.1 FJ897765 多酸光岡菌 ABWK02000005 芽孢桿菌屬物種 GB9 FJ897766 光岡菌屬口腔分類群 521 GU413658 芽孢桿菌屬物種 HU19.1 FJ897769 光岡菌屬口腔分類群 G68 GU432166 芽孢桿菌屬物種 HU29 FJ897771 膿腫分枝桿菌 AGQU01000002 芽孢桿菌屬物種 HU33.1 FJ897772 非洲分枝桿菌 AF480605 芽孢桿菌屬物種 JC6 JF824800 Mycobacterium alsiensis AJ938169 芽孢桿菌屬口腔分類群 F26 HM099642 鳥分枝桿菌 CP000479 芽孢桿菌屬口腔分類群 F28 HM099650 龜分枝桿菌 AB548610 芽孢桿菌屬口腔分類群 F79 HM099654 哥倫比亞分枝桿菌 AM062764 芽孢桿菌屬物種 SRC_DSF1 GU797283 象皮病分枝桿菌 AF385898 芽孢桿菌屬物種 SRC_DSF10 GU797292 戈登分枝桿菌 GU142930 芽孢桿菌屬物種 SRC_DSF2 GU797284 胞內分枝桿菌 GQ153276 芽孢桿菌屬物種 SRC_DSF6 GU797288 堪薩斯分枝桿菌 AF480601 芽孢桿菌屬物種 tc09 HQ844242 拉克絲分枝桿菌 NR_025175 芽孢桿菌屬物種 zh168 FJ851424 麻風分枝桿菌 FM211192 球形芽孢桿菌 DQ286318 彌漫型麻風分枝桿菌 EU203590 產孢芽孢桿菌 NR_026010 麥氏分枝桿菌 FR798914 枯草芽孢桿菌 EU627588 曼氏分枝桿菌 FJ042897 嗜熱澱粉芽孢桿菌 NR_029151 海分枝桿菌 NC_010612 魏氏芽孢桿菌 NR_074926 田鼠分枝桿菌 NR_025234 擬桿菌目細菌 ph8 JN837494 新金分枝桿菌 AF268445 擬桿菌屬複合群 P1 AY341819 副瘰鬁分枝桿菌 ADNV01000350 擬桿菌屬複合群 P2 口腔植株 MB1_G13 DQ003613 副土分枝桿菌 EU919229 擬桿菌屬複合群 P3 口腔植株 MB1_G34 DQ003615 草分枝桿菌 GU142920 擬桿菌屬複合群 P4 口腔植株 MB2_G17 DQ003617 恥垢分枝桿菌 DQ536403 擬桿菌屬複合群 P5 口腔植株 MB2_P04 DQ003619 包皮垢分枝桿菌 CP000480 擬桿菌屬複合群 P6 口腔植株 MB3_C19 DQ003634 分枝桿菌屬物種 1761 EU703150 擬桿菌屬複合群 P7 口腔植株 MB3_P19 DQ003623 分枝桿菌屬物種 1776 EU703152 擬桿菌屬複合群 P8 口腔植株 MB4_G15 DQ003626 分枝桿菌屬物種 1781 EU703147 生酸擬桿菌 NR_028607 分枝桿菌屬物種 1791 EU703148 巴氏桿菌擬桿菌 NR_041446 分枝桿菌屬物種 1797 EU703149 人糞擬桿菌 EU136686 分枝桿菌屬 AQ1GA4 HM210417 解纖維素擬桿菌 ACCH01000108 分枝桿菌屬物種 B10_07.09.0206 HQ174245 克拉氏擬桿菌 AFBM01000011 分枝桿菌屬物種 GN_10546 FJ497243 凝固擬桿菌 AB547639 分枝桿菌屬物種 GN_10827 FJ497247 糞居擬桿菌 ABIY02000050 分枝桿菌屬物種 GN_11124 FJ652846 嗜糞擬桿菌 ACBW01000012 分枝桿菌屬物種 GN_9188 FJ497240 多裡氏擬桿菌 ABWZ01000093 分枝桿菌屬物種 GR_2007_210 FJ555538 埃氏擬桿菌 ACWG01000065 分枝桿菌屬物種 HE5 AJ012738 糞便擬桿菌 GQ496624 分枝桿菌屬物種 NLA001000736 HM627011 芬戈爾德氏擬桿菌 AB222699 分枝桿菌屬 W DQ437715 麯黴擬桿菌 AFBN01000029 結核分枝桿菌 CP001658 脆弱擬桿菌 AP006841 潰瘍分枝桿菌 AB548725 半乳糖醛酸擬桿菌 DQ497994 脆弱分枝桿菌 EU834055 潰瘍擬桿菌 CP002352 無乳支原體 AF010477 解肝素擬桿菌 JN867284 兩形支原體 AY531656 腸擬桿菌 ABJL02000006 關節炎支原體 NC_011025 馬賽擬桿菌 AB200226 牛眼支原體 NR_025987 諾德擬桿菌 NR_043017 咽支原體 NR_024983 擬南芥擬桿菌（ Bacteroides oleiciplenus ） AB547644 發酵支原體 CP002458 卵形擬桿菌 ACWH01000036 絮狀支原體 X62699 果膠擬桿菌 ABVQ01000036 生殖器支原體 L43967 平常擬桿菌 AB200218 人型支原體 AF443616 化膿性擬桿菌 NR_041280 口腔支原體 AY796060 Bacteroides salanitronis CP002530 綿羊肺炎支原體 NR_025989 薩利爾斯氏擬桿菌（ Bacteroides salyersiae ） EU136690 穿透支原體 NC_004432 擬桿菌屬 1_1_14 ACRP01000155 肺炎支原體 NC_000912 擬桿菌屬 1_1_30 ADCL01000128 腐敗支原體 U26055 擬桿菌屬 1_1_6 ACIC01000215 唾液支原體 M24661 擬桿菌屬 2_1_22 ACPQ01000117 支原體科複合群 P1 口腔植株 MB1_G23 DQ003614 擬桿菌屬 2_1_56FAA ACWI01000065 桿狀奈瑟菌 AFAY01000058 擬桿菌屬 2_2_4 ABZZ01000168 灰色奈瑟菌 ACDY01000037 擬桿菌屬 20_3 ACRQ01000064 長形奈瑟菌 ADBF01000003 擬桿菌屬 3_1_19 ADCJ01000062 淺黃奈瑟菌 ACQV01000025 擬桿菌屬 3_1_23 ACRS01000081 奈瑟菌屬複合群 P2 口腔植株 MB5_P15 DQ003630 擬桿菌屬物種 3_1_33FAA ACPS01000085 淋病奈瑟菌 CP002440 擬桿菌屬物種 3_1_40A ACRT01000136 乳糖奈瑟菌 ACEQ01000095 擬桿菌屬 3_2_5 ACIB01000079 獼猴奈瑟菌 AFQE01000146 擬桿菌屬 315_5 FJ848547 腦膜炎奈瑟菌 NC_003112 擬桿菌屬物種 31SF15 AJ583248 黏膜奈瑟菌 ACDX01000110 擬桿菌屬物種 31SF18 AJ583249 咽奈瑟菌 AJ239281 擬桿菌屬物種 35AE31 AJ583244 多糖奈瑟菌 ADBE01000137 擬桿菌屬物種 35AE37 AJ583245 乾燥奈瑟菌 ACKO02000016 擬桿菌屬物種 35BE34 AJ583246 奈瑟菌屬 KEM232 GQ203291 擬桿菌屬物種 35BE35 AJ583247 奈瑟菌屬口腔植株 AP132 AY005027 擬桿菌屬 4_1_36 ACTC01000133 奈瑟菌屬物種口腔植株 JC012 AY349388 擬桿菌屬物種 4_3_47FAA ACDR02000029 奈瑟菌屬口腔菌株 B33KA AY005028 擬桿菌屬物種 9_1_42FAA ACAA01000096 奈瑟菌屬口腔分類群 014 ADEA01000039 擬桿菌屬物種 AR20 AF139524 奈瑟菌屬物種 SMC_A9199 FJ763637 擬桿菌屬物種 AR29 AF139525 奈瑟菌屬物種 TM10_1 DQ279352 擬桿菌屬物種 B2 EU722733 淡黃色奈瑟菌 ACEO01000067 擬桿菌屬物種 D1 ACAB02000030 紋臭桿菌 AB490805 擬桿菌屬物種 D2 ACGA01000077 內臟臭桿菌 CP002544 擬桿菌屬物種 D20 ACPT01000052 顫桿菌屬 G2 HM626173 擬桿菌屬物種 D22 ADCK01000151 產戊酸顫桿菌 NR_074793 擬桿菌屬物種 F_4 AB470322 克魯斯顫螺菌 AB040495 擬桿菌屬物種 NB_8 AB117565 巴賽隆納類芽孢桿菌 NR_042272 擬桿菌屬物種 WH2 AY895180 巴倫葛茲類芽孢桿菌 NR_042756 擬桿菌屬物種 XB12B AM230648 千葉類芽孢桿菌 NR_040885 擬桿菌屬物種 XB44A AM230649 庫氏類芽孢桿菌 NR_025372 排泄物擬桿菌 ABFZ02000022 堅韌類芽孢桿菌 NR_037017 多形擬桿菌 NR_074277 解葡聚糖類芽孢桿菌 D78470 單形擬桿菌 AB050110 乳酸類芽孢桿菌 NR_025739 解尿素擬桿菌 GQ167666 燦爛類芽孢桿菌 NR_040882 普通擬桿菌 CP000139 飼料類芽孢桿菌 NR_040853 木聚糖酶擬桿菌 ADKP01000087 多黏類芽孢桿菌 NR_037006 擬桿菌門細菌口腔分類群 D27 HM099638 金龜子類芽孢桿菌 NR_040888 擬桿菌門細菌口腔分類群 F31 HM099643 類芽孢桿菌屬 CIP 101062 HM212646 擬桿菌門細菌口腔分類群 F44 HM099649 狄氏副擬桿菌 CP000140 腸道巴氏桿菌 AB370251 古氏副擬桿菌 AY974070 雙歧桿菌屬複合群 C1 AY278612 戈登氏副擬桿菌 AB470344 青春雙歧桿菌 AAXD02000018 約氏副擬桿菌 ABYH01000014 角雙歧桿菌 ABYS02000004 屎副擬桿菌 EU136685 動物雙歧桿菌 CP001606 副擬桿菌屬 D13 ACPW01000017 兩歧雙歧桿菌 ABQP01000027 副擬桿菌屬物種 NS31_3 JN029805 短雙歧桿菌 CP002743 黑色消化球菌 NR_029221 鏈狀雙歧桿菌 ABXY01000019 消化球菌屬口腔植株 JM048 AY349389 牙雙歧桿菌 CP001750 消化球菌屬口腔分類群 167 GQ422727 沒食子雙歧桿菌 ABXB03000004 不解糖嗜腖菌 D14145 嬰兒雙歧桿菌 AY151398 杜爾丹尼氏嗜腖菌 EU526290 卡氏雙歧桿菌 AB491757 海氏嗜腖菌 NR_026358 長雙歧桿菌 ABQQ01000041 吲哚嗜腖菌 AY153431 假鏈狀雙歧桿菌 ABXX02000002 艾弗嗜腖菌 Y07840 偽長雙歧桿菌 NR_043442 淚腺嗜腖菌 ADDO01000050 斯氏雙歧桿菌 AJ307005 嗜腖菌屬 gpac007 AM176517 雙歧桿菌屬 HM2 AB425276 嗜腖菌屬物種 gpac018A AM176519 雙歧桿菌屬物種 HMLN12 JF519685 嗜腖菌屬物種 gpac077 AM176527 雙歧桿菌屬物種 M45 HM626176 嗜腖菌屬物種 gpac148 AM176535 雙歧桿菌屬物種 MSX5B HQ616382 嗜腖菌屬物種 JC140 JF824803 雙歧桿菌屬物種 TM_7 AB218972 嗜腖菌屬物種口腔分類群 386 ADCS01000031 嗜熱雙歧桿菌 DQ340557 嗜腖菌屬物種口腔分類群 836 AEAA01000090 尿雙歧桿菌 AJ278695 消化鏈球菌科細菌 ph1 JN837495 球形布勞特氏菌 AB571656 厭氧消化鏈球菌 AY326462 格魯氏布勞特氏菌（ Blautia glucerasea ） AB588023 微小消化鏈球菌 AM176538 格魯斯布勞特氏菌（ Blautia glucerasei ） AB439724 消化鏈球菌屬 9succ1 X90471 漢森布勞特氏菌 ABYU02000037 消化鏈球菌屬口腔植株 AP24 AB175072 產氫營養型布勞特氏菌 ACBZ01000217 消化鏈球菌屬物種口腔植株 FJ023 AY349390 盧氏布勞特氏菌 AB691576 消化鏈球菌屬 P4P_31 P3 AY207059 生產性布勞特氏菌 AB600998 口炎消化鏈球菌 ADGQ01000048 申克布勞特氏菌 NR_026312 卟啉單胞菌科細菌 NML 060648 EF184292 布勞特氏菌屬 M25 HM626178 不解糖卟啉單胞菌 AENO01000048 排泄物布勞特氏菌 HM626177 牙髓卟啉單胞菌 ACNN01000021 韋氏布勞特氏菌 EF036467 牙齦卟啉單胞菌 AE015924 支氣管炎鮑特氏菌 NR_025949 利氏卟啉單胞菌 NR_025907 霍爾氏鮑特氏菌 AB683187 獼猴卟啉單胞菌 NR_025908 副百日咳鮑特氏菌 NR_025950 索拉卟啉單胞菌 AB547667 百日咳鮑特氏菌 BX640418 卟啉單胞菌屬口腔植株 BB134 AY005068 阿氏螺旋體 ABCU01000001 卟啉單胞菌屬物種口腔植株 F016 AY005069 伯氏螺旋體 ABGI01000001 卟啉單胞菌屬口腔植株 P2PB_52 P1 AY207054 麝鼠勺螺旋體 DQ057990 卟啉單胞菌屬物種口腔植株 P4GB_100 P2 AY207057 達頓螺旋體 NC_011229 卟啉單胞菌屬 UQD 301 EU012301 伽氏螺旋體 ABJV01000001 上野卟啉單胞菌 ACLR01000152 赫氏螺旋體 AY597657 阿爾伯斯普雷沃菌 NR_025300 西班牙螺旋體 DQ057988 安氏普雷沃菌 AB547670 伊朗包柔氏螺旋體 HM161645 伯氏普雷沃菌 ACKS01000100 回歸熱包柔氏螺旋體 AF107367 二路普雷沃菌 ADFO01000096 螺旋體屬 NE49 AJ224142 短雷沃菌 NR_041954 斯皮爾曼螺旋體 ABKB01000002 頰普雷沃菌 ACRB01000001 墨西哥包柔氏螺旋體 NC_008710 口頰普雷沃菌 JN867261 法雷斯螺旋體 ABCY01000002 糞便普雷沃菌 ACBX02000014 綿羊布氏桿菌 NC_009504 人體普雷沃菌 L16465 布氏桿菌屬 83_13 ACBQ01000040 牙普雷沃菌 AB547678 布氏桿菌屬 BO1 EU053207 棲牙普雷沃菌 CP002589 豬布氏桿菌 ACBK01000034 解糖腖普雷沃菌 AEDO01000026 須芒草伯克霍爾德菌 AAUZ01000009 普雷沃菌屬複合群 C1 AY278624 新洋蔥伯克霍爾德菌 AAHI01000060 普雷沃菌屬複合群 C2 AY278625 洋蔥伯克霍爾德菌 NR_041719 普雷沃菌屬複合群 P7 口腔植株 MB2_P31 DQ003620 鼻疽伯克霍爾德菌 CP000547 普雷沃菌屬複合群 P8 口腔植株 MB3_P13 DQ003622 多食伯克霍爾德菌 NC_010086 普雷沃菌屬複合群 P9 口腔植株 MB7_G16 DQ003633 俄克拉何馬伯克霍爾德菌 DQ108388 解肝素普雷沃菌 GQ422742 類鼻疽伯克霍爾德菌 CP001408 棲組織普雷沃菌 JN867315 產根黴素伯克霍爾德菌 HQ005410 中間普雷沃菌 AF414829 伯克霍爾德菌屬 383 CP000151 洛氏普雷沃菌 JN867231 食異生素伯克霍爾德菌 U86373 斑狀普雷沃菌 AGEK01000035 伯克霍爾德菌細菌 1_1_47 ADCQ01000066 馬氏普雷沃菌 AEEI01000070 穗狀丁酸弧菌 ABWN01000012 產黑色素普雷沃菌 CP002122 溶纖維丁酸弧菌 U41172 彩虹普雷沃菌 AGWK01000061 鼠衣原體 AE002160 多形普雷沃菌 AEWX01000054 鸚鵡熱衣原體 NR_036864 食多糖普雷沃菌 AFJE01000016 沙眼衣原體 U68443 南錫普雷沃菌 JN867228 衣原體目細菌 NS11 JN606074 變黑普雷沃菌 AFPX01000069 無丙二酸檸檬酸桿菌 FR870441 口腔普雷沃菌 AEPE01000021 布氏檸檬酸桿菌 NR_028687 口普雷沃菌 ADDV01000091 法氏檸檬酸桿菌 AF025371 齦炎普雷沃菌 L16472 弗氏檸檬酸桿菌 NR_028894 蒼白普雷沃菌 AFPY01000135 吉利檸檬酸桿菌 AF025367 棲瘤胃普雷沃菌 CP002006 柯氏檸檬酸桿菌 NC_009792 唾液普雷沃菌 AB108826 莫林檸檬酸桿菌 AF025369 普雷沃菌屬 BI_42 AJ581354 鼠檸檬酸桿菌 NR_074903 普雷沃菌屬物種 CM38 HQ610181 塞氏檸檬酸桿菌 AF025364 普雷沃菌屬物種 ICM1 HQ616385 檸檬酸桿菌屬 30_2 ACDJ01000053 普雷沃菌屬物種 ICM55 HQ616399 檸檬酸桿菌屬 KMSI_3 GQ468398 普雷沃菌屬 JCM 6330 AB547699 沃克曼檸檬酸桿菌 AF025373 普雷沃菌屬口腔植株 AA020 AY005057 楊氏檸檬酸桿菌 ABWL02000011 普雷沃菌屬物種口腔植株 ASCG10 AY923148 埃夫裡桿菌 GQ258966 普雷沃菌屬物種口腔植株 ASCG12 DQ272511 梭菌科細菌 END_2 EF451053 普雷沃菌屬物種口腔植株 AU069 AY005062 梭菌科細菌 JC13 JF824807 普雷沃菌屬物種口腔植株 CY006 AY005063 梭菌屬細菌 1_7_47FAA ABQR01000074 普雷沃菌屬物種口腔植株 DA058 AY005065 梭菌屬細菌 9400853 HM587320 普雷沃菌屬物種口腔植株 FL019 AY349392 梭菌屬細菌 9403326 HM587324 普雷沃菌屬物種口腔植株 FU048 AY349393 梭菌屬細菌口腔植株 P4PA_66 P1 AY207065 普雷沃菌屬物種口腔植株 FW035 AY349394 梭菌屬細菌口腔分類群 093 GQ422712 普雷沃菌屬物種口腔植株 GI030 AY349395 梭菌屬細菌口腔分類群 F32 HM099644 普雷沃菌屬物種口腔植株 GI032 AY349396 梭菌屬細菌 ph2 JN837487 普雷沃菌屬物種口腔植株 GI059 AY349397 梭菌屬細菌 SY8519 AB477431 普雷沃菌屬物種口腔植株 GU027 AY349398 梭菌屬複合群 BVAB3 CP001850 普雷沃菌屬物種口腔植株 HF050 AY349399 梭菌屬 SM4_1 FP929060 普雷沃菌屬物種口腔植株 ID019 AY349400 梭菌屬物種 SS3_4 AY305316 普雷沃菌屬物種口腔植株 IDR_CEC_0055 AY550997 梭菌屬物種 SSC_2 FP929061 普雷沃菌屬物種口腔植株 IK053 AY349401 丙酮丁醇梭酸 NR_074511 普雷沃菌屬物種口腔植株 IK062 AY349402 耐氧梭酸 X76163 普雷沃菌屬口腔植株 P4PB_83 P2 AY207050 阿爾登氏梭菌 NR_043680 普雷沃菌屬物種口腔分類群 292 GQ422735 奧德里奇氏梭菌 NR_026099 普雷沃菌屬物種口腔分類群 299 ACWZ01000026 藻狀梭菌 NR_041746 普雷沃菌屬物種口腔分類群 300 GU409549 解藻木聚糖梭菌 NR_028726 普雷沃菌屬物種口腔分類群 302 ACZK01000043 胺基戊酸梭菌 NR_029245 普雷沃菌屬物種口腔分類群 310 GQ422737 苦杏仁梭菌 AY353957 普雷沃菌屬物種口腔分類群 317 ACQH01000158 阿根廷梭菌 NR_029232 普雷沃菌屬物種口腔分類群 472 ACZS01000106 天門冬形梭菌 ACCJ01000522 普雷沃菌屬物種口腔分類群 781 GQ422744 巴氏梭菌 NR_029229 普雷沃菌屬物種口腔分類群 782 GQ422745 巴特氏梭菌 ABEZ02000012 普雷沃菌屬口腔分類群 F68 HM099652 拜氏梭菌 NR_074434 普雷沃菌屬物種口腔分類群 G60 GU432133 雙酵素梭菌 X73437 普雷沃菌屬物種口腔分類群 G70 GU432179 鮑氏梭菌 ABCC02000039 普雷沃菌屬物種口腔分類群 G71 GU432180 肉毒梭菌 NC_010723 普雷沃菌屬物種 SEQ053 JN867222 丁酸梭菌 ABDT01000017 普雷沃菌屬物種 SEQ065 JN867234 屍毒梭菌 AB542932 普雷沃菌屬物種 SEQ072 JN867238 食氧化碳梭菌 FR733710 普雷沃菌屬物種 SEQ116 JN867246 肉梭菌 NR_044716 普雷沃菌屬物種 SG12 GU561343 隱藏梭菌 X77844 普雷沃菌屬物種 sp24 AB003384 速生梭菌 JQ246092 普雷沃菌屬物種 sp34 AB003385 纖維素梭菌 NR_044624 糞普雷沃菌 AB244774 肖沃氏梭菌 EU106372 譚氏普雷沃菌 ACIJ02000018 香茅梭菌 ADLJ01000059 蒂蒙斯普雷沃菌 ADEF01000012 澄清梭菌 NR_041235 真口普雷沃菌 ACVA01000027 梭狀梭菌 M59089 普雷沃菌科細菌 P4P_62 P1 AY207061 梭形梭菌 NR_044715 丙酸桿菌科細菌 NML 02_0265 EF599122 球形梭菌 EF025906 產丙酸丙酸桿菌 NC_019395 匙形梭菌 NR_044717 痤瘡丙酸桿菌 ADJM01000010 耳蝸形梭菌 NR_026495 貪婪丙酸桿菌 AJ003055 犬腸梭菌 FJ957863 費氏丙酸桿菌 NR_036972 鷓鴣梭菌 NR_026151 顆粒丙酸桿菌 FJ785716 難辨梭菌 NC_013315 詹森丙酸桿菌 NR_042269 雙孢梭菌 NR_026491 丙酸丙酸桿菌 NR_025277 酯化梭菌 NR_042153 丙酸桿菌屬 434_HC2 AFIL01000035 福氏梭菌 NR_044714 丙酸桿菌屬物種 H456 AB177643 Clostridium favososporum X76749 丙酸桿菌屬 LG AY354921 費新尼亞梭菌 AF270502 丙酸桿菌屬口腔分類群 192 GQ422728 寒冷梭菌 NR_024919 丙酸桿菌屬物種 S555a AB264622 產氣梭菌 NR_024945 特恩氏丙酸桿菌 NR_042270 戈氏梭菌 AB542933 銅綠假單胞菌 AABQ07000001 乙二醇梭菌 FJ384385 螢光假單胞菌 AY622220 人糞梭菌 AB233029 蓋氏假單胞菌 FJ943496 溶血梭菌 NR_024749 門多薩假單胞菌 AAUL01000021 哈氏梭菌 AY552788 蒙氏假單胞菌 NR_024910 平野氏梭菌 AB023970 草假單胞菌 GU188951 溶組織梭菌 HF558362 類產鹼假單胞菌 NR_037000 海氏梭菌 AB023973 惡臭假單胞菌 AF094741 吲哚梭菌 AF028351 假單胞菌屬 2_1_26 ACWU01000257 無害梭菌 M23732 假單胞菌屬 G1229 DQ910482 不規則梭菌 NR_029249 假單胞菌屬物種 NP522b EU723211 板藍根梭菌 NR_026347 施氏假單胞菌 AM905854 克氏梭菌 NR_074165 托拉假單胞菌 AF320988 發酵乳糖梭菌 NR_025651 綠黃假單胞菌 NR_042764 拉瓦勒塞梭菌 EF564277 皮氏羅爾斯通氏菌 NC_010682 柔嫩梭菌 AJ305238 羅爾斯通氏菌屬 5_7_47FAA ACUF01000076 泥渣梭菌 FR870444 盲腸羅斯拜瑞氏菌 GU233441 大梭菌 X77835 糞羅斯拜瑞氏菌 AY804149 惡名梭菌 FR749893 糞便羅斯拜瑞氏菌 AY305310 馬約貝梭菌 FR733682 人羅斯拜瑞氏菌 AJ270482 甲基戊糖梭菌 ACEC01000059 腸道羅斯拜瑞氏菌 FP929050 系結梭菌 X73443 食菊糖羅斯拜瑞氏菌 AJ270473 諾維氏梭菌 NR_074343 羅斯拜瑞氏菌屬 11SE37 FM954975 酪酸梭菌 Y18187 羅斯拜瑞氏菌屬物種 11SE38 FM954976 乳清酸梭菌 FR749922 天空羅氏菌 DQ673320 副腐敗梭菌 AB536771 齲齒羅氏菌 ADDW01000024 產氣莢膜梭菌 ABDW01000023 黏滑羅氏菌 ACVO01000020 植物發酵梭菌 NR_074652 鼠鼻羅氏菌 NR_025310 毛髮狀梭菌 D14639 羅氏菌屬口腔分類群 188 GU470892 腐敗梭菌 NR_024995 嗜澱粉反芻桿菌 NR_026450 奎尼梭菌 NR_026149 瘤胃球菌科細菌 D16 ADDX01000083 多枝梭菌 M23731 白色瘤胃球菌 AY445600 直腸梭菌 NR_029271 布氏瘤胃球菌 EU266549 噬糖梭菌 DQ100445 伶俐瘤胃球菌 NR_029160 化糖梭菌 CP002109 Ruminococcus champanellensis FP929052 薩丁島梭菌 NR_041006 生黃瘤胃球菌 NR_025931 煎盤梭菌 NR_026490 活潑瘤胃球菌 X94967 裂解梭菌 AF262238 漢森瘤胃球菌 M59114 敗血梭菌 NR_026020 乳酸瘤胃球菌 ABOU02000049 索氏梭菌 AB448946 卵瘤胃球菌 AY169419 梭菌屬 7_2_43FAA ACDK01000101 瘤胃球菌屬 18P13 AJ515913 梭菌屬物種 D5 ADBG01000142 瘤胃球菌屬物種 5_1_39BFAA ACII01000172 梭菌屬物種 HGF2 AENW01000022 瘤胃球菌屬物種 9SE51 FM954974 梭菌屬物種 HPB_46 AY862516 瘤胃球菌屬物種 ID8 AY960564 梭菌屬物種 JC122 CAEV01000127 瘤胃球菌屬物種 K_1 AB222208 梭菌屬物種 L2_50 AAYW02000018 扭鏈瘤胃球菌 AAVP02000002 梭菌屬 LMG 16094 X95274 邦戈爾沙門氏菌 NR_041699 梭菌屬物種 M62_1 ACFX02000046 腸炎沙門氏菌 NC_011149 梭菌屬物種 MLG055 AF304435 腸炎沙門氏菌 NC_011205 梭菌屬 MT4 E FJ159523 腸炎沙門氏菌 DQ344532 梭菌屬物種 NMBHI_1 JN093130 腸炎沙門氏菌 ABEH02000004 梭菌屬 NML 04A032 EU815224 腸炎沙門氏菌 ABAK02000001 梭菌屬物種 SS2_1 ABGC03000041 腸炎沙門氏菌 NC_011080 梭菌屬物種 SY8519 AP012212 腸炎沙門氏菌 EU118094 梭菌屬物種 TM_40 AB249652 腸炎沙門氏菌 NC_011094 梭菌屬物種 YIT 12069 AB491207 腸炎沙門氏菌 AE014613 梭菌屬物種 YIT 12070 AB491208 腸炎沙門氏菌 ABFH02000001 楔樣梭菌 X73449 腸炎沙門氏菌 ABEM01000001 螺狀梭菌 X73441 腸炎沙門氏菌 ABAM02000001 生孢梭菌 ABKW02000003 鼠傷寒沙門氏菌 DQ344533 球孢梭菌 NR_044835 鼠傷寒沙門氏菌 AF170176 糞堆梭菌 NR_025100 蛛形月形單胞菌 HM596274 斯蒂克蘭德氏梭菌 L04167 魚月形單胞菌 GQ422719 斯特拉文斯梭菌 NR_024829 福氏月形單胞菌 AF287803 近端梭菌 NR_041795 月形單胞菌屬複合群 C1 AY278627 產硫梭菌 NR_044161 月形單胞菌屬複合群 C2 AY278628 共生梭菌 ADLQ01000114 月形單胞菌屬複合群 P5 AY341820 第三梭菌 Y18174 月形單胞菌屬複合群 P6 口腔植株 MB3_C41 DQ003636 破傷風梭菌 NC_004557 月形單胞菌屬複合群 P7 口腔植株 MB5_C08 DQ003627 嗜熱纖維梭菌 NR_074629 月形單胞菌屬複合群 P8 口腔植株 MB5_P06 DQ003628 酪丁酸梭菌 NR_044718 損傷新月形單胞菌 AF287802 綠色梭菌 NR_026204 有害月形單胞菌 GU470909 解木聚糖梭菌 NR_037068 反芻動物月形單胞菌 NR_075026 產氣柯林斯菌 AAVN02000007 月形單胞菌屬 FOBRC9 HQ616378 腸柯林斯菌 ABXH02000037 月形單胞菌屬口腔植株 FT050 AY349403 排泄物柯林斯菌 ABXJ01000150 月形單胞菌屬物種口腔植株 GI064 AY349404 田中氏柯林斯菌 AB490807 月形單胞菌屬物種口腔植株 GT010 AY349405 鏈型糞芽孢菌 AB030218 月形單胞菌屬物種口腔植株 HU051 AY349406 糞芽孢菌屬 29_1 ADKX01000057 月形單胞菌屬物種口腔植株 IK004 AY349407 糞芽孢菌屬 D7 ACDT01000199 月形單胞菌屬物種口腔植株 IQ048 AY349408 靈巧糞球菌 EU266552 月形單胞菌屬物種口腔植株 JI021 AY349409 陪伴糞球菌 ABVR01000038 月形單胞菌屬物種口腔植株 JS031 AY349410 一致糞球菌 EF031543 月形單胞菌屬物種口腔植株 OH4A AY947498 糞球菌屬 ART55_1 AY350746 月形單胞菌屬口腔植株 P2PA_80 P4 AY207052 渾濁戴阿利斯特菌 ACIM02000001 月形單胞菌屬物種口腔分類群 137 AENV01000007 微好氣戴阿利斯特菌 AFBB01000028 月形單胞菌屬物種口腔分類群 149 AEEJ01000007 微嗜氣戴阿利斯特菌 AENT01000008 生痰月形單胞菌 ACKP02000033 侵肺戴阿利斯特菌 HM596297 居泉沙雷菌 NR_025339 產丙酸戴阿利斯特菌 NR_043231 液化沙雷菌 NR_042062 戴阿利斯特菌屬口腔分類群 502 GQ422739 黏質沙雷菌 GU826157 嗜琥珀酸戴阿利斯特菌 AB370249 臭味沙雷菌 ADBY01000001 產甲酸多爾氏菌 AAXA02000006 變形班沙雷菌 AAUN01000015 長鏈多爾氏菌 AJ132842 波伊德氏志賀氏菌 AAKA01000007 氣囊棲水菌 ACYI01000081 痢疾志賀氏菌 NC_007606 產氣腸桿菌 AJ251468 福氏志賀氏菌 AE005674 阿氏腸桿菌 NR_024640 宋內志賀氏菌 NC_007384 生癌腸桿菌 Z96078 糞鞘胺醇桿菌 NR_025537 陰溝腸桿菌 FP929040 水氏鞘胺醇桿菌 JF708889 考氏腸桿菌 NR_025566 多食鞘胺醇桿菌 NR_040953 霍氏腸桿菌 AFHR01000079 食神鞘胺醇桿菌 ACHA02000013 腸桿菌屬 247BMC HQ122932 刺狀鞘胺醇單胞菌 NR_024700 腸桿菌屬 638 NR_074777 鞘胺醇單胞菌屬口腔植株 FI012 AY349411 腸桿菌屬物種 JC163 JN657217 鞘胺醇單胞菌屬物種口腔植株 FZ016 AY349412 腸桿菌屬 SCSS HM007811 鞘胺醇單胞菌屬口腔分類群 A09 HM099639 腸桿菌屬物種 TSE38 HM156134 鞘胺醇單胞菌屬物種口腔分類群 F71 HM099645 腸桿菌科細菌 9_2_54FAA ADCU01000033 葡萄球菌科細菌 NML 92_0017 AY841362 腸桿菌科細菌 CF01Ent_1 AJ489826 金黃色葡萄球菌 CP002643 腸桿菌科細菌 Smarlab 3302238 AY538694 耳葡萄球菌 JQ624774 鳥腸球菌 AF133535 頭狀葡萄球菌 ACFR01000029 人糞腸球菌 AY943820 山羊葡萄球菌 ACRH01000033 酪黃腸球菌 AEWT01000047 肉葡萄球菌 NR_075003 耐久腸球菌 AJ276354 科氏葡萄球菌 JN175375 糞腸球菌 AE016830 香料葡萄球菌 NR_029345 屎腸球菌 AM157434 表皮葡萄球菌 ACHE01000056 鶉雞腸球菌 AB269767 馬胃葡萄球菌 NR_027520 灰黃腸球菌 AY033814 弗氏葡萄球菌 NR_041326 夏威夷腸球菌 AY321377 溶血性葡萄球菌 NC_007168 希氏腸球菌 AF061011 人葡萄球菌 AM157418 義大利腸球菌 AEPV01000109 路鄧葡萄球菌 AEQA01000024 蒙氏腸球菌 NR_024906 巴氏葡萄球菌 FJ189773 棉子糖腸球菌 FN600541 假中間葡萄球菌 CP002439 腸球菌屬 BV2CASA2 JN809766 解糖葡萄球菌 NR_029158 腸球菌屬物種 CCRI_16620 GU457263 腐生性葡萄球菌 NC_007350 腸球菌屬物種 F95 FJ463817 松鼠葡萄球菌 NR_025520 腸球菌屬物種 RfL6 AJ133478 葡萄球菌屬植株 bottae7 AF467424 泰國腸球菌 AY321376 葡萄球菌屬 H292 AB177642 丹毒絲菌科細菌 3_1_53 ACTJ01000113 葡萄球菌屬物種 H780 AB177644 丹毒絲菌科細菌 5_2_54FAA ACZW01000054 琥珀酸葡萄球菌 NR_028667 艾伯氏大腸桿菌 ABKX01000012 小牛葡萄球菌 NR_024670 大腸桿菌 NC_008563 瓦氏葡萄球菌 ACPZ01000009 弗格森氏大腸桿菌 CU928158 木糖葡萄球菌 AY395016 赫爾曼氏大腸桿菌 HQ407266 念珠狀鏈桿菌 NR_027615 大腸桿菌屬 1_1_43 ACID01000033 無乳鏈球菌 AAJO01000130 大腸桿菌屬 4_1_40B ACDM02000056 非解乳鏈球菌 NR_041781 大腸桿菌屬物種 B4 EU722735 咽峽炎鏈球菌 AECT01000011 傷口埃希菌 NR_041927 澳大利亞鏈球菌 AEQR01000024 真桿菌科細菌 P4P_50 P4 AY207060 牛鏈球菌 AEEL01000030 巴克氏真桿菌 NR_044661 犬鏈球菌 AJ413203 兩形真桿菌 ABYT01000002 星座鏈球菌 AY277942 短真桿菌 U13038 脊鏈球菌 AEVC01000028 布氏真桿菌 NR_024682 道恩鏈球菌 AEKN01000002 卡氏真桿菌 NR_026330 停乳鏈球菌 AP010935 溶纖維素真桿菌 AY178842 馬鏈球菌 CP001129 扭曲真桿菌 FR749946 馬腸鏈球菌 AEVB01000043 產糞甾醇真桿菌 HM037995 解沒食子酸鏈球菌 FR824043 圓柱狀真桿菌 FP929041 鏈球菌屬複合群 C1 AY278629 鏈狀真桿菌 NR_044644 鏈球菌屬複合群 C2 AY278630 細長真桿菌 L34682 鏈球菌屬複合群 C3 AY278631 挑剔真桿菌 CP001104 鏈球菌屬複合群 C4 AY278632 斷鏈真桿菌 FR749935 鏈球菌屬複合群 C5 AY278633 龐大真桿菌 FR749933 鏈球菌屬複合群 C6 AY278634 霍氏真桿菌 L34621 鏈球菌屬複合群 C7 AY278635 嬌弱真桿菌 U13039 鏈球菌屬複合群 C8 AY278609 淤泥真桿菌 CP002273 戈登氏鏈球菌 NC_009785 串珠狀真桿菌 HF558373 小兒鏈球菌 ABJK02000017 多形真桿菌 NR_024683 嬰兒鏈球菌 AFNN01000024 產亞硝酸真桿菌 NR_024684 中間鏈球菌 NR_028736 糾纏真桿菌 U13041 巴黎鏈球菌 NR_037096 細枝真桿菌 AJ011522 馬賽鏈球菌 AY769997 直腸真桿菌 FP929042 米勒鏈球菌 X81023 反芻真桿菌 NR_024661 緩症鏈球菌 AM157420 口臭真桿菌 AB525414 突變鏈球菌 AP010655 隱枝真桿菌 NR_026031 寡發酵鏈球菌 AY099095 惰性真桿菌 ABCA03000054 口腔鏈球菌 ADMV01000001 真桿菌屬 3_1_31 ACTL01000045 副血鏈球菌 AEKM01000012 真桿菌屬 AS15b HQ616364 巴氏鏈球菌 AP012054 真桿菌屬物種 OBRC9 HQ616354 泛口腔鏈球菌 AEVF01000016 真桿菌屬口腔植株 GI038 AY349374 肺炎鏈球菌 AE008537 真桿菌屬物種口腔植株 IR009 AY349376 豕鏈球菌 EF121439 真桿菌屬物種口腔植株 JH012 AY349373 假性肺炎鏈球菌 FJ827123 真桿菌屬物種口腔植株 JI012 AY349379 假豕鏈球菌 AENS01000003 真桿菌屬物種口腔植株 JN088 AY349377 釀膿鏈球菌 AE006496 真桿菌屬物種口腔植株 JS001 AY349378 鼠鏈球菌 X58304 真桿菌屬物種口腔植株 OH3A AY947497 唾液鏈球菌 AGBV01000001 真桿菌屬 WAL 14571 FJ687606 血鏈球菌 NR_074974 纖細真桿菌 M59118 中華鏈球菌 AF432857 多曲真桿菌 NR_044648 鏈球菌屬物種 16362 JN590019 凸腹真桿菌 L34421 鏈球菌屬 2_1_36FAA ACOI01000028 嗜木聚糖真桿菌 L34628 鏈球菌屬 2285_97 AJ131965 尤氏真桿菌 AEES01000073 鏈球菌屬物種 69130 X78825 犬貓科梭桿菌 AY162222 鏈球菌屬物種 AC15 HQ616356 梭桿菌屬複合群 C1 AY278616 鏈球菌屬物種 ACS2 HQ616360 梭桿菌屬複合群 C2 AY278617 鏈球菌屬物種 AS20 HQ616366 微生子梭桿菌 ACET01000043 鏈球菌屬物種 BS35a HQ616369 死亡梭桿菌 ACDB02000034 鏈球菌屬物種 C150 ACRI01000045 舟形梭桿菌 HQ223106 鏈球菌屬物種 CM6 HQ616372 壞疽梭桿菌 X55408 鏈球菌屬物種 CM7 HQ616373 壞死梭桿菌 AM905356 鏈球菌屬物種 ICM10 HQ616389 核粒梭桿菌 ADVK01000034 鏈球菌屬物種 ICM12 HQ616390 牙周梭桿菌 ACJY01000002 鏈球菌屬物種 ICM2 HQ616386 拉氏梭桿菌 NR_044687 鏈球菌屬物種 ICM4 HQ616387 梭桿菌屬 1_1_41FAA ADGG01000053 鏈球菌屬物種 ICM45 HQ616394 梭桿菌屬 11_3_2 ACUO01000052 鏈球菌屬物種 M143 ACRK01000025 梭桿菌屬物種 12_1B AGWJ01000070 鏈球菌屬物種 M334 ACRL01000052 梭桿菌屬 2_1_31 ACDC02000018 鏈球菌屬物種 OBRC6 HQ616352 梭桿菌屬 3_1_27 ADGF01000045 鏈球菌屬物種口腔植株 ASB02 AY923121 梭桿菌屬 3_1_33 ACQE01000178 鏈球菌屬物種口腔植株 ASCA03 DQ272504 梭桿菌屬物種 3_1_36A2 ACPU01000044 鏈球菌屬物種口腔植株 ASCA04 AY923116 梭桿菌屬物種 3_1_5R ACDD01000078 鏈球菌屬物種口腔植株 ASCA09 AY923119 梭桿菌屬物種 AC18 HQ616357 鏈球菌屬物種口腔植株 ASCB04 AY923123 梭桿菌屬物種 ACB2 HQ616358 鏈球菌屬物種口腔植株 ASCB06 AY923124 梭桿菌屬物種 AS2 HQ616361 鏈球菌屬物種口腔植株 ASCC04 AY923127 梭桿菌屬物種 CM1 HQ616371 鏈球菌屬物種口腔植株 ASCC05 AY923128 梭桿菌屬物種 CM21 HQ616375 鏈球菌屬物種口腔植株 ASCC12 DQ272507 梭桿菌屬物種 CM22 HQ616376 鏈球菌屬物種口腔植株 ASCD01 AY923129 梭桿菌屬物種 D12 ACDG02000036 鏈球菌屬物種口腔植株 ASCD09 AY923130 梭桿菌屬口腔植株 ASCF06 AY923141 鏈球菌屬物種口腔植株 ASCD10 DQ272509 梭桿菌屬物種口腔植株 ASCF11 AY953256 鏈球菌屬物種口腔植株 ASCE03 AY923134 潰瘍梭桿菌 ACDH01000090 鏈球菌屬物種口腔植株 ASCE04 AY953253 變形梭桿菌 ACIE01000009 鏈球菌屬物種口腔植株 ASCE05 DQ272510 溶血孿生球菌 ACDZ02000012 鏈球菌屬物種口腔植株 ASCE06 AY923135 麻疹孿生球菌 NR_025904 鏈球菌屬物種口腔植株 ASCE09 AY923136 麻疹孿生球菌 ACRX01000010 鏈球菌屬物種口腔植株 ASCE10 AY923137 血孿生球菌 ACRY01000057 鏈球菌屬物種口腔植株 ASCE12 AY923138 孿生球菌屬口腔植株 ASCE02 AY923133 鏈球菌屬物種口腔植株 ASCF05 AY923140 孿生球菌屬物種口腔植株 ASCF04 AY923139 鏈球菌屬物種口腔植株 ASCF07 AY953255 孿生球菌屬物種口腔植株 ASCF12 AY923143 鏈球菌屬物種口腔植株 ASCF09 AY923142 孿生球菌屬 WAL 1945J EU427463 鏈球菌屬物種口腔植株 ASCG04 AY923145 催產克雷白氏菌 AY292871 鏈球菌屬物種口腔植株 BW009 AY005042 肺炎克雷白氏菌 CP000647 鏈球菌屬物種口腔植株 CH016 AY005044 克雷白氏菌屬 AS10 HQ616362 鏈球菌屬物種口腔植株 GK051 AY349413 克雷白氏菌屬物種 Co9935 DQ068764 鏈球菌屬物種口腔植株 GM006 AY349414 克雷白氏菌屬富集培養植株 SRC_DSD25 HM195210 鏈球菌屬口腔植株 P2PA_41 P2 AY207051 克雷白氏菌屬物種 OBRC7 HQ616353 鏈球菌屬物種口腔植株 P4PA_30 P4 AY207064 克雷白氏菌屬 SP_BA FJ999767 鏈球菌屬口腔分類群 071 AEEP01000019 克雷白氏菌屬物種 SRC_DSD1 GU797254 鏈球菌屬口腔分類群 G59 GU432132 克雷白氏菌屬物種 SRC_DSD11 GU797263 鏈球菌屬物種口腔分類群 G62 GU432146 克雷白氏菌屬物種 SRC_DSD12 GU797264 鏈球菌屬物種口腔分類群 G63 GU432150 克雷白氏菌屬物種 SRC_DSD15 GU797267 鏈球菌屬物種 SHV515 Y07601 克雷白氏菌屬物種 SRC_DSD2 GU797253 豬鏈球菌 FM252032 克雷白氏菌屬物種 SRC_DSD6 GU797258 嗜熱鏈球菌 CP000419 變異克雷白氏菌 CP001891 乳房鏈球菌 HQ391900 牛毛桿菌 GU324407 尿鏈球菌 DQ303194 多產毛螺菌 FR733699 前庭鏈球菌 AEKO01000008 裂果膠毛螺菌 L14675 綠色鏈球菌 AF076036 毛螺菌科細菌 1_1_57FAA ACTM01000065 莫比利尼薩特菌 AJ832129 毛螺菌科細菌 1_4_56FAA ACTN01000028 帕維魯布拉柴維爾特菌 AB300989 毛螺菌科細菌 2_1_46FAA ADLB01000035 血根薩特菌 AJ748647 毛螺菌科細菌 2_1_58FAA ACTO01000052 薩特菌屬 YIT 12072 AB491210 毛螺菌科細菌 3_1_57FAA_CT1 ACTP01000124 犬糞薩特菌 NR_025600 毛螺菌科細菌 4_1_37FAA ADCR01000030 華德薩特菌 ADMF01000048 毛螺菌科細菌 5_1_57FAA ACTR01000020 互養菌屬複合群 C1 AY278615 毛螺菌科細菌 5_1_63FAA ACTS01000081 互養菌屬 RMA 14551 DQ412722 毛螺菌科細菌 6_1_63FAA ACTV01000014 互養菌門細菌 ADV897 GQ258968 毛螺菌科細菌 8_1_57FAA ACWQ01000079 互養菌門細菌 LBVCM1157 GQ258969 毛螺菌科細菌 9_1_43BFAA ACTX01000023 互養菌門細菌口腔分類群 362 GU410752 毛螺菌科細菌 A4 DQ789118 互養菌門細菌口腔分類群 D48 GU430992 毛螺菌科細菌 DJF VP30 EU728771 Turicibacter sanguinis AF349724 毛螺菌科細菌 ICM62 HQ616401 非典型韋榮氏球菌 AEDS01000059 毛螺菌科細菌 MSX33 HQ616384 殊異韋榮氏球菌 ACIK02000021 毛螺菌科細菌口腔分類群 107 ADDS01000069 韋榮氏球菌屬複合群 P1 口腔植株 MB5_P17 DQ003631 毛螺菌科細菌口腔分類群 F15 HM099641 蒙皮立韋榮氏球菌 AF473836 毛螺菌科複合群 C1 AY278618 小韋榮氏球菌 ADFU01000009 酸魚乳桿菌 NR_024718 韋榮氏球菌屬 3_1_44 ADCV01000019 嗜酸乳桿菌 CP000033 韋榮氏球菌屬 6_1_27 ADCW01000016 食品乳桿菌 NR_044701 韋榮氏球菌屬 ACP1 HQ616359 解澱粉乳桿菌 ADNY01000006 韋榮氏球菌屬物種 AS16 HQ616365 噬澱粉乳桿菌 CP002338 韋榮氏球菌屬物種 BS32b HQ616368 胃竇乳桿菌 ACLL01000037 韋榮氏球菌屬物種 ICM51a HQ616396 短乳桿菌 EU194349 韋榮氏球菌屬物種 MSA12 HQ616381 布赫內氏乳桿菌 ACGH01000101 韋榮氏球菌屬 NVG 100cf EF108443 乾酪乳桿菌 CP000423 韋榮氏球菌屬物種 OK11 JN695650 鏈狀乳桿菌 M23729 韋榮氏球菌屬口腔植株 ASCA08 AY923118 人陰道乳桿菌 ACOH01000030 韋榮氏球菌屬物種口腔植株 ASCB03 AY923122 棒狀乳桿菌 NR_044705 韋榮氏球菌屬物種口腔植株 ASCG01 AY923144 捲曲乳桿菌 ACOG01000151 韋榮氏球菌屬物種口腔植株 ASCG02 AY953257 彎曲乳桿菌 NR_042437 韋榮氏球菌屬物種口腔植株 OH1A AY947495 戴耳布呂克氏乳桿菌 CP002341 韋榮氏球菌屬口腔分類群 158 AENU01000007 糊精乳桿菌 NR_036861 韋榮氏球菌科細菌口腔分類群 131 GU402916 香腸乳桿菌 NR_044707 韋榮氏球菌科細菌口腔分類群 155 GU470897 發酵乳桿菌 CP002033 霍亂弧菌 AAUR01000095 加氏乳桿菌 ACOZ01000018 河流弧菌 X76335 胃乳桿菌 AICN01000060 弗氏弧菌 CP002377 乳桿菌屬複合群 C1 AY278619 擬態弧菌 ADAF01000001 乳桿菌屬複合群 C2 AY278620 副溶血性弧菌 AAWQ01000116 瑞士乳桿菌 ACLM01000202 弧菌屬 RC341 ACZT01000024 希氏乳桿菌 ACGP01000200 創傷弧菌 AE016796 人乳桿菌 FR681902 阿氏耶爾森氏菌 AJ871363 惰性乳桿菌 AEKJ01000002 阿裡克謝耶爾森氏菌 AJ627597 詹氏乳桿菌 ACQD01000066 貝氏耶爾森氏菌 AF366377 約氏乳桿菌 AE017198 小腸結腸炎耶爾森菌 FR729477 卡裡乳桿菌 NR_029083 弗氏耶爾森氏菌 AF366379 馬乳酒樣乳桿菌 NR_042440 中間耶爾森氏菌 AF366380 高加索乳桿菌 NR_042230 克裡斯滕耶爾森氏菌 ACCA01000078 泡菜乳桿菌 NR_025045 莫氏耶爾森氏菌 NR_027546 萊希曼氏乳桿菌 JX986966 鼠疫耶爾森氏菌 AE013632 黏膜乳桿菌 FR693800 假結核耶爾森氏菌 NC_009708 羅氏耶爾森氏菌 ACCD01000071 [ 表 3] ：示例性細菌菌株 菌株 保藏號 古氏副擬桿菌 PTA-126574 動物雙歧桿菌乳酸亞種菌株 A PTA-125097 馬賽布勞特氏菌菌株 A PTA-125134 普雷沃菌屬菌株 B NRRL保藏號B 50329 棲組織普雷沃菌 PTA-126140 布勞特氏菌菌株 A PTA-125346 乳酸乳球菌乳脂亞種菌株 A PTA-125368 唾液乳桿菌 PTA-125893 活潑瘤胃球菌菌株 PTA-125706 納西利斯泰澤菌菌株 PTA-125707 解苯副梭菌 PTA-125894 活潑瘤胃球菌（又稱 Mediterraneibacter gnavus ） PTA-126695 小韋榮氏球菌 PTA-125710 非典型韋榮氏球菌菌株 A PTA-125709 非典型韋榮氏球菌菌株 B PTA-125711 小韋榮氏球菌菌株 A PTA-125691 小韋榮氏球菌菌株 B PTA-125711 當別町韋榮氏球菌菌株 A PTA-125708 阿加薩桿菌屬物種 PTA-125892 Turicibacter sanguinis PTA-125889 類肺炎克雷白氏菌擬肺炎亞種 PTA-125891 催產克雷白氏菌 PTA-125890 巨型球菌屬物種菌株 A PTA-126770 巨型球菌屬物種 PTA-126837 Harryflintia acetispora PTA-126694 Fournierella massiliensis PTA-126696 [ 表 4] . 示例性細菌菌株 大腸桿菌 NCIMB 12210 糞腸球菌 NCIMB 13280 脆弱擬桿菌 DSM 2151 普通擬桿菌 DSM 1447 卵形擬桿菌 DSM 1896 馬賽巨型球菌 DSM 26228 埃氏巨型球菌 NCIMB 8927 馬賽巨型球菌 NCIMB 42787 短雙歧桿菌 DSM 20213 長雙歧桿菌長亞種（ Bifidobacterium longum subsp. longum ） DSM 20219 普氏糞桿菌 DSM 17677 丁酸厭氧棒桿菌 DSM 3319 球形布勞特氏菌 DSM 935 長鏈多爾氏菌 DSM 13814 狄氏副擬桿菌 DSM 20701 扭曲真桿菌 f （ Faecalicatena contorta ） DSM 3982 活潑瘤胃球菌 ATCC 29149 馬賽巨型球菌 NCIMB 43388 馬賽巨型球菌 NCIMB 43389 巨型球菌屬物種 NCIMB 43385 巨型球菌屬物種 NCIMB 43386 巨型球菌屬物種 NCIMB 43387 狄氏副擬桿菌（也稱為「副擬桿菌屬物種 755 」） NCIMB 42382 經修飾的細菌和mEV In some embodiments, the bacteria are from the genus Lactobacillus. In some embodiments, the bacterium is from the species Lactobacillus gasseri. In some embodiments, bacteria from Dysosmobacterbelongs to. In some embodiments, the bacteria are from the species Dysosmobacter welbionis. [ surface 1] : Bacteria, by class outlining head division belongs to species Actinomycetes Actinomycetes Mycobacteriaceae Mycobacterium Streptomycetes Streptomyces Streptomyces lividans, Streptomyces coelicolor, Streptomyces sudanesis , Streptomyces somalia Bifidobacteriaceae Bifidobacteriaceae Bifidobacterium Bifidobacterium adolescentis, Bifidobacterium animalis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium lactis, Bifidobacterium longum, Bifidobacterium pseudobacterium Coriobacteriaceae Coriobacteriaceae Collinsella Collinsella aerogenes Eulandia E. faecalis Propionibacteriaceae Propionibacteriaceae Propionibacterium Bacilli _ _ Bacilluses Bacillus order undetermined XI family twin cocci Gemella haemolyticus, Gemella measles Listeriaceae Listeria Listeria monocytogenes, Listeria weideri Lactobacillus Enterococcus Enterococcus Enterococcus duras, Enterococcus faecalis, Enterococcus faecalis, Enterococcus gallinarum, Enterococcus villosa Lactobacillus Lactobacillus casei, Lactobacillus fermentum, Lactococcus lactis subsp. cremoris, Lactobacillus mucous membranes, Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus salivarius, Lactobacillus gasseri Streptococcus Lactococcus Lactococcus lactis subsp. cremoris staphylococcus Staphylococcus aureus Streptococcus Streptococcus agalactiae, Streptococcus aureus, Streptococcus australis, Streptococcus mutans, Streptococcus parablood, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus salivarius Bacteroides Bacteroidales Bacteroidaceae Bacteroides Bacteroides faecalis, Bacteroides cellulolyticus, Bacteroides faecium, Bacteroides doryei, Bacteroides fragilis, Bacteroides ovale, Bacteroides putrefaciens, Bacteroides serrai, Bacteroides polymorpha, Bacteroides vulgaris Ostrichaceae Ostrichum Osteobacterium viscera Porphyromonas Parabacteroides Parabacteroides distirii, Parabacteroides guerneri, Parabacteroides faecium Porphyromonas Porphyromonas gingivalis Prevotaceae Prevotella Prevotella albers, Prevotella amnioticus, Prevotella aurantia, Prevotti burgdorferi, Prevotella bergenii, Prevotella errata, Prevotella brevius, Brucella Prevotella buccal, Prevotella buccal, Prevotella buccal, Prevotella pigmented, Prevotella human, Prevotella faecalis, Prevotella dental, Prevotella danta, Denta Prevotella, Prevotella saccharolyticus, Prevotella inhabitant, Prevotella fischeri, Prevotella dark black, Prevotella heparinus, Prevotella tissue habitat, Prevotella intermediate Revotobacter, Prevotella jejuni, Prevotella loxeri, Prevotella minor spotted, Prevotella masperiformis, Prevotella nigerigenes, Prevotella rainbow, Prevotella polymorpha , Prevotella saccharophila, Prevotella Nancy, Prevotella nigricans, Prevotella oral cavity, Prevotella oralis, Prevotella rice, Prevotella gingivitis, Prevotella pallidum Worm bacteria, Prevotella marsh, Prevotella pleurisy, Prevotella rumen-dwelling, Prevotella saccharolyticus, Prevotella salivarius, Prevotella bull's-eye, Prevotella syringae, St. Prevotella sera, Prevotella tannera, Prevotella timo, Prevotella vacuum chamber, Prevotella kinetoides Rikenbacteriaceae Alstipes _ _ Alistipes ihumii, Alistipes inops, Alistipes ihumii , Alistipes inops , Alistipes megaguti, Alistipes obesi , Alistipes obesi , Alistipes ihumii, Alistipes obesi Alistipes provencensis , Alistipes provencensis , Alistipes senegalensis, Alistipes senegalensis, Alistipes senegalensis, Alistipes senegalensis , Alistipes senegalensis, Alistipes senegalensis Betaproteobacteria _ _ _ Holderiaceae Alcaligenes Alcaligenes ( Paenalcaligenes ) Alcaligenes human Bordella _ _ Pertussis Burkholderiaceae Burkholderia Burkholderia mallei, Burkholderia pseudo Ralstonia _ _ Ralstonia solanacearum _ Neisseriaceae Neisseria Neisseria meningitidis Sutterellaceae Sutterella Sutterella parvirubra , Sutterella stercoricanis , Sutterella wadsworthhensis Clostridia Clostridiales Catabacteriaceae Seagull bacteria ( Catabacter ) Hong Kong Seagull Fungus Clostridiaceae Aminiphila Anaerosphaera aminiphila Christensenellaceae Christensen martensenii, Timo Christensen Hungatella Hungatella effluvia Eubacteriaceae Eubacterium Eubacterium distorts, Eubacterium fastidiosa, Eubacterium faecalis, Eubacterium gigantea, Eubacterium hallii, Eubacterium mucilage, Eubacterium tenifolia, Eubacterium rectale Lachnospiraceae Anaerobic Corynebacteria ( Anaerostipes ) Anaerobic coryneform bacteria, Anaerostipes hadrus Blautia Hydrogenotrophic Blautia, Blautia marseilles , Blautia excreta, Blautia weideri Cattoella Cattoella sputum Faecococcus Faecalicoccus definiens, Faecococcus chaperone, Faecalicoccus unanimously Diaalisteria Dialister invisus , Dialister micraeophilus , Dialister succinatiphilus Dorella Dorerella formogenes, Dorerella long-chain, Johnsonella Lazy Johnsonella ( Johnsonella ignava ) Oral bacterium Oribacterium parvum , Oribacterium sinus Lachnobacterium _ _ Lachnoclostridium Lacrimispora Lacrimispora sacchaarolytica Roseburia Rosella hominis, Rosella enterica Taizedia Stazerella nascilii Fibrospiraceae Fibroids C.valericibacterium Harryflintia Harryflinta acetispora Peptococcus Peptostreptococcus Paraclostridium Clostridium benzolyticum Peptostreptococcus Peptostreptococcus rosenbergii Ruminococcus Agartsia species Fournierella Fournierella masssiliensis Ruminococcus Ruminococcus albicans, Ruminococcus brucei, Ruminococcus witii, Ruminococcus vivabilis, Ruminococcus inulinivorans, Ruminococcus inulinivorans , Ruminococcus ovale, Ruminococcus twisterensis Faecalibacterium Faecalibacterium prausnitzii Clostridiaceae XIII family/status undecided Intestimonas butyriciproducens Fusobacteria Fusobacteriales Fusobacteriaceae Fusobacterium Fusobacterium nucleatum, Fusobacterium navicularis Ciliary Mycetes ( Leptotrichiaceae ) Cellulomyces Ciliophora C-proteobacteria Enterobacterales _ _ Enterobacteriaceae Klebsiella Klebsiella oxytoca, Klebsiella pneumoniae, Klebsiella pneumoniae subspecies pneumoniae, Escherichia E. coli strain Nissle 1917 ( EcN ) E. coli strain ECOR12 E. coli strain ECOR63 Shigella Negativicutes Acidaminococcaceae _ _ Aminococcus Aminococcus fermentum, Aminococcus enterica Phascolarctobacterium _ _ Koalabacter faecalis, Koalabacter succineri Lunatomonadaceae Lueromonas Lunatomonas Felix, Lunatomonas undetermined, Lunatomonas sputum Sporomusaceae Luneomonales Veillonellaceae Allisonella _ _ Anaerobic coccus Anaeroglobus germinatus Caecibacter Colibacter Megacoccus Megasphera elsedenii , Megasphera marseilles, Megasphera micronuciformis Megasphera species Bacillus ( Massilibacillus ) Bacillus massiliensis _ Propionispira _ _ _ Negativicoccus Negativicoccus succinicivornas Veillonella Veillonella terrestris, Veillonella parvum, Veillonella ratti , Veillonella dobetsu Syntrophyles Syntrophyceae Aminobacterium Aminobacterium mobilis Cloacibacillus _ _ _ Evrybacteria Rarimicrobium Rarimicrobium hominis Verrucobacteria Verrucobacteria Akkermansiaceae Akkermansia Akkermansia mucinophila [ surface 2] : Exemplary bacterial strains OTUs Public DB accession number OTUs Public DB accession number Actinobacillus actinomycetes AY362885 Lactobacillus murine NR_042231 Actinobacillus minor ACFT01000025 Lactobacillus nordensis NR_041629 Actinobacillus pleuropneumoniae NR_074857 Lactobacillus alcohol NR_043095 Actinobacillus succinogenes CP000746 Lactobacillus oralis AEKL01000077 Actinobacillus urea AEVG01000167 Lactobacillus brevis NR_042456 Actinocystium marsiliella AF487679 Lactobacillus Brucella NR_041294 Actinocystium chackei AY957507 Lactobacillus paracasei ABQV01000067 Actinomycetes BM#101342 AY282578 Lactobacillus caucasusoid NR_029039 Actinocoryne sp. P2P_19 P1 AY207066 Lactobacillus pentosus JN813103 Akkermansia muciniphila CP001071 Lactobacillus putalis NR_029360 Mycobacterium fingoldii NR_043064 Lactobacillus plantarum ACGZ02000033 Mycobacterium obscura AB490804 Lactobacillus pontine HM218420 Mycobacterium audendocles NR_043318 Lactobacillus reuteri ACGW02000012 Mycobacterium putrefaciens ABFK02000017 Lactobacillus rhamnosus ABWJ01000068 Mycobacterium salveurii FP929032 Lactobacillus rosenbergii GU269544 Mycobacterium sp . HGB5 AENZ01000082 Lactobacillus rumen ACGS02000043 Anothermycetes sp . JC50 JF824804 Lactobacillus sake DQ989236 Mycobacterium RMA 9912 GQ140629 Lactobacillus salivarius AEBA01000145 Fecal anaerobic coryneform bacteria ABAX03000023 Lactobacillus saniviri _ AB602569 Anaerobic Corynebacterium 3_2_56FAA ACWB01000002 Lactobacillus senile AB602570 Bacillus weatherans NR_025557 Lactobacillus 66c FR681900 Bacillus aerophilus NR_042339 Lactobacillus sp. BT6 HQ616370 Bacillus ehrlichii GQ980243 Lactobacillus sp. KLDS 1.0701 EU600905 Alkalophilic bacillus X76436 Lactobacillus sp. KLDS 1.0702 EU600906 Bacillus amyloliquefaciens NR_075005 Lactobacillus sp. KLDS 1.0703 EU600907 Bacillus anthracis AAEN01000020 Lactobacillus species KLDS 1.0704 EU600908 Bacillus atrophaeus NR_075016 Lactobacillus species KLDS 1.0705 EU600909 Bacillus chestnut NR_036893 Lactobacillus species KLDS 1.0707 EU600911 Bacillus cereus ABDJ01000015 Lactobacillus species KLDS 1.0709 EU600913 Bacillus circulans AB271747 Lactobacillus sp. KLDS 1.0711 EU600915 Bacillus clausii FN397477 Lactobacillus species KLDS 1.0712 EU600916 Bacillus coagulans DQ297928 Lactobacillus species KLDS 1.0713 EU600917 Bacillus tenacious NR_025842 Lactobacillus species KLDS 1.0716 EU600921 Bacillus flexus NR_024691 Lactobacillus species KLDS 1.0718 EU600922 Bacillus flexneri NR_025786 Lactobacillus species KLDS 1.0719 EU600923 Bacillus gelatin NR_025595 Lactobacillus oral plant HT002 AY349382 Bacillus salina NR_026144 Lactobacillus sp. oral plant HT070 AY349383 Bacillus halotolerant AY144582 Lactobacillus oral taxa 052 GQ422710 Bacillus hebstein NR_042286 Lactobacillus salami NR_042194 Bacillus halleri NR_036860 Lactobacillus ulane ACGU01000081 Bacillus NR_043268 Lactobacillus vaginalis ACGV01000168 Bacillus lentus NR_040792 Lactobacillus alcohol NR_042196 Bacillus licheniformis NC_006270 Lactobacillus calf NR_041305 Bacillus megaterium GU252124 Lactobacillus corn NR_037122 Bacillus nissleri NR_044546 Lactococcus gasseri AF061005 Bacillus NR_043334 Lactococcus lactis CP002365 Bacillus Niacinum NR_024695 Lactococcus raffinosus NR_044359 Bacillus spp. NR_041377 Listeria greyii ACCR02000003 Bacillus pumilus NR_074977 Non-toxic Listeria JF967625 Bacillus suffolus JQ624766 Listeria eziri X56151 Bacillus simplex NR_042136 Listeria monocytogenes CP002003 Bacillus sonouri NR_025130 Listeria wesleyi AM263198 Bacillus 10403023 MM10403188 CAET01000089 Megacoccus escherichia AY038996 Bacillus 2_A_57_CT2 ACWD01000095 Megacoccus complex C1 AY278622 Bacillus sp. 2008724126 GU252108 Megacoccus complex type_1 ADGP01000010 Bacillus sp. 2008724139 GU252111 M.micronucleus AECS01000020 Bacillus sp . 7_16AIA FN397518 Megasphaera BLPYG_07 HM990964 Bacillus sp . 9_3AIA FN397519 Megacoccus UPII 199_6 AFIJ01000040 Bacillus sp. AP8 JX101689 Microbacteria gulbaensis NR_025098 Bacillus B27 ( 2008 ) EU362173 Lactobacillus EU714351 Bacillus sp . BT1B_CT2 ACWC01000034 A. jasoni NR_028840 Bacillus sp. GB1.1 FJ897765 Acidum polyacidum ABWK02000005 Bacillus sp. GB9 FJ897766 Mitsuoka oral taxa 521 GU413658 Bacillus sp . HU19.1 FJ897769 Oral taxon G68 of the genus Mitsuoka GU432166 Bacillus sp. HU29 FJ897771 Mycobacterium abscessus AGQU01000002 Bacillus sp. HU33.1 FJ897772 Mycobacterium africanum AF480605 Bacillus sp. JC6 JF824800 Mycobacterium alsiensis AJ938169 Bacillus oral taxa F26 HM099642 Mycobacterium avium CP000479 Bacillus oral taxa F28 HM099650 Mycobacterium chelonis AB548610 Bacillus oral taxa F79 HM099654 Mycobacterium columbia AM062764 Bacillus sp . SRC_DSF1 GU797283 Mycobacterium elephantiasis AF385898 Bacillus sp . SRC_DSF10 GU797292 Mycobacterium gordonii GU142930 Bacillus sp . SRC_DSF2 GU797284 Mycobacterium intracellulare GQ153276 Bacillus sp . SRC_DSF6 GU797288 Mycobacterium kansasii AF480601 Bacillus sp. tc09 HQ844242 Mycobacterium laxi NR_025175 Bacillus sp. zh168 FJ851424 Mycobacterium leprae FM211192 Bacillus sphaericus DQ286318 Diffuse Mycobacterium leprae EU203590 Bacillus sporogenes NR_026010 Mycobacterium mezei FR798914 Bacillus subtilis EU627588 Mycobacterium mansoni FJ042897 Bacillus thermophiles NR_029151 Mycobacterium marinum NC_010612 Bacillus wilsonii NR_074926 Mycobacterium microti NR_025234 Bacteroides ph8 JN837494 Mycobacterium neogold AF268445 Bacteroides complex P1 AY341819 Mycobacterium parascrofula ADNV01000350 Bacteroides complex P2 oral plant MB1_G13 DQ003613 Mycobacterium parateri EU919229 Bacteroides complex P3 oral plant MB1_G34 DQ003615 Mycobacterium phlei GU142920 Bacteroides complex P4 oral plant MB2_G17 DQ003617 Mycobacterium smegmatis DQ536403 Bacteroides complex P5 oral plant MB2_P04 DQ003619 Mycobacterium smegmatis CP000480 Bacteroides complex P6 oral plant MB3_C19 DQ003634 Mycobacterium sp. 1761 EU703150 Bacteroides complex P7 oral plant MB3_P19 DQ003623 Mycobacterium sp. 1776 EU703152 Bacteroides complex P8 oral plant MB4_G15 DQ003626 Mycobacterium sp. 1781 EU703147 Bacteroides acidogenicum NR_028607 Mycobacterium sp. 1791 EU703148 Bacteroides pasteurella NR_041446 Mycobacterium sp. 1797 EU703149 Bacteroides faecalis EU136686 Mycobacterium AQ1GA4 HM210417 Bacteroides cellulolyticus ACCH01000108 Mycobacterium sp. B10_07.09.0206 HQ174245 Bacteroides clarkii AFBM01000011 Mycobacterium sp. GN_10546 FJ497243 Bacteroides coagulans AB547639 Mycobacterium sp. GN_10827 FJ497247 Bacteroides faecalis ABIY02000050 Mycobacterium sp. GN_11124 FJ652846 Bacteroides faecalis ACBW01000012 Mycobacterium sp. GN_9188 FJ497240 Bacteroides doreesii ABWZ01000093 Mycobacterium sp. GR_2007_210 FJ555538 Bacteroides escherichia ACWG01000065 Mycobacterium sp. HE5 AJ012738 Bacteroides faecalis GQ496624 Mycobacterium sp. NLA001000736 HM627011 Bacteroides fingoldii AB222699 Mycobacterium W DQ437715 Bacteroides Aspergillus AFBN01000029 Mycobacterium tuberculosis CP001658 Bacteroides fragilis AP006841 Mycobacterium ulcerans AB548725 Bacteroides galacturonan DQ497994 Mycobacterium fragilis EU834055 Bacteroides ulcerans CP002352 Mycoplasma agalactiae AF010477 Bacteroides heparin JN867284 Mycoplasma amphimorpha AY531656 Enterobacteriaceae ABJL02000006 Mycoplasma arthritis NC_011025 Bacteroides marseille AB200226 Mycoplasma bovis NR_025987 Bacteroides nordii NR_043017 Mycoplasma pharynx NR_024983 Arabidopsis Bacteroides ( Bacteroides oleiciplenus ) AB547644 Mycoplasma fermentum CP002458 Bacteroides ovale ACWH01000036 Mycoplasma flocculus X62699 Bacteroides pectin ABVQ01000036 Mycoplasma genitalium L43967 Bacteroides vulgaris AB200218 Mycoplasma hominis AF443616 Bacteroides pyogenes NR_041280 oral mycoplasma AY796060 Bacteroides salanitronis CP002530 Mycoplasma pneumoniae NR_025989 Bacteroides salyersiae _ EU136690 penetrating mycoplasma NC_004432 Bacteroides 1_1_14 ACRP01000155 Mycoplasma pneumoniae NC_000912 Bacteroides 1_1_30 ADCL01000128 Mycoplasma putrescens U26055 Bacteroides 1_1_6 ACIC01000215 Mycoplasma salivarius M24661 Bacteroides 2_1_22 ACPQ01000117 Mycoplasma complex P1 oral plant MB1_G23 DQ003614 Bacteroides 2_1_56FAA ACWI01000065 Neisseria rod-shaped AFAY01000058 Bacteroides 2_2_4 ABZZ01000168 Neisseria griseus ACDY01000037 Bacteroides 20_3 ACRQ01000064 Neisseria longum ADBF01000003 Bacteroides 3_1_19 ADCJ01000062 Neisseria flavinus ACQV01000025 Bacteroides 3_1_23 ACRS01000081 Neisseria complex P2 oral plant MB5_P15 DQ003630 Bacteroides sp . 3_1_33FAA ACPS01000085 Neisseria gonorrhoeae CP002440 Bacteroides sp . 3_1_40A ACRT01000136 Neisseria lactis ACEQ01000095 Bacteroides 3_2_5 ACIB01000079 Neisseria macaque AFQE01000146 Bacteroides 315_5 FJ848547 Neisseria meningitidis NC_003112 Bacteroides sp . 31SF15 AJ583248 Neisseria mucosa ACDX01000110 Bacteroides sp . 31SF18 AJ583249 Neisseria pharynx AJ239281 Bacteroides sp . 35AE31 AJ583244 Neisseria polysaccharide ADBE01000137 Bacteroides sp . 35AE37 AJ583245 Dried Neisseria ACKO02000016 Bacteroides sp . 35BE34 AJ583246 Neisseria KEM232 GQ203291 Bacteroides sp . 35BE35 AJ583247 Neisseria oral plant AP132 AY005027 Bacteroides 4_1_36 ACTC01000133 Neisseria sp. oral plant JC012 AY349388 Bacteroides sp . 4_3_47FAA ACDR02000029 Neisseria oral strain B33KA AY005028 Bacteroides sp. 9_1_42FAA ACAA01000096 Neisseria oral taxa 014 ADEA01000039 Bacteroides sp. AR20 AF139524 Neisseria sp . SMC_A9199 FJ763637 Bacteroides sp . AR29 AF139525 Neisseria sp . TM10_1 DQ279352 Bacteroides sp. B2 EU722733 Neisseria flaxenum ACEO01000067 Bacteroides sp. D1 ACAB02000030 Bacillus striata AB490805 Bacteroides sp. D2 ACGA01000077 Osteobacterium viscera CP002544 Bacteroides sp. D20 ACPT01000052 Fibroids G2 HM626173 Bacteroides sp. D22 ADCK01000151 C.valericibacterium NR_074793 Bacteroides sp. F_4 AB470322 Spirulina krusei AB040495 Bacteroides sp. NB_8 AB117565 Paenibacillus barcelona NR_042272 Bacteroides species WH2 AY895180 Paenibacillus barengerzii NR_042756 Bacteroides sp . XB12B AM230648 Paenibacillus chiba NR_040885 Bacteroides sp . XB44A AM230649 Paenibacillus kursenii NR_025372 Bacteroides excreta ABFZ02000022 Paenibacillus tenus NR_037017 Bacteroides polymorpha NR_074277 Paenibacillus glucan D78470 Bacteroides monomorpha AB050110 Paenibacillus lactis NR_025739 Bacteroides urealyticum GQ167666 Paenibacillus brilliant NR_040882 Bacteroides vulgaris CP000139 Feed Paenibacillus NR_040853 Bacteroides xylanase ADKP01000087 Paenibacillus polymyxa NR_037006 Bacteroides Bacteria Oral Taxon D27 HM099638 Paenibacillus scarab NR_040888 Bacteroides Bacteria Oral Taxon F31 HM099643 Paenibacillus CIP 101062 HM212646 Bacteroides bacterial oral taxa F44 HM099649 Parabacteroides distrobacter CP000140 Pasteurella enterica AB370251 Parabacteroides guerzii AY974070 Bifidobacterium complex C1 AY278612 Parabacteroides gordonii AB470344 Bifidobacterium adolescent AAXD02000018 Parabacteroides johnsonii ABYH01000014 Bifidobacterium angle ABYS02000004 Parabacteroides faecium EU136685 Bifidobacterium animalis CP001606 Parabacteroides sp. D13 ACPW01000017 Bifidobacterium bifidum ABQP01000027 Parabacteroides sp. NS31_3 JN029805 Bifidobacterium breve CP002743 Peptococcus niger NR_029221 Bifidobacterium chainus ABXY01000019 Peptococcus oral plant JM048 AY349389 Bifidobacterium dental CP001750 Peptococcus oral taxa 167 GQ422727 Bifidobacterium gallatus ABXB03000004 Saccharophila D14145 Bifidobacterium infantis AY151398 Durdaniella spp. EU526290 Bifidobacterium carinii AB491757 Haytophilia NR_026358 Bifidobacterium longum ABQQ01000041 Indoleophilus AY153431 Bifidobacterium pseudostrandum ABXX02000002 Iverophilus Y07840 Bifidobacterium pseudolongum NR_043442 Lacrimal Glandophila ADDO01000050 Bifidobacterium stutzeri AJ307005 Xerophila gpac007 AM176517 Bifidobacterium HM2 AB425276 Acanthophila sp . gpac018A AM176519 Bifidobacterium sp . HMLN12 JF519685 Acanthophila sp . gpac077 AM176527 Bifidobacterium sp. M45 HM626176 Acanthophila sp . gpac148 AM176535 Bifidobacterium sp . MSX5B HQ616382 Acanthophila sp . JC140 JF824803 Bifidobacterium sp . TM_7 AB218972 Oral Taxa 386 ADCS01000031 Bifidobacterium thermophila DQ340557 Oral taxa of the genus Aerophila 836 AEAA01000090 urinary bifidobacteria AJ278695 Peptostreptococcus ph1 JN837495 Blautia globosa AB571656 Anaerobic Peptostreptococcus AY326462 Blautia glucerasea _ AB588023 Peptostreptococcus parvus AM176538 Blautia glucerasei _ AB439724 Peptostreptococcus 9succ1 X90471 Blautia hansenii ABYU02000037 Peptostreptococcus oral plant AP24 AB175072 Hydrogenotrophic Blautia ACBZ01000217 Peptostreptococcus sp. oral plant FJ023 AY349390 Broutia louckeri AB691576 Peptostreptococcus P4P_31 P3 AY207059 Blautia productive AB600998 Peptostreptococcus stomatitis ADGQ01000048 Schenckblaut NR_026312 Porphyromonadaceae NML 060648 EF184292 Blautia sp. M25 HM626178 Porphyromonas saccharolytica AENO01000048 Fecal Blautia HM626177 Porphyromonas pulposus ACNN01000021 Blautia weschleri EF036467 Porphyromonas gingivalis AE015924 Bordetella bronchiseptica NR_025949 Porphyromonas leeseri NR_025907 Bordetella halleri AB683187 Porphyromonas macaque NR_025908 Bordetella parapertussis NR_025950 Porphyromonas sora AB547667 Bordetella pertussis BX640418 Porphyromonas oral plant BB134 AY005068 Borrelia ABCU01000001 Porphyromonas sp. oral plant F016 AY005069 Borrelia burgdorferi ABGI01000001 Porphyromonas oral plant P2PB_52 P1 AY207054 muskrat spirochetes DQ057990 Porphyromonas sp. oral plant P4GB_100 P2 AY207057 Borrelia darton NC_011229 Porphyromonas UQD 301 EU012301 Borrelia ABJV01000001 Porphyromonas Ueno ACLR01000152 Borrelia AY597657 Prevotella alberis NR_025300 spirochete DQ057988 Prevotella amersui AB547670 Borrelia iranii HM161645 Prevotella burgdorferi ACKS01000100 Borrelia regressive AF107367 Prevotella two-way ADFO01000096 Borrelia NE49 AJ224142 Revobacterium brevis NR_041954 Spielmann spirochetes ABKB01000002 Prevotella buccal ACRB01000001 Borrelia mexicani NC_008710 Prevotella buccal JN867261 Borrelia Faris ABCY01000002 Prevotella faecalis ACBX02000014 Brucellosis ovis NC_009504 Human Prevotella L16465 Brucella 83_13 ACBQ01000040 Prevotella tooth AB547678 Brucella BO1 EU053207 Prevotella dentatus CP002589 Brucella suis ACBK01000034 Prevotella saccharolyticum AEDO01000026 Burkholderia bluestem AAUZ01000009 Prevotella complex C1 AY278624 Burkholderia cenocepacia AAHI01000060 Prevotella complex C2 AY278625 Burkholderia cepacia NR_041719 Prevotella complex P7 oral plant MB2_P31 DQ003620 Burkholderia mallei CP000547 Prevotella complex P8 oral plant MB3_P13 DQ003622 Burkholderia polyphagous NC_010086 Prevotella complex P9 oral plant MB7_G16 DQ003633 Burkholderia oklahoma DQ108388 Prevotella heparinus GQ422742 Burkholderia pseudomallei CP001408 Prevotella histotropica JN867315 Burkholderia rhizogenes HQ005410 Prevotella intermedia AF414829 Burkholderia 383 CP000151 Prevotella lobei JN867231 Xenobiotic Burkholderia U86373 Prevotella plaque AGEK01000035 Burkholderia bacterium 1_1_47 ADCQ01000066 Prevotella mazei AEEI01000070 Butyribrio spiciformis ABWN01000012 Prevotella melanogenes CP002122 Vibrio fibrinolyticus U41172 Prevotella rainbow AGWK01000061 Chlamydia murine AE002160 Prevotella polymorpha AEWX01000054 Chlamydia psittaci NR_036864 Prevotella polysaccharide AFJE01000016 Chlamydia trachomatis U68443 Prevotella nancy JN867228 Chlamydiales NS11 JN606074 Prevotella niger AFPX01000069 Citrobacter amalonate FR870441 Oral Prevotella AEPE01000021 Citrobacter brucei NR_028687 Prevotella oralis ADDV01000091 Citrobacter fasdenii AF025371 Prevotella gingivitidis L16472 Citrobacter freundii NR_028894 Prevotella pallidum AFPY01000135 Citrobacter auscule AF025367 Prevotella rumen CP002006 Citrobacter kirkii NC_009792 Prevotella salivarius AB108826 Citrobacter molini AF025369 Prevotella BI_42 AJ581354 Citrobacter murine NR_074903 Prevotella sp. CM38 HQ610181 Citrobacter sebei AF025364 Prevotella sp . ICM1 HQ616385 Citrobacter 30_2 ACDJ01000053 Prevotella sp . ICM55 HQ616399 Citrobacter KMSI_3 GQ468398 Prevotella JCM 6330 AB547699 Citrobacter workmannii AF025373 Prevotella oral plant AA020 AY005057 Citrobacter youngae ABWL02000011 Prevotella sp. oral plant ASCG10 AY923148 Evrybacteria GQ258966 Oral plant of Prevotella sp . ASCG12 DQ272511 ClostridiaceaeEND_2 _ EF451053 Prevotella sp. oral plant AU069 AY005062 Clostridiaceae JC13 JF824807 Prevotella sp. oral plant CY006 AY005063 Clostridium 1_7_47FAA ABQR01000074 Prevotella sp. oral plant DA058 AY005065 Clostridium bacteria 9400853 HM587320 Prevotella sp. oral plant FL019 AY349392 Clostridium bacteria 9403326 HM587324 Prevotella sp. oral plant FU048 AY349393 Clostridium bacteria oral plant P4PA_66 P1 AY207065 Prevotella sp. oral plant FW035 AY349394 Clostridia Bacteria Oral Taxon 093 GQ422712 Prevotella sp. oral plant GI030 AY349395 Clostridia Bacteria Oral Taxon F32 HM099644 Prevotella sp. oral plant GI032 AY349396 Clostridium ph2 JN837487 Prevotella sp. oral plant GI059 AY349397 Clostridium bacterium SY8519 AB477431 Prevotella sp. oral plant GU027 AY349398 Clostridium complex BVAB3 CP001850 Prevotella sp. oral plant HF050 AY349399 Clostridium SM4_1 FP929060 Prevotella sp. oral plant ID019 AY349400 Clostridium sp. SS3_4 AY305316 Oral plant of Prevotella sp . IDR_CEC_0055 AY550997 Clostridium species SSC_2 FP929061 Prevotella sp. oral plant IK053 AY349401 Acetone Butanol Sulfate NR_074511 Prevotella sp. oral plant IK062 AY349402 Oxycloxacid X76163 Prevotella oral plant P4PB_83 P2 AY207050 Clostridium aldenia NR_043680 Prevotella species oral taxa 292 GQ422735 Clostridium aldrichia NR_026099 Prevotella species oral taxa 299 ACWZ01000026 Clostridium algae NR_041746 Prevotella species oral taxa 300 GU409549 Clostridium alginolyticus NR_028726 Prevotella species oral taxa 302 ACZK01000043 Clostridium aminovalerate NR_029245 Prevotella species oral taxa 310 GQ422737 Clostridium amygdala AY353957 Prevotella species oral taxa 317 ACQH01000158 Clostridium argentinosus NR_029232 Prevotella species oral taxa 472 ACZS01000106 Clostridium asparticum ACCJ01000522 Prevotella species oral taxa 781 GQ422744 Clostridium pasteuriani NR_029229 Prevotella species oral taxa 782 GQ422745 Clostridium barthelii ABEZ02000012 Prevotella oral taxa F68 HM099652 Clostridium beijerinckii NR_074434 Prevotella species oral taxa G60 GU432133 Dizyme Clostridium X73437 Prevotella species oral taxa G70 GU432179 Clostridium boaumannii ABCC02000039 Prevotella species oral taxa G71 GU432180 Clostridium botulinum NC_010723 Prevotella sp . SEQ053 JN867222 Clostridium butyricum ABDT01000017 Prevotella sp . SEQ065 JN867234 Clostridium cadavericum AB542932 Prevotella sp . SEQ072 JN867238 Clostridium carbotrophans FR733710 Prevotella sp . SEQ116 JN867246 Clostridium sarcomatum NR_044716 Prevotella sp. SG12 GU561343 Hidden Clostridium X77844 Prevotella sp. sp24 AB003384 Clostridium fast-growing JQ246092 Prevotella sp34 AB003385 Clostridium cellulosus NR_044624 Prevotella faecalis AB244774 Clostridium showardii EU106372 Prevotella tannai ACIJ02000018 Clostridium citronella ADLJ01000059 Timmons Prevotella ADEF01000012 Clarifying Clostridium NR_041235 Prevotella euforum ACVA01000027 Clostridium M59089 Prevotellaceae P4P_62 P1 AY207061 Clostridium clostridium NR_044715 Propionibacteriaceae NML 02_0265 EF599122 Clostridium sphaericus EF025906 Propionibacterium propionici NC_019395 Clostridium sp. NR_044717 Propionibacterium acnes ADJM01000010 Clostridium cochlea NR_026495 Propionibacterium greedy AJ003055 Clostridium canis FJ957863 Propionibacterium freunderi NR_036972 Clostridium partridge NR_026151 Propionibacterium granulosa FJ785716 Clostridium difficile NC_013315 Propionibacterium janssenii NR_042269 Clostridium bisporus NR_026491 Propionibacterium propionii NR_025277 Clostridium Esterifera NR_042153 Propionibacterium 434_HC2 AFIL01000035 Clostridium flexneri NR_044714 Propionibacterium sp. H456 AB177643 Clostridium favososporum X76749 Propionibacterium LG AY354921 Clostridium phyllonii AF270502 Propionibacterium oral taxa 192 GQ422728 Clostridium cold NR_024919 Propionibacterium sp . S555a AB264622 Clostridium aerogenes NR_024945 Propionibacterium ternii NR_042270 Clostridium gordii AB542933 Pseudomonas aeruginosa AABQ07000001 Clostridium glycolate FJ384385 Pseudomonas fluorescens AY622220 Clostridium faecalis AB233029 Pseudomonas gailizii FJ943496 Clostridium hemolyticus NR_024749 Pseudomonas mendoza AAUL01000021 Clostridium harveyii AY552788 Pseudomonas monsonii NR_024910 Clostridium Hiranoi AB023970 Pseudomonas phrysalis GU188951 Clostridium histolyticum HF558362 Pseudomonas pseudoalcaligenes NR_037000 Clostridium hilari AB023973 Pseudomonas putida AF094741 Clostridium indole AF028351 Pseudomonas 2_1_26 ACWU01000257 Clostridium harmless M23732 Pseudomonas sp. G1229 DQ910482 Clostridium irregular NR_029249 Pseudomonas sp . NP522b EU723211 Clostridium isatidis NR_026347 Pseudomonas stutzeri AM905854 Clostridium krustani NR_074165 Pseudomonas tola AF320988 Clostridium lactis fermentum NR_025651 Pseudomonas aeruginosa NR_042764 Clostridium lavalla EF564277 R.pieteri NC_010682 Clostridium tenabilis AJ305238 Ralstonia 5_7_47FAA ACUF01000076 Clostridium saccharum FR870444 Bairrellia cecum GU233441 Clostridium macrophylla X77835 B. faecalis AY804149 Clostridium notoria FR749893 Bairrellia faecalis AY305310 Clostridium mayobe FR733682 Bairrellia hominis AJ270482 Clostridium pentosacillus ACEC01000059 Rosborella enterica FP929050 Clostridium conjunctivum X73443 Bairretia rosea AJ270473 Clostridium novyi NR_074343 Roseborella sp . 11SE37 FM954975 Clostridium butyricum Y18187 Roseborella sp . 11SE38 FM954976 Clostridium oroticum FR749922 Aerobicella DQ673320 Clostridium paracorrosion AB536771 Rostella cari ADDW01000024 Clostridium perfringens ABDW01000023 R. slime ACVO01000020 Clostridium phytofermentum NR_074652 Rothella murhiza NR_025310 Clostridium pilaris D14639 Rhodesia oral taxa 188 GU470892 Clostridium putrefaciens NR_024995 Bacillus amylovora Rumininum NR_026450 Clostridium quinine NR_026149 Ruminococcus D16 ADDX01000083 Clostridium mycobacterium M23731 Ruminococcus albicans AY445600 Clostridium rectum NR_029271 Ruminococcus brucei EU266549 Clostridium saccharophores DQ100445 Ruminococcus witii NR_029160 Clostridium saccharifera CP002109 Ruminococcus champanellensis FP929052 Clostridium sardinia NR_041006 Ruminococcus xanthococcus NR_025931 Clostridium pan NR_026490 Ruminococcus mobilis X94967 Clostridium lyticum AF262238 Ruminococcus hansenii M59114 Clostridium septicemia NR_026020 Ruminococcus lactis ABOU02000049 Clostridium sordarii AB448946 Ruminococcus ova AY169419 Clostridium 7_2_43FAA ACDK01000101 Ruminococcus 18P13 AJ515913 Clostridium sp. D5 ADBG01000142 Ruminococcus sp. 5_1_39BFAA ACII01000172 Clostridium sp . HGF2 AENW01000022 Ruminococcus sp . 9SE51 FM954974 Clostridium sp. HPB_46 AY862516 Ruminococcus sp. ID8 AY960564 Clostridium sp. JC122 CAEV01000127 Ruminococcus sp . K_1 AB222208 Clostridium sp. L2_50 AAYW02000018 Ruminococcus twisterensis AAVP02000002 Clostridium LMG 16094 X95274 Salmonella Bongor NR_041699 Clostridium sp . M62_1 ACFX02000046 Salmonella Enteritidis NC_011149 Clostridium sp. MLG055 AF304435 Salmonella Enteritidis NC_011205 Clostridium MT4 E FJ159523 Salmonella Enteritidis DQ344532 Clostridium species NMBHI_1 JN093130 Salmonella Enteritidis ABEH02000004 Clostridium NML 04A032 EU815224 Salmonella Enteritidis ABAK02000001 Clostridium sp . SS2_1 ABGC03000041 Salmonella Enteritidis NC_011080 Clostridium sp . SY8519 AP012212 Salmonella Enteritidis EU118094 Clostridium sp. TM_40 AB249652 Salmonella Enteritidis NC_011094 Clostridium sp. YIT 12069 AB491207 Salmonella Enteritidis AE014613 Clostridium sp. YIT 12070 AB491208 Salmonella Enteritidis ABFH02000001 Clostridium cuneiformis X73449 Salmonella Enteritidis ABEM01000001 Clostridium spirochetes X73441 Salmonella Enteritidis ABAM02000001 Clostridium sporogenes ABKW02000003 Salmonella typhimurium DQ344533 Clostridium sporogenes NR_044835 Salmonella typhimurium AF170176 Clostridium faecalis NR_025100 Luneomonas arachnoid HM596274 Clostridium sticklandii L04167 ichthymoonas GQ422719 Clostridium stravins NR_024829 Luuemonas flexneri AF287803 Clostridium proximal NR_041795 Luneomonas complex C1 AY278627 Clostridium thiogenes NR_044161 Luneomonas complex C2 AY278628 Clostridium symbiotica ADLQ01000114 Lueromonas complex P5 AY341820 Clostridium tertiary Y18174 Oral Plant MB3_C41 of Luneumonas Complex P6 DQ003636 Clostridium tetani NC_004557 Oral plant MB5_C08 from Seuromonas complex P7 DQ003627 Clostridium thermophilus NR_074629 Oral plant MB5_P06 from Seuromonas complex P8 DQ003628 Clostridium tyrobutyricum NR_044718 Crescentomonas lesion AF287802 Clostridium viridans NR_026204 Harmful Lunatomonas GU470909 Clostridium xylanolyticum NR_037068 Lunatomonas ruminants NR_075026 Collinsella aerogenes AAVN02000007 Lueromonas sp . FOBRC9 HQ616378 Collinsella enterica ABXH02000037 Luuemonas oral plant FT050 AY349403 Collinsella feces ABXJ01000150 Lueromonas sp. oral plant GI064 AY349404 Collinsella Tanaka AB490807 Lueromonas sp. oral plant GT010 AY349405 Streptococcus faecalis AB030218 Luuemonas sp. oral plant HU051 AY349406 Faecalibacterium 29_1 ADKX01000057 Lueromonas sp. oral plant IK004 AY349407 Faecalibacterium D7 ACDT01000199 Lueromonas sp. oral plant IQ048 AY349408 Faecococcus definiens EU266552 Lueromonas sp. oral plant JI021 AY349409 Coprococcus ABVR01000038 Lueromonas sp. oral plant JS031 AY349410 Faecococcus unanimously EF031543 Lueromonas sp oral plant OH4A AY947498 Coprococcus ART55_1 AY350746 Luuemonas oral plant P2PA_80 P4 AY207052 Diaalisteria turbidity ACIM02000001 Lueromonas species oral taxa 137 AENV01000007 Alisteria microaerobica AFBB01000028 Lueromonas species oral taxa 149 AEEJ01000007 Alisteria microaerophila AENT01000008 Luteomonas sputum ACKP02000033 Alisteria pneumoniae HM596297 Serratia genus NR_025339 Alisteria propionici NR_043231 Serratia liquefaction NR_042062 Diaalisteria oral taxa 502 GQ422739 Serratia marcescens GU826157 Alisteria succiniphila AB370249 Serratia odorifera ADBY01000001 Dorrelia formigenes AAXA02000006 Serratia proteus AAUN01000015 long chain dorsella AJ132842 Shigella boydella AAKA01000007 Aquacystis aeruginosa ACYI01000081 Shigella dysenteriae NC_007606 Enterobacter aerogenes AJ251468 Shigella flexneri AE005674 Enterobacter arseni NR_024640 Shigella sonnei NC_007384 Enterobacter carcinogens Z96078 Sphingobacter faecalis NR_025537 Enterobacter cloacae FP929040 Sphingobacterium water JF708889 Enterobacter courier NR_025566 Sphingobacterium multivorum NR_040953 Enterobacter hallii AFHR01000079 S.sphingobacterium eaturus ACHA02000013 Enterobacter 247BMC HQ122932 Sphingomonas spinosa NR_024700 Enterobacter 638 NR_074777 Sphingomonas oral plant FI012 AY349411 Enterobacter sp. JC163 JN657217 Sphingomonas sp. oral plant FZ016 AY349412 Enterobacter SCSS HM007811 Sphingomonas oral taxa A09 HM099639 Enterobacter sp . TSE38 HM156134 Sphingomonas species oral taxa F71 HM099645 Enterobacteriaceae 9_2_54FAA ADCU01000033 Staphylococcus NML 92_0017 AY841362 Enterobacteriaceae CF01Ent_1 AJ489826 Staphylococcus aureus CP002643 Enterobacteriaceae Smarlab 3302238 AY538694 Staphylococcus auris JQ624774 Enterococcus avium AF133535 Staphylococcus capitis ACFR01000029 Enterococcus faecalis AY943820 Staphylococcus goatis ACRH01000033 Enterococcus caseoflavus AEWT01000047 Staphylococcus meatus NR_075003 Enterococcus duras AJ276354 Staphylococcus coli JN175375 Enterococcus faecalis AE016830 Staphylococcus spice NR_029345 Enterococcus faecium AM157434 Staphylococcus epidermidis ACHE01000056 Enterococcus gallinarum AB269767 Staphylococcus equi NR_027520 Enterococcus griseus AY033814 Staphylococcus freundii NR_041326 Enterococcus hawaii AY321377 Haemolytic Staphylococcus NC_007168 Enterococcus hirsuti AF061011 Staphylococcus hominis AM157418 Enterococcus italiana AEPV01000109 Staphylococcus ludunensis AEQA01000024 Enterococcus monsonii NR_024906 Staphylococcus pasteurianus FJ189773 Enterococcus raffinose FN600541 Staphylococcus pseudointermediates CP002439 Enterococcus sp. BV2CASA2 JN809766 Staphylococcus saccharolyticus NR_029158 Enterococcus species CCRI_16620 GU457263 saprophytic staphylococcus NC_007350 Enterococcus sp. F95 FJ463817 Staphylococcus squirrel NR_025520 Enterococcus sp. RfL6 AJ133478 Staphylococcus sp. bottae7 AF467424 Enterococcus thailand AY321376 Staphylococcus H292 AB177642 Erysipelothrixaceae 3_1_53 ACTJ01000113 Staphylococcus sp. H780 AB177644 Erysipelothrixaceae 5_2_54FAA ACZW01000054 Staphylococcus succinate NR_028667 Escherichia coli ABKX01000012 Staphylococcus calf NR_024670 Escherichia coli NC_008563 Staphylococcus varrera ACPZ01000009 Escherichia coli CU928158 Staphylococcus xylosus AY395016 Escherichia coli Hermannii HQ407266 streptobacter moniliform NR_027615 Escherichia coli 1_1_43 ACID01000033 Streptococcus agalactiae AAJO01000130 Escherichia coli 4_1_40B ACDM02000056 Non-lactating Streptococcus NR_041781 Escherichia coli species B4 EU722735 Streptococcus angina AECT01000011 Escherichia wounds NR_041927 Streptococcus australis AEQR01000024 Eubacteriaceae P4P_50 P4 AY207060 Streptococcus bovis AEEL01000030 Eubacterium barkeri NR_044661 Streptococcus canis AJ413203 Eubacterium amphimorpha ABYT01000002 Streptococcus constellation AY277942 Eubacterium brevis U13038 Streptococcus spine AEVC01000028 Eubacterium brucei NR_024682 Streptococcus daunensis AEKN01000002 Eubacterium carinii NR_026330 Streptococcus dysgalactiae AP010935 Eubacterium cellulolyticum AY178842 Streptococcus equi CP001129 Eubacterium twistus FR749946 Streptococcus equi AEVB01000043 Eubacterium faecalis HM037995 Streptococcus gallolyticum FR824043 Cylindrical Eubacterium FP929041 Streptococcus complex C1 AY278629 Eubacterium streptoides NR_044644 Streptococcus complex C2 AY278630 Eubacterium elongatus L34682 Streptococcus complex C3 AY278631 Eubacterium fusilis CP001104 Streptococcus complex C4 AY278632 chain-disrupting Eubacterium FR749935 Streptococcus complex C5 AY278633 Eubacterium mammothum FR749933 Streptococcus complex C6 AY278634 Eubacterium hallii L34621 Streptococcus complex C7 AY278635 Eubacterium delicate U13039 Streptococcus complex C8 AY278609 Eubacterium silt CP002273 Streptococcus gordonii NC_009785 Eubacterium moniliforme HF558373 Pediatric Streptococcus ABJK02000017 Eubacterium polymorpha NR_024683 Streptococcus infantis AFNN01000024 Eubacterium nitrosogenes NR_024684 Streptococcus intermedia NR_028736 Eubacterium entanglement U13041 Streptococcus paris NR_037096 Mycobacterium mycobacterium AJ011522 Streptococcus marseille AY769997 Eubacterium rectum FP929042 Streptococcus muelleri X81023 Eubacterium ruminantum NR_024661 Streptococcus mitis AM157420 Eubacterium halitosis AB525414 Streptococcus mutans AP010655 Cryptobacterium NR_026031 Streptococcus oligofermentum AY099095 Inert Eubacteria ABCA03000054 Oral Streptococcus ADMV01000001 Eubacterium 3_1_31 ACTL01000045 Streptococcus parasanguis AEKM01000012 Eubacteria AS15b HQ616364 Streptococcus pasteuri AP012054 Eubacterium sp . OBRC9 HQ616354 Pan-oral Streptococcus AEVF01000016 Eubacterium oral plant GI038 AY349374 Streptococcus pneumoniae AE008537 Eubacterium sp. oral plant IR009 AY349376 Streptococcus boar EF121439 Eubacterium sp. oral plant JH012 AY349373 Streptococcus pseudopneumoniae FJ827123 Eubacterium sp. oral plant JI012 AY349379 Streptococcus pseudoboar AENS01000003 Eubacterium sp. oral plant JN088 AY349377 Streptococcus pyogenes AE006496 Eubacterium sp. oral plant JS001 AY349378 Streptococcus murine X58304 Eubacterium sp. oral plant OH3A AY947497 Streptococcus salivarius AGBV01000001 Eubacteria WAL 14571 FJ687606 Streptococcus sanguinis NR_074974 Eubacterium gracilis M59118 Streptococcus sinensis AF432857 Eubacterium polyformis NR_044648 Streptococcus sp . 16362 JN590019 Eubacterium proboscis L34421 Streptococcus 2_1_36FAA ACOI01000028 Eubacterium xylanophilus L34628 Streptococcus 2285_97 AJ131965 Eubacterium eu AEES01000073 Streptococcus sp . 69130 X78825 Fusobacterium canis AY162222 Streptococcus sp. AC15 HQ616356 Fusobacterium complex C1 AY278616 Streptococcus sp . ACS2 HQ616360 Fusobacterium complex C2 AY278617 Streptococcus sp. AS20 HQ616366 Fusobacterium microbiota ACET01000043 Streptococcus sp. BS35a HQ616369 fusobacterium death ACDB02000034 Streptococcus sp. C150 ACRI01000045 Fusobacterium navifii HQ223106 Streptococcus sp. CM6 HQ616372 Fusobacterium gangrene X55408 Streptococcus sp. CM7 HQ616373 Fusobacterium necroptosis AM905356 Streptococcus sp. ICM10 HQ616389 Fusobacterium nucleatum ADVK01000034 Streptococcus sp. ICM12 HQ616390 Fusobacterium periodontal ACJY01000002 Streptococcus sp . ICM2 HQ616386 Fusobacterium lageri NR_044687 Streptococcus sp. ICM4 HQ616387 Fusobacterium 1_1_41FAA ADGG01000053 Streptococcus sp. ICM45 HQ616394 Fusobacterium 11_3_2 ACUO01000052 Streptococcus sp. M143 ACRK01000025 Fusobacterium sp . 12_1B AGWJ01000070 Streptococcus sp. M334 ACRL01000052 Fusobacterium 2_1_31 ACDC02000018 Streptococcus sp . OBRC6 HQ616352 Fusobacterium 3_1_27 ADGF01000045 Streptococcus sp. oral plant ASB02 AY923121 Fusobacterium 3_1_33 ACQE01000178 Streptococcus sp. oral plant ASCA03 DQ272504 Fusobacterium sp. 3_1_36A2 ACPU01000044 Streptococcus sp. oral plant ASCA04 AY923116 Fusobacterium sp . 3_1_5R ACDD01000078 Streptococcus sp. oral plant ASCA09 AY923119 Fusobacterium sp. AC18 HQ616357 Streptococcus sp. oral plant ASCB04 AY923123 Fusobacterium sp . ACB2 HQ616358 Streptococcus sp. oral plant ASCB06 AY923124 Fusobacterium sp. AS2 HQ616361 Streptococcus sp. oral plant ASCC04 AY923127 Fusobacterium sp. CM1 HQ616371 Streptococcus sp. oral plant ASCC05 AY923128 Fusobacterium sp. CM21 HQ616375 Streptococcus sp. oral plant ASCC12 DQ272507 Fusobacterium sp. CM22 HQ616376 Streptococcus sp. oral plant ASCD01 AY923129 Fusobacterium sp. D12 ACDG02000036 Streptococcus sp. oral plant ASCD09 AY923130 Fusobacterium oral plant ASCF06 AY923141 Streptococcus sp. oral plant ASCD10 DQ272509 Fusobacterium sp. oral plant ASCF11 AY953256 Streptococcus sp. oral plant ASCE03 AY923134 Fusobacterium ulcerans ACDH01000090 Streptococcus sp. oral plant ASCE04 AY953253 Fusobacterium proteus ACIE01000009 Streptococcus sp. oral plant ASCE05 DQ272510 Geminococcus haemolyticus ACDZ02000012 Streptococcus sp. oral plant ASCE06 AY923135 Gemella measles NR_025904 Streptococcus sp. oral plant ASCE09 AY923136 Gemella measles ACRX01000010 Streptococcus sp. oral plant ASCE10 AY923137 Haemotwinia ACRY01000057 Streptococcus sp. oral plant ASCE12 AY923138 Geminococcus oral plant ASCE02 AY923133 Streptococcus sp. oral plant ASCF05 AY923140 Geminococcus sp. oral plant ASCF04 AY923139 Streptococcus sp. oral plant ASCF07 AY953255 Geminococcus sp. oral plant ASCF12 AY923143 Streptococcus sp. oral plant ASCF09 AY923142 Geminicoccus WAL 1945J EU427463 Streptococcus sp. oral plant ASCG04 AY923145 Klebsiella oxytoca AY292871 Streptococcus sp. oral plant BW009 AY005042 Klebsiella pneumoniae CP000647 Streptococcus sp. oral plant CH016 AY005044 Klebsiella AS10 HQ616362 Streptococcus sp. oral plant GK051 AY349413 Klebsiella sp . Co9935 DQ068764 Streptococcus sp. oral plant GM006 AY349414 Klebsiella enrichment culture plant SRC_DSD25 HM195210 Streptococcus oral plant P2PA_41 P2 AY207051 Klebsiella sp . OBRC7 HQ616353 Streptococcus sp. oral plant P4PA_30 P4 AY207064 Klebsiella SP_BA FJ999767 Streptococcus oral taxa 071 AEEP01000019 Klebsiella sp . SRC_DSD1 GU797254 Streptococcus oral taxa G59 GU432132 Klebsiella sp . SRC_DSD11 GU797263 Streptococcus species oral taxa G62 GU432146 Klebsiella sp . SRC_DSD12 GU797264 Streptococcus species oral taxa G63 GU432150 Klebsiella sp . SRC_DSD15 GU797267 Streptococcus sp . SHV515 Y07601 Klebsiella sp . SRC_DSD2 GU797253 Streptococcus suis FM252032 Klebsiella sp . SRC_DSD6 GU797258 Streptococcus thermophilus CP000419 Klebsiella mutans CP001891 Streptococcus uberis HQ391900 Bacillus bovis GU324407 Urinary Streptococcus DQ303194 Lachnospira multigenes FR733699 Streptococcus vestibularis AEKO01000008 Lachnospira spectinosa L14675 Streptococcus viridans AF076036 Lachnospiraceae 1_1_57FAA ACTM01000065 mobilinisarteria AJ832129 Lachnospiraceae 1_4_56FAA ACTN01000028 Vertella pavelula AB300989 Lachnospiraceae 2_1_46FAA ADLB01000035 Sagittarius haemarootus AJ748647 Lachnospiraceae 2_1_58FAA ACTO01000052 Sutterella YIT 12072 AB491210 Lachnospiraceae 3_1_57FAA_CT1 ACTP01000124 Satterella canis NR_025600 Lachnospiraceae 4_1_37FAA ADCR01000030 Howard Sartre ADMF01000048 Lachnospiraceae 5_1_57FAA ACTR01000020 Syntrophic complex C1 AY278615 Lachnospiraceae 5_1_63FAA ACTS01000081 Syntrophy RMA 14551 DQ412722 Lachnospiraceae 6_1_63FAA ACTV01000014 Syntrophic bacteria ADV897 GQ258968 Lachnospiraceae 8_1_57FAA ACWQ01000079 Syntrophic bacteria LBVCM1157 GQ258969 Lachnospiraceae 9_1_43BFAA ACTX01000023 Oral taxa of syntrophic bacteria 362 GU410752 Lachnospiraceae A4 DQ789118 Oral Taxon D48 of Syntrophic Bacteria GU430992 Lachnospiraceae DJF VP30 EU728771 Turicibacter sanguinis AF349724 Lachnospiraceae ICM62 HQ616401 Atypical Veillonella AEDS01000059 Lachnospiraceae MSX33 HQ616384 Veillonella versicolor ACIK02000021 Lachnospiraceae oral taxa 107 ADDS01000069 Veillonella complex P1 oral plant MB5_P17 DQ003631 Oral Taxon F15 of Lachnospiraceae Bacteria HM099641 Veillonella epidermis AF473836 Lachnospiraceae complex C1 AY278618 Veillonella parvum ADFU01000009 Lactobacillus acidfish NR_024718 Veillonella 3_1_44 ADCV01000019 Lactobacillus acidophilus CP000033 Veillonella 6_1_27 ADCW01000016 Lactobacillus food NR_044701 Veillonella ACP1 HQ616359 Lactobacillus amyloliquefaciens ADNY01000006 Veillonella sp . AS16 HQ616365 Lactobacillus amylovora CP002338 Veillonella sp. BS32b HQ616368 Lactobacillus gastric antrum ACLL01000037 Veillonella sp . ICM51a HQ616396 Lactobacillus brevis EU194349 Veillonella sp . MSA12 HQ616381 Lactobacillus buchneri ACGH01000101 Veillonella NVG 100cf EF108443 Lactobacillus casei CP000423 Veillonella sp . OK11 JN695650 Lactobacillus streptoides M23729 Veillonella oral plant ASCA08 AY923118 Lactobacillus human vaginalis ACOH01000030 Veillonella sp oral plant ASCB03 AY923122 Lactobacillus coryneformis NR_044705 Veillonella sp. oral plant ASCG01 AY923144 Lactobacillus crispatus ACOG01000151 Veillonella sp. oral plant ASCG02 AY953257 Lactobacillus flexus NR_042437 Veillonella sp oral plant OH1A AY947495 Lactobacillus delbrueckii CP002341 Veillonella oral taxa 158 AENU01000007 Lactobacillus dextrin NR_036861 Veillonellaceae Bacterial Oral Taxon 131 GU402916 Lactobacillus sausage NR_044707 Veillonellaceae Bacterial Oral Taxon 155 GU470897 Lactobacillus fermentum CP002033 Vibrio cholerae AAUR01000095 Lactobacillus gasseri ACOZ01000018 Vibrio river X76335 Lactobacillus stomach AICN01000060 Vibrio flexneri CP002377 Lactobacillus complex C1 AY278619 Mimic Vibrio ADAF01000001 Lactobacillus complex C2 AY278620 Vibrio parahaemolyticus AAWQ01000116 Lactobacillus helveticus ACLM01000202 Vibrio RC341 ACZT01000024 Lactobacillus hirsuti ACGP01000200 Vibrio vulnificus AE016796 Lactobacillus human FR681902 Yersinia arzii AJ871363 Inert Lactobacillus AEKJ01000002 Yersinia alexis AJ627597 Lactobacillus jennis ACQD01000066 Yersinia bellii AF366377 Lactobacillus johnsonii AE017198 Yersinia enterocolitica FR729477 Lactobacillus cari NR_029083 Yersinia flexneri AF366379 Lactobacillus kefir NR_042440 Yersinia intermedia AF366380 Lactobacillus caucasus NR_042230 Yersinia kristen ACCA01000078 Lactobacillus kimchi NR_025045 Yersinia morkii NR_027546 Lactobacillus reichmannii JX986966 Yersinia pestis AE013632 Lactobacillus mucosa FR693800 Yersinia pseudotuberculosis NC_009708 Yersinia rochei ACCD01000071 [ surface 3] : Exemplary bacterial strains strain Accession number Parabacteroides guerzii PTA-126574 Bifidobacterium animalis subsp. lactis strain A PTA-125097 Broutia marseille strain A PTA-125134 Prevotella strain B NRRL Deposit No. B 50329 Prevotella histotropica PTA-126140 Blautia strain A PTA-125346 Lactococcus lactis subsp. cremoris strain A PTA-125368 Lactobacillus salivarius PTA-125893 Ruminococcus vivabilis PTA-125706 Stazerella nascilii strain PTA-125707 Clostridium benzolyticum PTA-125894 Ruminococcus vivabilis (also known as Mediterraneibacter gnavus ) PTA-126695 Veillonella parvum PTA-125710 Atypical Veillonella strain A PTA-125709 Atypical Veillonella strain B PTA-125711 Veillonella parvum strain A PTA-125691 Veillonella parvum strain B PTA-125711 Veillonella dabetsuchoi strain A PTA-125708 Agartsia species PTA-125892 Turicibacter sanguinis PTA-125889 Klebsiella pneumoniae subsp. pneumoniae PTA-125891 Klebsiella oxytoca PTA-125890 Megasphaera sp. strain A PTA-126770 Megacoccus species PTA-126837 Harryflintia acetispora PTA-126694 Fournierella massiliensis PTA-126696 [ surface 4] . Exemplary Bacterial Strains Escherichia coli NCIMB 12210 Enterococcus faecalis NCIMB 13280 Bacteroides fragilis DSM 2151 Bacteroides vulgaris DSM 1447 Bacteroides ovale DSM 1896 M. marseilles DSM 26228 Megacoccus escherichia NCIMB 8927 M. marseilles NCIMB 42787 Bifidobacterium breve DSM 20213 Bifidobacterium longum subsp. longum DSM 20219 Faecalibacterium prausnitzii DSM 17677 Corynebacterium butyricum DSM 3319 Blautia globosa DSM 935 long chain dorsella DSM 13814 Parabacteroides distrobacter DSM 20701 Eubacterium contorta f ( Faecalicatena contorta ) DSM 3982 Ruminococcus mobilis ATCC 29149 M. marseilles NCIMB 43388 M. marseilles NCIMB 43389 Megacoccus species NCIMB 43385 Megacoccus species NCIMB 43386 Megacoccus species NCIMB 43387 Parabacteroides distirii (also known as "Parabacteroides sp. 755 ") NCIMB 42382 Modified bacteria and mEVs

在一些方面，本文所述之細菌和/或mEV（如smEV和/或pmEV）經修飾，使得它們包含、連接至和/或結合治療性部分。In some aspects, the bacteria and/or mEVs (eg, smEV and/or pmEV) described herein are modified such that they contain, are linked to, and/or bind a therapeutic moiety.

在一些實施方式中，治療性部分係癌症特異性部分。在一些實施方式中，該癌症特異性部分對癌細胞具有結合特異性（例如對癌症特異性抗原具有結合特異性）。在一些實施方式中，該癌症特異性部分包含抗體或其抗原結合片段。在一些實施方式中，該癌症特異性部分包含T細胞受體或嵌合抗原受體（CAR）。在一些實施方式中，該癌症特異性部分包含表現於癌細胞表面上受體的配位基或其受體結合片段。在一些實施方式中，該癌症特異性部分係二分（bipartite）融合蛋白，其具有兩個部分：結合至和/或連接至細菌的第一部分及可結合至癌細胞（例如藉由對癌症特異性抗原具有結合特異性）的第二部分。在一些實施方式中，第一部分係全長肽聚糖識別蛋白（諸如PGRP）的片段或全長肽聚糖識別蛋白。在一些實施方式中，該第一部分對mEV具有結合特異性（例如藉由對細菌抗原具有結合特異性）。在一些實施方式中，該第一和/或第二部分包含抗體或其抗原結合片段。在一些實施方式中，該第一和/或第二部分包含T細胞受體或嵌合抗原受體（CAR）。在一些實施方式中，該第一和/或第二部分包含表現於癌細胞表面上受體的配位基或其受體結合片段。在某些實施方式中，癌症特異性部分與藥劑的共施用（組合施用或分開施用）增加藥劑對癌細胞的靶向。In some embodiments, the therapeutic moiety is a cancer specific moiety. In some embodiments, the cancer-specific portion has binding specificity for cancer cells (eg, has binding specificity for a cancer-specific antigen). In some embodiments, the cancer-specific portion comprises an antibody or antigen-binding fragment thereof. In some embodiments, the cancer specific portion comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the cancer-specific moiety comprises a ligand for a receptor expressed on the surface of a cancer cell, or a receptor-binding fragment thereof. In some embodiments, the cancer-specific portion is a bipartite fusion protein that has two portions: a first portion that binds and/or is linked to bacteria and that can bind to cancer cells (e.g., antigen has binding specificity). In some embodiments, the first portion is a fragment of a full-length peptidoglycan recognition protein, such as PGRP, or a full-length peptidoglycan recognition protein. In some embodiments, the first portion has binding specificity for mEV (eg, by having binding specificity for a bacterial antigen). In some embodiments, the first and/or second portion comprises an antibody or antigen-binding fragment thereof. In some embodiments, the first and/or second portion comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the first and/or second moiety comprises a ligand for a receptor expressed on the surface of a cancer cell, or a receptor-binding fragment thereof. In certain embodiments, co-administration (in combination or separately) of the cancer-specific moiety with the agent increases the targeting of the agent to the cancer cell.

在一些實施方式中，本文描述的細菌和/或mEV可以是經修飾的，使得它們包含、連接至和/或結合磁性和/或順磁性部分（例如磁珠）。在一些實施方式中，磁性和/或順磁性部分包含細菌和/或直接連接至細菌。在一些實施方式中，該磁性和/或順磁性部分連接至結合至細菌或mEV的細菌或mEV結合部分的一部分和/或為結合至細菌或mEV的細菌或mEV結合部分的一部分。在一些實施方式中，細菌或mEV結合部分係全長肽聚糖識別蛋白（諸如PGRP）的片段或全長肽聚糖識別蛋白。在一些實施方式中，細菌或mEV結合部分具有對細菌或mEV的結合特異性（例如藉由對細菌抗原具有結合特異性）。在一些實施方式中，細菌或mEV結合部分包含抗體或其抗原結合片段。在一些實施方式中，細菌或mEV結合部分包含T細胞受體或嵌合抗原受體（CAR）。在一些實施方式中，細菌或mEV結合部分包含表現於癌細胞表面上受體的配位基或其受體結合片段。在某些實施方式中，磁性和/或順磁性部分及細菌或mEV的共施用（一起施用或分開施用）可用以增加mEV靶向（例如靶向癌症細胞和/或受試者存在癌細胞的一部分）。 經加工的微生物胞外囊泡（pmEV）的產生 In some embodiments, bacteria and/or mEVs described herein can be modified such that they contain, attach to, and/or bind magnetic and/or paramagnetic moieties (eg, magnetic beads). In some embodiments, the magnetic and/or paramagnetic moieties comprise bacteria and/or are directly attached to bacteria. In some embodiments, the magnetic and/or paramagnetic moiety is linked to and/or is part of a bacterium or mEV binding moiety that binds to bacteria or mEV. In some embodiments, the bacterial or mEV binding portion is a fragment or a full length peptidoglycan recognition protein such as PGRP. In some embodiments, the bacteria or mEV binding moiety has binding specificity for bacteria or mEV (eg, by having binding specificity for a bacterial antigen). In some embodiments, the bacterium or mEV binding moiety comprises an antibody or antigen-binding fragment thereof. In some embodiments, the bacterial or mEV binding moiety comprises a T cell receptor or a chimeric antigen receptor (CAR). In some embodiments, the bacterial or mEV binding moiety comprises a ligand for a receptor expressed on the surface of a cancer cell, or a receptor binding fragment thereof. In certain embodiments, co-administration (either together or separately) of magnetic and/or paramagnetic moieties and bacteria or mEVs can be used to increase mEV targeting (e.g., targeting cancer cells and/or the presence of cancer cells in a subject). part). Production of processed microbial extracellular vesicles (pmEVs)

在某些方面，本文所述之pmEV可以使用本領域已知的任何方法製備。In certain aspects, the pmEVs described herein can be prepared using any method known in the art.

在一些實施方式中，在沒有pmEV純化步驟的情況下製備pmEV。例如，在一些實施方式中，將釋放本文所述之pmEV的細菌使用使細菌pmEV保持完整之方法殺死，並將所得的細菌組分（包括pmEV）用於本文所述之方法和組成物中。在一些實施方式中，該等細菌藉由使用抗生素（例如，使用本文描述的抗生素）被殺死。在一些實施方式中，該等細菌藉由使用UV輻射被殺死。In some embodiments, pmEVs are produced without a pmEV purification step. For example, in some embodiments, bacteria that release pmEVs described herein are killed using methods that leave bacterial pmEVs intact, and the resulting bacterial components, including pmEVs, are used in the methods and compositions described herein . In some embodiments, the bacteria are killed by using an antibiotic (eg, using an antibiotic described herein). In some embodiments, the bacteria are killed by using UV radiation.

在一些實施方式中，本文描述的pmEV純化自一種或多種其他細菌組分。從細菌（和視需要的其他細菌組分）純化pmEV之方法係本領域已知的。在一些實施方式中，pmEV藉由使用Thein,等人.（ J. Proteome Res. [ 蛋白質組學研究雜誌 ]9(12):6135-6147 (2010)）或Sandrini, 等人.（ Bio-protocol[生物方案] 4(21): e1287 (2014)）中描述之方法從細菌培養物製備，其中每個藉由引用以其全文特此併入。在一些實施方式中，該等細菌經培養至高光密度及然後經離心以使細菌沈澱（例如，在室溫或4°C下10,000- 15,000 x g，持續10-15 min）。在一些實施方式中，丟棄上清液，並將細胞沈澱物在-80°C冷凍。在一些實施方式中，將細胞沈澱物在冰上解凍，並重懸於補充有1 mg/mL DNA酶I的100 mM Tris-HCl（pH 7.5）中。在一些實施方式中，在製造商建議的條件下使用Emulsiflex C-3（奧維斯丁公司（Avestin, Inc.））裂解細胞。在一些實施方式中，藉由在4°C下以10,000 x g離心15 min來沈澱碎片和未裂解的細胞。在一些實施方式中，然後將上清液在4°C下以120,000 x g離心1小時。在一些實施方式中，將沈澱物重懸於冰冷的pH 11的100 mM碳酸鈉中，在4°C下攪拌孵育1小時，然後在4°C下以120,000 x g離心1小時。在一些實施方式中，將沈澱重懸於pH 7.5的100 mM Tris-HCl中，在4°C下以120,000 x g再離心20分鐘，然後重懸於0.1 M Tris-HCl（pH 7.5）中或於PBS中。在一些實施方式中，樣本被存儲在-20°C。 In some embodiments, the pmEVs described herein are purified from one or more other bacterial components. Methods for purifying pmEV from bacteria (and optionally other bacterial components) are known in the art. In some embodiments, pmEV is obtained by using Thein, et al. ( J. Proteome Res. [ Proteomics Research Journal ] 9(12):6135-6147 (2010)) or Sandrini, et al. ( Bio-protocol [Biological Protocols] 4(21): e1287 (2014)) prepared from bacterial cultures, each of which is hereby incorporated by reference in its entirety. In some embodiments, the bacteria are grown to high optical density and then centrifuged to pellet the bacteria (eg, 10,000-15,000 xg for 10-15 min at room temperature or 4°C). In some embodiments, the supernatant is discarded, and the cell pellet is frozen at -80°C. In some embodiments, cell pellets are thawed on ice and resuspended in 100 mM Tris-HCl (pH 7.5) supplemented with 1 mg/mL DNase I. In some embodiments, cells are lysed using Emulsiflex C-3 (Avestin, Inc.) under conditions recommended by the manufacturer. In some embodiments, debris and unlysed cells are pelleted by centrifugation at 10,000 xg for 15 min at 4°C. In some embodiments, the supernatant is then centrifuged at 120,000 xg for 1 hour at 4°C. In some embodiments, the pellet is resuspended in ice-cold 100 mM sodium carbonate, pH 11, incubated with agitation at 4°C for 1 hour, and then centrifuged at 120,000 xg for 1 hour at 4°C. In some embodiments, the pellet is resuspended in 100 mM Tris-HCl, pH 7.5, recentrifuged at 120,000 xg for 20 minutes at 4°C, and then resuspended in 0.1 M Tris-HCl, pH 7.5 or at PBS. In some embodiments, samples are stored at -20°C.

在某些方面，pmEV係藉由改編自Sandrini等人（2014年）之方法獲得的。在一些實施方式中，將細菌培養物在室溫或4°C下以10,000-15,500 x g離心10-15 min。在一些實施方式中，將細胞沈澱物在-80°C冷凍，並丟棄上清液。在一些實施方式中，將細胞沈澱物在冰上解凍，並重懸於10 mM Tris-HCl（pH 8.0）、補充有0.1 mg/mL溶菌酶的1 mM EDTA中。在一些實施方式中，將樣本在室溫或37°C下混合孵育30 min。在一些實施方式中，將樣本在-80°C下重新冷凍，然後再次在冰上解凍。在一些實施方式中，添加DNA酶I至終濃度為1.6 mg/mL，並添加MgCl2至終濃度為100 mM。在一些實施方式中，使用QSonica Q500超音波波儀以30 sec開啟和30 sec關閉的7個循環對樣本進行超音波處理。在一些實施方式中，藉由在4°C下以10,000 x g離心15分鐘來沈澱碎片和未裂解的細胞。在一些實施方式中，然後將上清液在4°C下以110,000 x g離心15 min。在一些實施方式中，將沈澱重懸於10 mM Tris-HCl（pH 8.0）、2% Triton X-100中，並在室溫下混合孵育30-60 min。在一些實施方式中，將樣本在4°C下以110,000 x g離心15 min。在一些實施方式中，將沈澱物重懸於PBS中並儲存在-20°C。In certain aspects, pmEVs are obtained by methods adapted from Sandrini et al. (2014). In some embodiments, the bacterial culture is centrifuged at 10,000-15,500 x g for 10-15 min at room temperature or 4°C. In some embodiments, cell pellets are frozen at -80°C, and supernatants are discarded. In some embodiments, cell pellets are thawed on ice and resuspended in 10 mM Tris-HCl (pH 8.0), 1 mM EDTA supplemented with 0.1 mg/mL lysozyme. In some embodiments, the sample is incubated with mixing for 30 min at room temperature or 37°C. In some embodiments, samples are refrozen at -80°C and then thawed again on ice. In some embodiments, DNase I is added to a final concentration of 1.6 mg/mL and MgCl is added to a final concentration of 100 mM. In some embodiments, samples are sonicated using a QSonica Q500 sonicator with 7 cycles of 30 sec on and 30 sec off. In some embodiments, debris and unlysed cells are pelleted by centrifugation at 10,000 xg for 15 minutes at 4°C. In some embodiments, the supernatant is then centrifuged at 110,000 x g for 15 min at 4°C. In some embodiments, the pellet is resuspended in 10 mM Tris-HCl (pH 8.0), 2% Triton X-100, and incubated with mixing at room temperature for 30-60 min. In some embodiments, the sample is centrifuged at 110,000 x g for 15 min at 4°C. In some embodiments, the pellet is resuspended in PBS and stored at -20°C.

在某些方面，本文描述的形成（例如，製備）分離的細菌pmEV之方法包括以下步驟：(a) 離心細菌培養物，從而形成第一沈澱物和第一上清液，其中該第一沈澱物包含細胞；(b) 丟棄該第一上清液；(c) 將該第一沈澱物重懸於溶液中；(d) 裂解細胞；(e) 對裂解的細胞進行離心，從而形成第二沈澱物和第二上清液；(f) 丟棄該第二沈澱物並對該第二上清液進行離心，從而形成第三沈澱物和第三上清液；(g) 丟棄該第三上清液並將該第三沈澱物重懸於第二溶液中，從而形成分離的細菌pmEV。In certain aspects, the methods described herein of forming (e.g., preparing) isolated bacterial pmEVs comprise the steps of: (a) centrifuging a bacterial culture, thereby forming a first pellet and a first supernatant, wherein the first pellet (b) discard the first supernatant; (c) resuspend the first pellet in solution; (d) lyse the cells; (e) centrifuge the lysed cells to form a second precipitate and a second supernatant; (f) discarding the second precipitate and centrifuging the second supernatant to form a third precipitate and a third supernatant; (g) discarding the third supernatant supernatant and resuspend this third pellet in the second solution, thereby forming isolated bacterial pmEVs.

在一些實施方式中，該方法進一步包括以下步驟：(h) 對步驟 (g) 的溶液進行離心，從而形成第四沈澱物和第四上清液；(i) 丟棄該第四上清液，並將該第四沈澱物重懸於第三溶液中。在一些實施方式中，該方法進一步包括以下步驟：(j) 對步驟 (i) 的溶液進行離心，從而形成第五沈澱物和第五上清液；以及 (k) 丟棄該第五上清液，並將該第五沈澱物重懸於第四溶液中。In some embodiments, the method further comprises the steps of: (h) centrifuging the solution of step (g), thereby forming a fourth precipitate and a fourth supernatant; (i) discarding the fourth supernatant, And resuspend the fourth pellet in the third solution. In some embodiments, the method further comprises the steps of: (j) centrifuging the solution of step (i), thereby forming a fifth pellet and a fifth supernatant; and (k) discarding the fifth supernatant , and resuspend the fifth precipitate in the fourth solution.

在一些實施方式中，步驟 (a) 的離心係以10,000 x g進行的。在一些實施方式中，步驟 (a) 的離心進行10-15分鐘。在一些實施方式中，步驟 (a) 的離心係在4°C或室溫下進行的。在一些實施方式中，步驟 (b) 還包括將第一沈澱物在-80°C冷凍。在一些實施方式中，步驟 (c) 中的溶液係補充有1mg/ml DNA酶I的100 mM Tris-HCl（pH 7.5）。在一些實施方式中，步驟 (c) 中的溶液係10 mM Tris-HCl（pH 8.0）、1 mM EDTA，補充有0.1 mg/ml溶菌酶。在一些實施方式中，步驟 (c) 進一步包括在37℃或室溫下孵育30分鐘。在一些實施方式中，步驟 (c) 進一步包括將第一沈澱物在-80°C冷凍。在一些實施方式中，步驟 (c) 進一步包括添加DNA酶I至1.6 mg/ml的終濃度。在一些實施方式中，步驟 (c) 進一步包括添加MgCl 2至100 mM的終濃度。在一些實施方式中，在步驟 (d) 中藉由勻漿裂解細胞。在一些實施方式中，在步驟 (d) 中藉由emulsiflex C3裂解細胞。在一些實施方式中，在步驟 (d) 中藉由超音波裂解細胞。在一些實施方式中，將細胞超音波處理7個循環，其中每個循環包括30秒的超音波處理和30秒的無超音波處理。在一些實施方式中，步驟 (e) 的離心係以10,000 x g進行的。在一些實施方式中，步驟 (e) 的離心進行15分鐘。在一些實施方式中，步驟 (e) 的離心係在4℃或室溫下。 In some embodiments, the centrifugation of step (a) is performed at 10,000 xg. In some embodiments, the centrifugation of step (a) is performed for 10-15 minutes. In some embodiments, the centrifugation of step (a) is performed at 4°C or room temperature. In some embodiments, step (b) further comprises freezing the first pellet at -80°C. In some embodiments, the solution in step (c) is 100 mM Tris-HCl (pH 7.5) supplemented with 1 mg/ml DNase I. In some embodiments, the solution in step (c) is 10 mM Tris-HCl (pH 8.0), 1 mM EDTA supplemented with 0.1 mg/ml lysozyme. In some embodiments, step (c) further comprises incubating at 37° C. or room temperature for 30 minutes. In some embodiments, step (c) further comprises freezing the first pellet at -80°C. In some embodiments, step (c) further comprises adding DNase I to a final concentration of 1.6 mg/ml. In some embodiments, step (c) further comprises adding MgCl to a final concentration of 100 mM. In some embodiments, the cells are lysed by homogenization in step (d). In some embodiments, the cells are lysed by emulsiflex C3 in step (d). In some embodiments, the cells are lysed by sonication in step (d). In some embodiments, the cells are sonicated for 7 cycles, wherein each cycle includes 30 seconds of sonication and 30 seconds of no sonication. In some embodiments, the centrifugation of step (e) is performed at 10,000 xg. In some embodiments, the centrifugation of step (e) is performed for 15 minutes. In some embodiments, the centrifugation of step (e) is at 4°C or room temperature.

在一些實施方式中，步驟 (f) 的離心係以120,000 x g進行的。在一些實施方式中，步驟 (f) 的離心係以110,000 x g進行的。在一些實施方式中，步驟 (f) 的離心進行1小時。在一些實施方式中，步驟 (f) 的離心進行15分鐘。在一些實施方式中，步驟 (f) 的離心係在4°C或室溫下。在一些實施方式中，步驟 (g) 中的第二溶液係pH 11的100 mM碳酸鈉。在一些實施方式中，步驟 (g) 中的第二溶液係10 mM Tris-HCl pH 8.0、2% triton X-100。在一些實施方式中，步驟 (g) 還包括將溶液在4°C下孵育1小時。在一些實施方式中，步驟 (g) 進一步包括將溶液在室溫下孵育30-60分鐘。在一些實施方式中，步驟 (h) 的離心係以120,000 x g進行的。在一些實施方式中，步驟 (h) 的離心係以110,000 x g進行的。在一些實施方式中，步驟 (h) 的離心進行1小時。在一些實施方式中，步驟 (h) 的離心進行15分鐘。在一些實施方式中，步驟 (h) 的離心係在4°C或室溫下。在一些實施方式中，步驟 (i) 中的第三溶液係100 mM Tris-HCl（pH 7.5）。在一些實施方式中，步驟 (i) 中的第三溶液係PBS。在一些實施方式中，步驟 (j) 的離心係以120,000 x g進行的。在一些實施方式中，步驟 (j) 的離心進行20分鐘。在一些實施方式中，步驟 (j) 的離心係在4℃或室溫下。在一些實施方式中，步驟 (k) 中的第四溶液係100 mM Tris-HCl（pH 7.5）或PBS。In some embodiments, the centrifugation of step (f) is performed at 120,000 x g. In some embodiments, the centrifugation of step (f) is performed at 110,000 x g. In some embodiments, the centrifugation of step (f) is performed for 1 hour. In some embodiments, the centrifugation of step (f) is performed for 15 minutes. In some embodiments, the centrifugation of step (f) is at 4°C or room temperature. In some embodiments, the second solution in step (g) is 100 mM sodium carbonate at pH 11. In some embodiments, the second solution in step (g) is 10 mM Tris-HCl pH 8.0, 2% triton X-100. In some embodiments, step (g) further comprises incubating the solution for 1 hour at 4°C. In some embodiments, step (g) further comprises incubating the solution at room temperature for 30-60 minutes. In some embodiments, the centrifugation of step (h) is performed at 120,000 x g. In some embodiments, the centrifugation of step (h) is performed at 110,000 x g. In some embodiments, the centrifugation of step (h) is performed for 1 hour. In some embodiments, the centrifugation of step (h) is performed for 15 minutes. In some embodiments, the centrifugation of step (h) is at 4°C or room temperature. In some embodiments, the third solution in step (i) is 100 mM Tris-HCl (pH 7.5). In some embodiments, the third solution in step (i) is PBS. In some embodiments, the centrifugation of step (j) is performed at 120,000 x g. In some embodiments, the centrifuging of step (j) is performed for 20 minutes. In some embodiments, the centrifugation of step (j) is at 4°C or room temperature. In some embodiments, the fourth solution in step (k) is 100 mM Tris-HCl (pH 7.5) or PBS.

藉由本文提供之方法獲得的pmEV可藉由基於尺寸的柱層析法、藉由親和層析法及藉由梯度超速離心，使用可包括但不限於使用蔗糖梯度或Optiprep梯度之方法加以進一步純化。簡言之，在使用蔗糖梯度方法時，如果使用硫酸銨沈澱或超速離心來濃縮經過濾的上清液，則將沈澱物重懸於60%蔗糖、30 mM Tris（pH 8.0）中。如果使用過濾來濃縮經過濾的上清液，則使用Amicon Ultra柱將濃縮物緩衝液交換至60%蔗糖、30 mM Tris（pH 8.0）中。將樣本施加至35%-60%不連續蔗糖梯度中並在4°C下以200,000 × g離心3-24小時。簡言之，在使用Optiprep梯度方法時，如果使用硫酸銨沈澱或超速離心來濃縮經過濾的上清液，則將沈澱物重懸於PBS中的35% Optiprep中。在一些實施方式中，如果使用過濾來濃縮經過濾的上清液，則使用60% Optiprep將濃縮物稀釋至最終濃度為35% Optiprep。將樣本施加至35%-60%不連續蔗糖梯度中並在4°C下以200,000 × g離心3-24小時。The pmEVs obtained by the methods provided herein can be further purified by size-based column chromatography, by affinity chromatography, and by gradient ultracentrifugation, using methods that can include, but are not limited to, the use of sucrose gradients or Optiprep gradients . Briefly, when using the sucrose gradient method, if using ammonium sulfate precipitation or ultracentrifugation to concentrate the filtered supernatant, resuspend the pellet in 60% sucrose, 30 mM Tris, pH 8.0. If filtration is used to concentrate the filtered supernatant, buffer exchange the concentrate into 60% sucrose, 30 mM Tris, pH 8.0, using an Amicon Ultra column. Samples were applied to a 35%-60% discontinuous sucrose gradient and centrifuged at 200,000 x g for 3-24 hours at 4°C. Briefly, when using the Optiprep gradient method, if using ammonium sulfate precipitation or ultracentrifugation to concentrate the filtered supernatant, resuspend the pellet in 35% Optiprep in PBS. In some embodiments, if filtration is used to concentrate the filtered supernatant, the concentrate is diluted with 60% Optiprep to a final concentration of 35% Optiprep. Samples were applied to a 35%-60% discontinuous sucrose gradient and centrifuged at 200,000 x g for 3-24 hours at 4°C.

在一些實施方式中，為證實pmEV製劑的無菌性及分離，將pmEV連續稀釋至瓊脂培養基（其用於測試中的細菌的例行培養）上，並使用例行條件進行孵育。使未經滅菌的製劑通過0.22 µm過濾器以去除完整細胞。為進一步增加純度，分離的pmEV可用DNA酶或蛋白酶K處理。In some embodiments, to demonstrate sterility and isolation of pmEV preparations, pmEVs were serially diluted onto agar medium (which is used for routine cultivation of the bacteria under test) and incubated using routine conditions. Pass the non-sterile preparation through a 0.22 µm filter to remove intact cells. To further increase purity, isolated pmEVs can be treated with DNase or proteinase K.

在一些實施方式中，pmEV製劑的無菌性可藉由將一部分pmEV接種至瓊脂培養基（其用於用以產生pmEV的細菌的標準培養）並使用標準條件進行孵育加以證實。In some embodiments, the sterility of a pmEV preparation can be demonstrated by inoculating a portion of the pmEVs onto an agar medium (which is used for standard cultivation of bacteria used to produce pmEVs) and incubating using standard conditions.

在一些實施方式中，藉由層析法和pmEV上的結合表面部分對所選pmEV進行分離和富集。在其他實施方式中，所選pmEV藉由螢光細胞分選藉由使用親和試劑、化學染料、重組蛋白之方法或熟悉該項技術者已知的其他方法分離和/或富集。In some embodiments, selected pmEVs are isolated and enriched by chromatography and binding surface moieties on the pmEVs. In other embodiments, selected pmEVs are isolated and/or enriched by fluorescent cell sorting by methods using affinity reagents, chemical dyes, recombinant proteins, or other methods known to those skilled in the art.

可以對pmEV進行分析，例如，如Jeppesen等人 Cell[細胞] 177:428 (2019)所述。Analysis of pmEVs can be performed, e.g., as described in Jeppesen et al. Cell 177:428 (2019).

在一些實施方式中，pmEV的凍乾的。In some embodiments, the pmEV is lyophilized.

在一些實施方式中，pmEV經γ照射（例如，以17.5或25 kGy）。In some embodiments, the pmEVs are gamma-irradiated (eg, at 17.5 or 25 kGy).

在一些實施方式中，pmEV經UV輻照。In some embodiments, the pmEVs are UV irradiated.

在一些實施方式中，pmEV被熱滅活（例如，在50°C下兩小時或在90°C下兩小時）。In some embodiments, the pmEVs are heat inactivated (eg, two hours at 50°C or two hours at 90°C).

在一些實施方式中，pmEV經酸處理。In some embodiments, the pmEVs are acid-treated.

在一些實施方式中，pmEV經氧噴射（例如，以0.1 vvm持續兩小時）。In some embodiments, pmEVs are sparged with oxygen (eg, at 0.1 vvm for two hours).

生長階段會影響細菌的量或性質。例如，在本文提供的pmEV製備方法中，可以例如在對數生長期開始時、在對數生長期的中間時、和/或一旦達到穩定生長期時從培養物中分離pmEV。 分泌型微生物胞外囊泡（smEV）的產生 The growth stage can affect the amount or nature of the bacteria. For example, in the pmEV production methods provided herein, pmEVs can be isolated from the culture, eg, at the beginning of the logarithmic growth phase, in the middle of the logarithmic growth phase, and/or once the stationary growth phase has been reached. Production of secreted microbial extracellular vesicles (smEVs)

在某些方面，本文所述之smEV可以使用本領域已知的任何方法製備。In certain aspects, the smEVs described herein can be prepared using any method known in the art.

在一些實施方式中，在沒有smEV純化步驟的情況下製備smEV。例如，在一些實施方式中，本文描述的細菌藉由使用讓smEV保持完整之方法被殺死且將所得的細菌組分（包括smEV）用於本文描述之方法及組成物中。在一些實施方式中，該等細菌藉由使用抗生素（例如，使用本文描述的抗生素）被殺死。在一些實施方式中，該等細菌藉由使用UV輻射被殺死。在一些實施方式中，細菌被熱殺死。In some embodiments, smEVs are produced without a smEV purification step. For example, in some embodiments, bacteria described herein are killed using methods that leave smEVs intact and the resulting bacterial components, including smEVs, are used in the methods and compositions described herein. In some embodiments, the bacteria are killed by using an antibiotic (eg, using an antibiotic described herein). In some embodiments, the bacteria are killed by using UV radiation. In some embodiments, bacteria are killed by heat.

在一些實施方式中，本文所述之smEV純化自一種或多種其他細菌組分。用於自細菌純化smEV之方法為本領域中已知。在一些實施方式中，smEV藉由使用S. Bin Park等人 PLoS ONE [公共科學圖書館·綜合].6(3): e17629 (2011)或G. Norheim等人 PLoS ONE[公共科學圖書館·綜合].10(9): e0134353 (2015)或Jeppesen等人 Cell [細胞] 177:428 (2019)中所述之方法從細菌培養物製備，其中每個藉由引用以其全文特此併入。在一些實施方式中，該等細菌經培養至高光密度及然後經離心以使細菌沈澱（例如，在4°C下以10,000 x g離心30 min，在4°C下以15,500 x g離心15 min）。在一些實施方式中，然後使培養上清液通過過濾器以排除完整細菌細胞（例如，0.22 µm過濾器）。在一些實施方式中，然後對上清液進行切向流過濾，在此過程中，將上清液濃縮，去除小於100 kDa的種類，並用PBS對培養基進行部分交換。在一些實施方式中，經過濾的上清液經離心以使細菌smEV沈澱（例如，在4°C下以100,000至150,000 x g離心1至3小時，在4°C下以200,000 x g離心1至3小時）。在一些實施方式中，該等smEV藉由重懸所得smEV沈澱物（例如，於PBS中），並將重懸的smEV施用至Optiprep（碘克沙醇）梯度或梯度（例如30%至60%不連續的梯度、0-45%不連續的梯度），接著離心（例如，在4°C下以200,000 x g離心4-20小時）加以進一步純化。可以收集smEV帶，用PBS稀釋並離心以使smEV沈澱（例如，在4°C下以150,000 x g離心3小時，在4°C下以200,000 x g離心1小時）。純化的smEV可經儲存（例如，在-80°C或-20°C下）直至使用。在一些實施方式中，smEV藉由用DNA酶和/或蛋白酶K處理加以進一步純化。In some embodiments, the smEVs described herein are purified from one or more other bacterial components. Methods for purifying smEVs from bacteria are known in the art. In some embodiments, smEVs are identified by using S. Bin Park et al. PLoS ONE [PLOS ONE].6(3): e17629 (2011) or G. Norheim et al. General]. 10(9): e0134353 (2015) or prepared from bacterial culture as described in Jeppesen et al. Cell 177:428 (2019), each of which is hereby incorporated by reference in its entirety. In some embodiments, the bacteria are grown to high optical density and then centrifuged to pellet the bacteria (eg, 10,000 x g for 30 min at 4°C, 15,500 x g for 15 min at 4°C). In some embodiments, the culture supernatant is then passed through a filter to exclude intact bacterial cells (eg, a 0.22 µm filter). In some embodiments, the supernatant is then subjected to tangential flow filtration, during which the supernatant is concentrated to remove species less than 100 kDa and the medium is partially exchanged with PBS. In some embodiments, the filtered supernatant is centrifuged to pellet bacterial smEVs (e.g., 100,000 to 150,000 x g at 4°C for 1 to 3 hours, 200,000 x g for 1 to 3 hours at 4°C. Hour). In some embodiments, the smEVs are prepared by resuspending the resulting smEV pellet (e.g., in PBS) and applying the resuspended smEVs to an Optiprep (iodixanol) gradient or gradient (e.g., 30% to 60% discontinuous gradient, 0-45% discontinuous gradient), followed by centrifugation (e.g., 200,000 x g for 4-20 hours at 4°C) for further purification. The smEV band can be collected, diluted with PBS and centrifuged to pellet the smEVs (e.g., 150,000 x g for 3 h at 4°C, 200,000 x g for 1 h at 4°C). Purified smEVs can be stored (eg, at -80°C or -20°C) until use. In some embodiments, smEVs are further purified by treatment with DNase and/or proteinase K.

例如，在一些實施方式中，細菌的培養物可在4°C下以11,000 x g離心20至40分鐘以使細菌沈澱。可使培養上清液通過0.22 µm過濾器以排除完整細菌細胞。然後可使用可包括但不限於硫酸銨沈澱、超速離心或過濾之方法濃縮經過濾的上清液。例如，就硫酸銨沈澱而言，可將1.5-3 M硫酸銨緩慢添加至經過濾的上清液，同時在4°C下攪拌。可將沈澱在4°C下孵育8-48小時，然後在4°C下以11,000 x g離心20-40 min。所得沈澱物含有細菌smEV及其他碎片。使用超速離心，將經過濾的上清液在4°C下以100,000-200,000 x g離心1-16小時。此離心的沈澱物含有細菌smEV和其他碎片（例如大蛋白複合物）。在一些實施方式中，使用過濾技術，如藉由使用Amicon超自旋過濾器或藉由切向流過濾，上清液可經過濾以便於保留分子量＞ 50或100 kDa的物質。For example, in some embodiments, a culture of bacteria can be centrifuged at 11,000 x g for 20 to 40 minutes at 4°C to pellet the bacteria. Culture supernatants can be passed through a 0.22 µm filter to exclude intact bacterial cells. The filtered supernatant can then be concentrated using methods that can include, but are not limited to, ammonium sulfate precipitation, ultracentrifugation, or filtration. For example, for ammonium sulfate precipitation, 1.5-3 M ammonium sulfate can be slowly added to the filtered supernatant while stirring at 4°C. The pellet can be incubated at 4°C for 8-48 hours and then centrifuged at 11,000 x g for 20-40 min at 4°C. The resulting pellet contained bacterial smEVs as well as other debris. Using ultracentrifugation, centrifuge the filtered supernatant at 100,000-200,000 x g for 1-16 h at 4 °C. The pellet of this centrifugation contains bacterial smEVs and other debris (e.g. large protein complexes). In some embodiments, the supernatant can be filtered using filtration techniques, such as by using an Amicon ultra spin filter or by tangential flow filtration, in order to retain species with a molecular weight >50 or 100 kDa.

可替代地，例如藉由將生物反應器連接至細胞培養交替切向流（ATF）系統（例如來自Repligen的XCell ATF），可在生長期間或在生長期間的選定時間點，從細菌培養物連續獲得smEV。該ATF系統保留完整細胞（＞ 0.22 µm）於生物反應器中，及容許較小組分（例如，smEV、游離蛋白質）通過過濾器以供收集。例如，該系統可經結構設計使得＜ 0.22 µm濾液然後通過100 kDa的第二過濾器，容許收集如在0.22 µm與100 kDa之間的smEV的物質，並將小於100 kDa的種類泵送回生物反應器中。可替代地，該系統可以經結構設計以容許生物反應器中的培養基在培養物的生長期間得到補充和/或修飾。藉由此方法收集的smEV可以藉由如上文描述用於經過濾的上清液的超離心或過濾進行進一步純化和/或濃縮。Alternatively, the bacterial culture can be continuously depleted during growth or at selected time points during growth, for example by connecting the bioreactor to a cell culture alternate tangential flow (ATF) system (e.g. XCell ATF from Repligen). Obtain smEV. The ATF system retains intact cells (>0.22 µm) in the bioreactor and allows smaller components (eg, smEV, free protein) to pass through the filter for collection. For example, the system can be structured so that the <0.22 µm filtrate is then passed through a second filter of 100 kDa, allowing collection of species such as smEVs between 0.22 µm and 100 kDa, and pumping species smaller than 100 kDa back to the biological in the reactor. Alternatively, the system may be structured to allow the medium in the bioreactor to be replenished and/or modified during the growth of the culture. The smEVs collected by this method can be further purified and/or concentrated by ultracentrifugation or filtration as described above for the filtered supernatant.

藉由本文提供之方法獲得的smEV可藉由基於尺寸的柱層析法、藉由親和層析法、藉由離子交換層析法及藉由梯度超速離心，使用可包括但不限於使用蔗糖梯度或Optiprep梯度之方法加以進一步純化。簡言之，在使用蔗糖梯度方法時，如果使用硫酸銨沈澱或超速離心來濃縮經過濾的上清液，則將沈澱物重懸於60%蔗糖、30 mM Tris（pH 8.0）中。如果使用過濾來濃縮經過濾的上清液，則使用Amicon Ultra柱將濃縮物緩衝液交換至60%蔗糖、30 mM Tris（pH 8.0）中。將樣本施加至35%-60%不連續蔗糖梯度中並在4°C下以200,000 × g離心3-24小時。簡言之，在使用Optiprep梯度方法時，如果使用硫酸銨沈澱或超速離心來濃縮經過濾的上清液，則將沈澱物重懸於PBS中並向樣本中添加3體積的60% Optiprep。在一些實施方式中，如果使用過濾來濃縮經過濾的上清液，則使用60% Optiprep將濃縮物稀釋至最終濃度為35% Optiprep。將樣本施加至0-45%不連續的Optiprep梯度，並在4°C下以200,000 x g離心3至24小時，例如，在4°C下離心4至24小時。The smEVs obtained by the methods provided herein can be obtained by size-based column chromatography, by affinity chromatography, by ion exchange chromatography, and by gradient ultracentrifugation, using methods that may include, but are not limited to, the use of sucrose gradients. Or Optiprep gradient method for further purification. Briefly, when using the sucrose gradient method, if using ammonium sulfate precipitation or ultracentrifugation to concentrate the filtered supernatant, resuspend the pellet in 60% sucrose, 30 mM Tris, pH 8.0. If filtration is used to concentrate the filtered supernatant, buffer exchange the concentrate into 60% sucrose, 30 mM Tris, pH 8.0, using an Amicon Ultra column. Samples were applied to a 35%-60% discontinuous sucrose gradient and centrifuged at 200,000 x g for 3-24 hours at 4°C. Briefly, when using the Optiprep gradient method, if using ammonium sulfate precipitation or ultracentrifugation to concentrate the filtered supernatant, resuspend the pellet in PBS and add 3 volumes of 60% Optiprep to the sample. In some embodiments, if filtration is used to concentrate the filtered supernatant, the concentrate is diluted with 60% Optiprep to a final concentration of 35% Optiprep. Apply the sample to a 0-45% discontinuous Optiprep gradient and centrifuge at 200,000 x g for 3 to 24 hours at 4°C, eg, 4 to 24 hours at 4°C.

在一些實施方式中，為證實smEV製劑的無菌性及分離，將smEV連續稀釋至瓊脂培養基（其用於測試中的細菌的例行培養）上，並使用例行條件進行孵育。使未經滅菌的製劑通過0.22 µm過濾器以去除完整細胞。為進一步增加純度，分離的smEV可用DNA酶或蛋白酶K處理。In some embodiments, to demonstrate sterility and isolation of smEV preparations, smEVs were serially diluted onto agar medium (which is used for routine cultivation of bacteria under test) and incubated using routine conditions. Pass the non-sterile preparation through a 0.22 µm filter to remove intact cells. To further increase purity, isolated smEVs can be treated with DNase or proteinase K.

在一些實施方式中，為製備用於體內注射的smEV，經純化的smEV如先前描述進行加工（G. Norheim等人, PLoS ONE. [公共科學圖書館·綜合]10(9): e0134353 (2015)）。簡言之，在蔗糖梯度離心後，將含有smEV的帶於含有3%蔗糖的溶液中或熟悉該項技術者已知的適用於體內注射的其他溶液中重懸至50 µg/mL的終濃度。該溶液還可含有濃度為0-0.5%（w/v）的佐劑（例如氫氧化鋁）。在一些實施方式中，為了製備用於體內注射的smEV，將PBS中的smEV無菌過濾至＜ 0.22 µm。 In some embodiments, to prepare smEVs for in vivo injection, purified smEVs are processed as previously described (G. Norheim et al., PLoS ONE . [PLOS ONE]. 10(9): e0134353 (2015 )). Briefly, after centrifugation in a sucrose gradient, tapes containing smEVs were resuspended to a final concentration of 50 µg/mL in a solution containing 3% sucrose or other solutions known to those skilled in the art to be suitable for in vivo injection. . The solution may also contain an adjuvant (eg aluminum hydroxide) at a concentration of 0-0.5% (w/v). In some embodiments, to prepare smEVs for in vivo injection, the smEVs in PBS are sterile filtered to <0.22 µm.

在某些實施方式中，為製備與其他測試（例如用以在TEM成像或活體外分析之前去除蔗糖）相容的樣本，使用過濾（例如，Amicon Ultra柱）將樣本緩衝液交換至PBS或30 mM pH 8.0 Tris中，透析，或超離心（200,000 × g，≥ 3小時，4°C）並重懸。In certain embodiments, to prepare samples compatible with other assays (e.g., to remove sucrose prior to TEM imaging or in vitro analysis), the sample is buffer exchanged to PBS or 30% using filtration (e.g., Amicon Ultra columns). Dialyze in mM Tris pH 8.0, or ultracentrifuge (200,000 × g, ≥ 3 hours, 4°C) and resuspend.

在一些實施方式中，smEV製劑的無菌性可藉由將一部分smEV接種至瓊脂培養基（其用於用以產生smEV的細菌的標準培養）上並使用標準條件進行孵育加以證實。In some embodiments, the sterility of the smEV preparation can be demonstrated by inoculating a portion of the smEV onto an agar medium (which is used for a standard culture of smEV-producing bacteria) and incubating using standard conditions.

在一些實施方式中，藉由層析法及smEV上的結合表面部分對所選smEV進行分離和富集。在其他實施方式中，所選smEV藉由螢光細胞分選藉由使用親和試劑、化學染料、重組蛋白之方法或熟悉該項技術者已知的其他方法分離和/或富集。In some embodiments, selected smEVs are isolated and enriched by chromatography and binding surface moieties on the smEVs. In other embodiments, selected smEVs are isolated and/or enriched by fluorescent cell sorting by methods using affinity reagents, chemical dyes, recombinant proteins, or other methods known to those skilled in the art.

可以對smEV進行分析，例如，如Jeppesen等人 Cell[細胞] 177:428 (2019) 所述。Analysis of smEVs can be performed, for example, as described in Jeppesen et al. Cell 177:428 (2019).

在一些實施方式中，smEV係凍乾的。In some embodiments, the smEVs are lyophilized.

在一些實施方式中，smEV被γ照射（例如，在17.5或25 kGy下）。In some embodiments, the smEVs are gamma irradiated (eg, at 17.5 or 25 kGy).

在一些實施方式中，smEV經UV輻照。In some embodiments, the smEVs are UV irradiated.

在一些實施方式中，smEV被熱滅活（例如，在50°C下兩小時或在90°C下兩小時）。In some embodiments, smEVs are heat inactivated (eg, two hours at 50°C or two hours at 90°C).

在一些實施方式中，smEV經酸處理。In some embodiments, the smEVs are acid-treated.

在一些實施方式中，smEV被噴氧（例如，以0.1 vvm持續兩小時）。In some embodiments, smEVs are sparged with oxygen (eg, at 0.1 vvm for two hours).

生長階段會影響細菌和/或細菌產生的smEV的量或性質。例如，在本文提供的smEV製備方法中，可以例如在對數生長期開始時、在對數生長期的中間時、和/或一旦達到穩定生長期時從培養物中分離smEV。The growth stage affects the bacteria and/or the amount or nature of smEVs produced by the bacteria. For example, in the smEV production methods provided herein, smEVs can be isolated from the culture, eg, at the beginning of the logarithmic growth phase, in the middle of the logarithmic growth phase, and/or once the stationary growth phase has been reached.

生長環境（如培養條件）可影響細菌產生smEV的量。例如，smEV誘導因子可以增加smEV的產率，如表4所示。 [ 表 4] ：增加 smEV 產率的培養技術 smEV誘導 smEV誘導因子 作用於 溫度          加熱 應激反應    RT至37°C溫度變化 模擬感染    37°C至40°C溫度變化 熱性感染 ROS          白花丹素 氧化應激反應    氫過氧化物異丙苯 氧化應激反應    過氧化氫 氧化應激反應 抗生素          環丙沙星 細菌SOS反應    建它黴素 蛋白質合成    多黏菌素B 外膜    D-環絲胺酸 細胞壁 滲壓劑          NaCl 滲透應激 金屬離子應激          鐵螯合 鐵水平    EDTA 去除二價陽離子    低氯化血紅素 鐵水平 培養基添加劑或去除          乳酸鹽 生長    胺基酸剝奪 應激    十六烷 應激    葡萄糖 生長    碳酸氫鈉 ToxT誘導    PQS 水泡劑（vesiculator）（來自細菌）    二胺+DFMO 膜錨定（僅negativicutes）    高營養素 增強的生長    低營養素    其他機制          氧 厭氧生物中的氧應激    無半胱胺酸 厭氧生物中的氧應激    誘導生物膜或絮凝       兩階段生長       噬菌體       尿素    The growth environment (such as culture conditions) can affect the amount of smEV produced by bacteria. For example, smEV inducing factors can increase the yield of smEV, as shown in Table 4. [ Table 4 ] : Culture techniques for increasing smEV yield smEV induction smEV-inducing factor Acting on temperature heating stress response RT to 37°C temperature change mock infection 37°C to 40°C temperature change febrile infection ROS plumbagin oxidative stress response cumene hydroperoxide oxidative stress response hydrogen peroxide oxidative stress response antibiotic Ciprofloxacin Bacterial SOS response Gentamycin protein synthesis Polymyxin B Adventitia D-Cycloserine cell wall Osmotic agent NaCl Osmotic stress metal ion stress iron chelation iron level EDTA Removal of divalent cations low hemin iron level Media Addition or Removal Lactate to grow amino acid deprivation stress Hexadecane stress glucose to grow sodium bicarbonate ToxT induction PQS vesiculator (from bacteria) Diamine+DFMO Membrane anchoring (negativicutes only) high nutrient enhanced growth low nutrient other mechanisms oxygen Oxygen stress in anaerobic organisms cysteine free Oxygen stress in anaerobic organisms induced biofilm or flocculation two-stage growth Phage urea

在本文提供的製備smEV之方法中，該方法可視需要包括在從細菌培養物中分離smEV之前，將細菌培養物暴露於smEV誘導因子。細菌培養物可以在對數生長期開始時、在對數生長期的中間時、和/或一旦達到穩定生長期時暴露於smEV誘導因子。 固體劑型組成物 In the methods of making smEV provided herein, the method optionally includes exposing the bacterial culture to a smEV-inducing factor prior to isolating the smEV from the bacterial culture. Bacterial cultures can be exposed to smEV-inducing factors at the beginning of the logarithmic growth phase, during the middle of the logarithmic growth phase, and/or once a stationary growth phase has been reached. Solid Dosage Form Composition

在某些實施方式中，本文提供了包含藥劑的固體劑型（例如，具有固體劑型的藥物產品），該藥劑含有細菌和/或mEV（例如smEV和/或pmEV）。在一些實施方式中，藥劑可以視需要包含一種或多種另外的組分，例如冷凍保護劑。可以將藥劑凍乾（例如，產生粉末）。藥劑可以與固體劑型中的一種或多種賦形劑（例如藥學上可接受的賦形劑）組合。藥劑也稱為原料藥。固體劑型也稱為固體劑量型。In certain embodiments, provided herein is a solid dosage form (eg, a pharmaceutical product having a solid dosage form) comprising a medicament comprising bacteria and/or mEV (eg, smEV and/or pmEV). In some embodiments, the medicament may optionally contain one or more additional components, such as cryoprotectants. Agents can be lyophilized (eg, to produce a powder). The medicament may be combined with one or more excipients (eg, pharmaceutically acceptable excipients) in a solid dosage form. Pharmaceuticals are also known as APIs. Solid dosage forms are also known as solid dosage forms.

在某些方面，本文提供了藥物組成物的固體劑型。藥物組成物也稱為藥物產品。在某些實施方式中，固體劑型包含藥劑（例如細菌和/或細菌起源的試劑（例如組分），如mEV，包含細菌和/或細菌起源的試劑（例如組分）如mEV的粉末）和一種或多種賦形劑。在某些實施方式中，藥劑總質量係藥物組成物總質量的至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%或75%。在一些實施方式中，藥劑總質量不超過藥物組成物總質量的75%、70%、65%、60%、55%、50%、45%、40%、35%、30%或25%。在一些實施方式中，一種或多種賦形劑的總質量為藥物組成物總質量的至少30%、至少35%、至少40%、至少45%、或至少50%、至少55%、至少65%、至少70%或至少75%。在一些實施方式中，一種或多種賦形劑的總質量不超過藥物組成物總質量的95%、90%、85%、80%、75%、70%、65%、60%或55%、50%、45%、40%或35%。在一些實施方式中，一種或多種賦形劑包含矽化微晶纖維素。（例如HD90級）。在一些實施方式中，一種或多種賦形劑包含交聚維酮（PVPP，例如科利當CL-F）。In certain aspects, provided herein are solid dosage forms of pharmaceutical compositions. A pharmaceutical composition is also referred to as a pharmaceutical product. In certain embodiments, the solid dosage form comprises a pharmaceutical agent (e.g., a bacterial and/or agent (e.g., component) of bacterial origin, such as mEV, a powder comprising bacteria and/or an agent (e.g., component) of bacterial origin, such as mEV) and one or more excipients. In certain embodiments, the total mass of the medicament is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% of the total mass of the pharmaceutical composition , 60%, 65%, 70% or 75%. In some embodiments, the total mass of the medicament does not exceed 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30% or 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more excipients is at least 30%, at least 35%, at least 40%, at least 45%, or at least 50%, at least 55%, at least 65% of the total mass of the pharmaceutical composition , at least 70%, or at least 75%. In some embodiments, the total mass of one or more excipients does not exceed 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60% or 55% of the total mass of the pharmaceutical composition, 50%, 45%, 40% or 35%. In some embodiments, the one or more excipients comprise silicified microcrystalline cellulose. (e.g. HD90 class). In some embodiments, the one or more excipients comprise crospovidone (PVPP, eg, Colidan CL-F).

在某些方面，本文提供了藥物組成物的固體劑型。在某些實施方式中，固體劑型包含藥劑（例如，細菌和/或細菌來源的試劑（如mEV），包含細菌和/或細菌來源的試劑（如mEV）的粉末）和一種或多種賦形劑（例如，一種、兩種或三種賦形劑）。在某些實施方式中，固體劑型包含藥劑（例如，細菌和/或細菌來源的試劑（如mEV），包含細菌和/或細菌來源的試劑（如mEV）的粉末）和兩種賦形劑。在某些實施方式中，藥劑總質量係藥物組成物總質量的至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%、70%或75%。在一些實施方式中，藥劑總質量不超過藥物組成物總質量的75%、70%、65%、60%、55%、50%、45%、40%、35%、30%、25%、20%、15%、10%或5%。在一些實施方式中，一種或多種賦形劑的總質量為藥物組成物總質量的至少5%、至少10%、至少20%、至少30%、至少35%、至少40%、至少45%或至少50%、至少55%、至少65%、至少70%或至少75%。在一些實施方式中，一種或多種賦形劑的總質量不超過藥物組成物總質量的95%、90%、85%、80%、75%、70%、65%、60%或55%、50%、45%、40%或35%。在一些實施方式中，一種或多種賦形劑包含矽化微晶纖維素。在一些實施方式中，一種或多種賦形劑包含交聚維酮（PVPP，例如科利當CL-F）。In certain aspects, provided herein are solid dosage forms of pharmaceutical compositions. In certain embodiments, a solid dosage form comprises a pharmaceutical agent (e.g., a bacterium and/or an agent of bacterial origin such as mEV, a powder comprising a bacterium and/or an agent of bacterial origin such as mEV) and one or more excipients (eg, one, two or three excipients). In certain embodiments, a solid dosage form comprises a pharmaceutical agent (eg, a bacterium and/or an agent of bacterial origin such as mEV, a powder comprising a bacterium and/or an agent of bacterial origin such as mEV) and two excipients. In certain embodiments, the total mass of the medicament is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% of the total mass of the pharmaceutical composition , 60%, 65%, 70% or 75%. In some embodiments, the total mass of the medicament does not exceed 75%, 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30%, 25%, 20%, 15%, 10% or 5%. In some embodiments, the total mass of one or more excipients is at least 5%, at least 10%, at least 20%, at least 30%, at least 35%, at least 40%, at least 45%, or At least 50%, at least 55%, at least 65%, at least 70%, or at least 75%. In some embodiments, the total mass of one or more excipients does not exceed 95%, 90%, 85%, 80%, 75%, 70%, 65%, 60% or 55% of the total mass of the pharmaceutical composition, 50%, 45%, 40% or 35%. In some embodiments, the one or more excipients comprise silicified microcrystalline cellulose. In some embodiments, the one or more excipients comprise crospovidone (PVPP, eg, Colidan CL-F).

在某些實施方式中，本文提供的固體劑型包含矽化微晶纖維素。在一些實施方式中，矽化微晶纖維素為HD90級。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的至少5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%。在某些實施方式中，矽化微晶纖維素總質量不超過藥物組成物總質量的5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約5%至約77%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約10%至約55%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約10%、約20%、約30%、約40%或約50%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約76.4%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約72.5%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約20%。In certain embodiments, the solid dosage forms provided herein comprise silicified microcrystalline cellulose. In some embodiments, the silicified microcrystalline cellulose is grade HD90. In some embodiments, the total mass of silicified microcrystalline cellulose is at least 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21% of the total mass of the pharmaceutical composition. %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54% , 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72 %, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%. In certain embodiments, the total mass of silicified microcrystalline cellulose does not exceed 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21% of the total mass of the pharmaceutical composition %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54% , 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72 %, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%. In some embodiments, the total mass of silicified microcrystalline cellulose is about 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21% of the total mass of the pharmaceutical composition %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54% , 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72 %, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%. In certain embodiments, the total mass of silicified microcrystalline cellulose is about 5% to about 77% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of silicified microcrystalline cellulose is about 10% to about 55% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of silicified microcrystalline cellulose is about 10%, about 20%, about 30%, about 40% or about 50% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of silicified microcrystalline cellulose is about 76.4% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of silicified microcrystalline cellulose is about 72.5% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of silicified microcrystalline cellulose is about 20% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含交聚維酮（例如PVPP、科利當CL-F、PVP CL-F）。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%。在某些實施方式中，交聚維酮總質量不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%。在某些實施方式中，交聚維酮總質量為藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%。在某些實施方式中，交聯維酮總質量係藥物組成物總質量的約5%至約20%。在某些實施方式中，交聚維酮總質量為藥物組成物總質量的約5%、6%、7%、10%、15%、18%、20%或30%。In certain embodiments, the solid dosage forms provided herein comprise crospovidone (eg, PVPP, Colidan CL-F, PVP CL-F). In certain embodiments, the total mass of crospovidone is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%. In some embodiments, the total mass of crospovidone does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%. In some embodiments, the total mass of crospovidone is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%. In certain embodiments, the total mass of crosvidone is about 5% to about 20% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of crospovidone is about 5%, 6%, 7%, 10%, 15%, 18%, 20% or 30% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含：(i) 藥劑，藥劑總質量為藥物組成物總質量的至少5%且不超過75%，和 (ii) 矽化微晶纖維素，矽化微晶纖維素總質量為藥物組成物總質量的至少5%（例如至少5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%）且不超過90%（例如不超過5%、7%、10%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%）。在某些實施方式中，固體劑型進一步包含交聚維酮，其具有的交聚維酮總質量係藥物組成物總質量的至少5%（例如，至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、或25%）且不超過藥物組成物總質量的25%（例如，不超過5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、或25%）。在某些實施方式中，矽化微晶纖維素總質量加上交聚維酮總質量為藥物組成物總質量的至少60%、70%、80%或90%。在一些實施方式中，固體劑型包含：L-HPC總質量為藥物組成物總質量的約50%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：L-HPC總質量為藥物組成物總質量的約76.4%，交聚維酮總質量為藥物組成物總質量的約15%。In certain embodiments, the solid dosage form provided herein comprises: (i) a medicament, the total mass of the medicament is at least 5% and no more than 75% of the total mass of the pharmaceutical composition, and (ii) silicified microcrystalline cellulose, the silicified microcrystalline cellulose The total mass of crystalline cellulose is at least 5% (for example, at least 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%) of the total mass of the pharmaceutical composition , 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39 %, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72%, 73% , 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90% %) and not more than 90% (such as not more than 5%, 7%, 10%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% , 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58 %, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%). In certain embodiments, the solid dosage form further comprises crospovidone having a total mass of crospovidone of at least 5% (e.g., at least 5%, 6%, 7%, 8%) of the total mass of the pharmaceutical composition , 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%) and not more than 25% of the total mass of the pharmaceutical composition (for example, not more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% %, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%). In some embodiments, the total mass of silicified microcrystalline cellulose plus the total mass of crospovidone is at least 60%, 70%, 80% or 90% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of L-HPC is about 50% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of L-HPC is about 76.4% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition.

在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的至少45%（例如至少45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%、90%、91%或92%）且不超過92%（例如不超過45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%）。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的約45%。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的約50%-56%。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的約62%-67%。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的約72%-77%。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的約80%-88%。在某些實施方式中，藥劑和矽化微晶纖維素總質量為藥物組成物總質量的約90.5%。In certain embodiments, the total mass of the medicament and silicified microcrystalline cellulose is at least 45% (e.g., at least 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68% , 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86 %, 87%, 88%, 89%, 90%, 91% or 92%) and not exceeding 92% (such as not exceeding 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68% , 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86 %, 87%, 88%, 89% or 90%). In some embodiments, the total mass of the medicament and the silicified microcrystalline cellulose is about 45% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the medicament and the silicified microcrystalline cellulose is about 50%-56% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the medicament and the silicified microcrystalline cellulose is about 62%-67% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of the medicament and the silicified microcrystalline cellulose is about 72%-77% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of the medicament and the silicified microcrystalline cellulose is about 80%-88% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of the medicament and the silicified microcrystalline cellulose is about 90.5% of the total mass of the pharmaceutical composition.

在某些實施方式中，固體劑型進一步包含總交聚維酮，交聚維酮總質量為藥物組成物總質量的至少5%（例如至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%）且不超過30%（不超過5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%或30%）。In certain embodiments, the solid dosage form further comprises total crospovidone, the total mass of crospovidone is at least 5% (eg, at least 5%, 6%, 7%, 8%, 9%) of the total mass of the pharmaceutical composition , 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26 %, 27%, 28%, 29% or 30%) and not exceeding 30% (not exceeding 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14 %, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29% or 30%) .

在某些實施方式中，矽化微晶纖維素總質量加上交聚維酮總質量為藥物組成物總質量的至少15%、17%、20%、25%、30%、35%、40%、45%、50%、55%、60%、70%、80%或90%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約50%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約76.4%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約72.5%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約20%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約5%-43%，交聚維酮總質量為藥物組成物總質量的約15%。In some embodiments, the total mass of silicified microcrystalline cellulose plus the total mass of crospovidone is at least 15%, 17%, 20%, 25%, 30%, 35%, 40% of the total mass of the pharmaceutical composition , 45%, 50%, 55%, 60%, 70%, 80%, or 90%. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 50% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is approximately 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 76.4% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 72.5% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 20% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is approximately 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 5%-43% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含硬脂酸鎂。在某些實施方式中，硬脂酸鎂總質量為藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，硬脂酸鎂總質量不超過藥物組成物總質量的0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，硬脂酸鎂總質量為藥物組成物總質量的約0.01%、0.1%、1%、1.5%、2%、2.5%、3%、3.5%、4%、4.5%、5%、5.5%、6%、6.5%、7%、7.5%、8%、8.5%、9%、9.5%、10%或11%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約0.5%至約1.5%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約1%至約2%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約1%。在某些實施方式中，硬脂酸鎂總質量係藥物組成物總質量的約1.5%。In certain embodiments, the solid dosage forms provided herein comprise magnesium stearate. In certain embodiments, the total mass of magnesium stearate is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of magnesium stearate does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of magnesium stearate is about 0.01%, 0.1%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5% of the total mass of the pharmaceutical composition , 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10% or 11%. In certain embodiments, the total mass of magnesium stearate is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium stearate is about 1% to about 2% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium stearate is about 1% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium stearate is about 1.5% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含膠體二氧化矽（colloidal silica）（也稱為膠體二氧化矽（colloidal silicon dioxide）或SiO 2）。在一些實施方式中，膠體二氧化矽係Aerosil 200。在某些實施方式中，膠體二氧化矽總質量係藥物組成物總質量的至少0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，膠體二氧化矽總質量不超過藥物組成物總質量的0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，膠體二氧化矽總質量係藥物組成物總質量的約0.01%、0.1%、1%、2%、3%、4%、5%、6%、7%、8%、9%、10%或11%。在某些實施方式中，膠體二氧化矽總質量係藥物組成物總質量的約0.5%至約1.5%。在某些實施方式中，膠體二氧化矽（例如Aerosil 200）總質量係藥物組成物總質量的約1%。在某些實施方式中，膠體二氧化矽（例如Aerosil 200）總質量係藥物組成物總質量的約3%。 In certain embodiments, the solid dosage forms provided herein comprise colloidal silica (also known as colloidal silicon dioxide or SiO 2 ). In some embodiments, the colloidal silica is Aerosil 200. In some embodiments, the total mass of colloidal silicon dioxide is at least 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silicon dioxide does not exceed 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In some embodiments, the total mass of colloidal silicon dioxide is about 0.01%, 0.1%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition , 9%, 10% or 11%. In certain embodiments, the total mass of colloidal silicon dioxide is about 0.5% to about 1.5% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of colloidal silicon dioxide (such as Aerosil 200) is about 1% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of colloidal silicon dioxide (such as Aerosil 200) is about 3% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含纖維素的低取代羥丙基醚（例如L-HPC級LH-B1）。在某些實施方式中，L-HPC總質量為藥物組成物總質量的至少9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%或32%。在某些實施方式中，L-HPC總質量不超過藥物組成物總質量的9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%或32%。在某些實施方式中，L-HPC總質量為藥物組成物總質量的約9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%或32%。在某些實施方式中，L-HPC總質量為藥物組成物總質量的約9%、14%、17%、22%、27%或32%。In certain embodiments, the solid dosage forms provided herein comprise a low-substituted hydroxypropyl ether of cellulose (eg, L-HPC grade LH-B1). In certain embodiments, the total mass of L-HPC is at least 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, or 32%. In certain embodiments, the total mass of L-HPC is no more than 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, or 32%. In some embodiments, the total mass of L-HPC is about 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, or 32%. In certain embodiments, the total mass of L-HPC is about 9%, 14%, 17%, 22%, 27% or 32% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含交聯羧甲基纖維素鈉（例如AcDiSol）。在某些實施方式中，交聯羧甲基纖維素鈉總質量為藥物組成物總質量的至少1%、2%、3%、4%、5%、6%或7%。在某些實施方式中，交聯羧甲基纖維素鈉總質量不超過藥物組成物總質量的1%、2%、3%、4%、5%、6%或7%。在某些實施方式中，交聯羧甲基纖維素鈉總質量為藥物組成物總質量的約1%、2%、3%、4%、5%、6%或7%。在某些實施方式中，交聯羧甲基纖維素鈉總質量為藥物組成物總質量的約2%、4%或6%。In certain embodiments, the solid dosage forms provided herein comprise croscarmellose sodium (eg, AcDiSol). In some embodiments, the total mass of croscarmellose sodium is at least 1%, 2%, 3%, 4%, 5%, 6% or 7% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of croscarmellose sodium does not exceed 1%, 2%, 3%, 4%, 5%, 6% or 7% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of croscarmellose sodium is about 1%, 2%, 3%, 4%, 5%, 6% or 7% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of croscarmellose sodium is about 2%, 4% or 6% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含碳酸氫鈉。在某些實施方式中，碳酸氫鈉總質量為藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%或22%。在某些實施方式中，碳酸氫鈉總質量不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%或22%。在某些實施方式中，碳酸氫鈉總質量為藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%或22%。在某些實施方式中，碳酸氫鈉總質量為藥物組成物總質量的約6.5%、7.5%、10%、12%、15%、18%或20%。In certain embodiments, the solid dosage forms provided herein comprise sodium bicarbonate. In some embodiments, the total mass of sodium bicarbonate is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, or 22%. In some embodiments, the total mass of sodium bicarbonate is no more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, or 22%. In some embodiments, the total mass of sodium bicarbonate is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, or 22%. In some embodiments, the total mass of sodium bicarbonate is about 6.5%, 7.5%, 10%, 12%, 15%, 18% or 20% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含檸檬酸。在某些實施方式中，檸檬酸總質量為藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%或22%。在某些實施方式中，總檸檬酸不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%或22%。在某些實施方式中，檸檬酸總質量為藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%或22%。在某些實施方式中，檸檬酸總質量為藥物組成物總質量的約5%、7.5%、10%、12%、15%、18%或20%。In certain embodiments, the solid dosage forms provided herein comprise citric acid. In certain embodiments, the total mass of citric acid is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition. %, 16%, 17%, 18%, 19%, 20%, 21% or 22%. In some embodiments, the total citric acid does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition , 16%, 17%, 18%, 19%, 20%, 21% or 22%. In some embodiments, the total mass of citric acid is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% of the total mass of the pharmaceutical composition %, 16%, 17%, 18%, 19%, 20%, 21% or 22%. In some embodiments, the total mass of citric acid is about 5%, 7.5%, 10%, 12%, 15%, 18% or 20% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含交聚維酮（例如聚乙烯吡咯啶酮-乙酸乙烯酯共聚物、PVP 64或科利當VA 64）。在某些實施方式中，交聚維酮總質量為藥物組成物總質量的至少3%、4%、5%、6%、7%、8%、9%或10%。在某些實施方式中，總交聚維酮不超過藥物組成物總質量的3%、4%、5%、6%、7%、8%、9%或10%。在某些實施方式中，交聚維酮總質量為藥物組成物總質量的約3%、4%、5%、6%、7%、8%、9%或10%。在某些實施方式中，檸檬酸總質量為藥物組成物總質量的約3%、3.5%、5%或10%。In certain embodiments, the solid dosage forms provided herein comprise crospovidone (eg, polyvinylpyrrolidone-vinyl acetate copolymer, PVP 64, or Corytan VA 64). In some embodiments, the total mass of crospovidone is at least 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the pharmaceutical composition. In certain embodiments, the total crospovidone does not exceed 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of crospovidone is about 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of citric acid is about 3%, 3.5%, 5% or 10% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含矽酸鋁鎂（例如維格姆（Veegum））。在某些實施方式中，矽酸鋁鎂總質量為藥物組成物總質量的至少3%、4%、5%、6%、7%、8%、9%或10%。在某些實施方式中，總矽酸鋁鎂不超過藥物組成物總質量的3%、4%、5%、6%、7%、8%、9%或10%。在某些實施方式中，矽酸鋁鎂總質量為藥物組成物總質量的約3%、4%、5%、6%、7%、8%、9%或10%。在某些實施方式中，矽酸鋁鎂總質量為藥物組成物總質量的約5%或10%。In certain embodiments, the solid dosage forms provided herein comprise magnesium aluminum silicate (eg, Veegum). In some embodiments, the total mass of magnesium aluminum silicate is at least 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the pharmaceutical composition. In certain embodiments, the total magnesium aluminum silicate does not exceed 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the pharmaceutical composition. In certain embodiments, the total mass of magnesium aluminum silicate is about 3%, 4%, 5%, 6%, 7%, 8%, 9% or 10% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of magnesium aluminum silicate is about 5% or 10% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含約33%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約50%矽化微晶纖維素（例如，HD90級）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 33% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 50% silicified microcrystalline cellulose (e.g., grade HD90) about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約6.6%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約76.4%矽化微晶纖維素（例如，HD90級）；約15%交聚維酮；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。在某些實施方式中，本文提供的固體劑型包含約10%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約72.5%矽化微晶纖維素（例如，HD90級）；約15%交聚維酮；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, the solid dosage forms provided herein comprise about 6.6% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 76.4% silicified microcrystalline cellulose (e.g., grade HD90) about 15% crospovidone; about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200P). In certain embodiments, the solid dosage forms provided herein comprise about 10% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 72.5% silicified microcrystalline cellulose (e.g., grade HD90) about 15% crospovidone; about 1.5% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200P).

在某些實施方式中，本文提供的固體劑型包含約62.5%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約20%矽化微晶纖維素（例如，HD90級）；約15%交聚維酮；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, the solid dosage forms provided herein comprise about 62.5% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 20% silicified microcrystalline cellulose (e.g., grade HD90) about 15% crospovidone; about 1.5% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200P).

在某些實施方式中，本文提供的固體劑型包含約10%至約70%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約20%至約73%矽化微晶纖維素（例如，HD90級）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise from about 10% to about 70% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); from about 20% to about 73% siliconized microcrystals Cellulose (eg, grade HD90); about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約33%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末或顆粒）；約50%矽化微晶纖維素（例如，HD90級）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 33% pharmaceutical agent (e.g., powder or granules comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 50% silicified microcrystalline cellulose (e.g., HD90 grade); about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約6.6%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末或顆粒）；約76.4%矽化微晶纖維素（例如，HD90級）；約15%交聚維酮；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, the solid dosage forms provided herein comprise about 6.6% pharmaceutical agent (e.g., powder or granules comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 76.4% silicified microcrystalline cellulose (e.g., HD90 grade); about 15% crospovidone; about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200P).

在某些實施方式中，本文提供的固體劑型包含約10%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末或顆粒）；約72.5%矽化微晶纖維素（例如，HD90級）；約15%交聚維酮；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, the solid dosage forms provided herein comprise about 10% pharmaceutical agent (e.g., powder or granules comprising bacteria and/or agents of bacterial origin (e.g., mEV); about 72.5% silicified microcrystalline cellulose (e.g., HD90 grade); about 15% crospovidone; about 1.5% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200P).

在某些實施方式中，本文提供的固體劑型包含約62.5%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末或顆粒）；約20%矽化微晶纖維素（例如，HD90級）；約15%交聚維酮；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如Aerosil 200P）。In certain embodiments, the solid dosage forms provided herein comprise about 62.5% pharmaceutical agent (e.g., powder or granules comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 20% silicified microcrystalline cellulose (e.g., HD90 grade); about 15% crospovidone; about 1.5% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200P).

在某些實施方式中，本文提供的固體劑型包含約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約43%矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 43% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約33%矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 33% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone (eg, PVPP); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約15.5%矽化微晶纖維素（例如，HD90）；約30%交聚維酮（例如，PVPP）；約1.5%硬脂酸鎂；和約3%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 15.5% silicified microcrystalline cellulose (e.g., HD90); about 30% crospovidone (eg, PVPP); about 1.5% magnesium stearate; and about 3% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約74.5%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約16%矽化微晶纖維素（例如，HD90）；約7%交聚維酮（例如，PVPP）；約1.5%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, a solid dosage form provided herein comprises about 74.5% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 16% silicified microcrystalline cellulose (e.g., HD90); about 7% crospovidone (eg, PVPP); about 1.5% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約37%矽化微晶纖維素（例如，HD90）；約7%交聚維酮（例如，PVPP）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 37% silicified microcrystalline cellulose (e.g., HD90); About 7% crospovidone (eg, PVPP); about 4% croscarmellose sodium (eg, AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200 ).

在某些實施方式中，本文提供的固體劑型包含約60%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約27%矽化微晶纖維素（例如，HD90）；約7%交聚維酮（例如，PVPP）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 27% silicified microcrystalline cellulose (e.g., HD90); About 7% crospovidone (eg, PVPP); about 4% croscarmellose sodium (eg, AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200 ).

在某些實施方式中，本文提供的固體劑型包含約60%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約21%矽化微晶纖維素（例如，HD90）；約13%交聚維酮（例如，PVPP）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 21% silicified microcrystalline cellulose (e.g., HD90); About 13% crospovidone (eg, PVPP); about 4% croscarmellose sodium (eg, AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200 ).

在某些實施方式中，本文提供的固體劑型包含約8%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末或顆粒）；約42%矽化微晶纖維素（例如，HD90級）；約27%低取代的纖維素羥丙基醚（例如，L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。In certain embodiments, the solid dosage forms provided herein comprise about 8% pharmaceutical agent (e.g., powder or granules comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 42% silicified microcrystalline cellulose (e.g., HD90 grade); about 27% low-substituted cellulose hydroxypropyl ether (for example, L-HPC grade LH-B1); about 6% croscarmellose sodium (for example, AcDiSol); about 15% crospovidone (PVPP, eg, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate.

在某些實施方式中，本文提供的固體劑型包含約23%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末或顆粒）；約27%矽化微晶纖維素（例如，HD90級）；約27%低取代的纖維素羥丙基醚（例如，L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。In certain embodiments, the solid dosage forms provided herein comprise about 23% pharmaceutical agent (e.g., powder or granules comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 27% silicified microcrystalline cellulose (e.g., HD90 grade); about 27% low-substituted cellulose hydroxypropyl ether (for example, L-HPC grade LH-B1); about 6% croscarmellose sodium (for example, AcDiSol); about 15% crospovidone (PVPP, eg, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate.

在某些實施方式中，本文提供的固體劑型包含約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末或顆粒）；約10%矽化微晶纖維素（例如，HD90級）；約27%低取代的纖維素羥丙基醚（例如，L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。In certain embodiments, the solid dosage forms provided herein comprise about 40% pharmaceutical agent (e.g., powder or granules comprising bacteria and/or agents of bacterial origin (e.g., mEV); about 10% silicified microcrystalline cellulose (e.g., HD90 grade); about 27% low-substituted cellulose hydroxypropyl ether (for example, L-HPC grade LH-B1); about 6% croscarmellose sodium (for example, AcDiSol); about 15% crospovidone (PVPP, eg, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate.

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末或顆粒）；約5%矽化微晶纖維素（例如，HD90級）；約22%低取代的纖維素羥丙基醚（例如L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., powder or granules comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 5% silicified microcrystalline cellulose (e.g., HD90 grade); about 22% low-substituted cellulose hydroxypropyl ether (such as L-HPC grade LH-B1); about 6% croscarmellose sodium (such as AcDiSol); about 15% crospovidone ( PVPP, e.g., Corytan CL-F); about 1% silicon dioxide; and about 1% magnesium stearate.

在某些實施方式中，本文提供的固體劑型包含約10%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約40%矽化微晶纖維素（例如，HD90級）；約27%低取代的纖維素羥丙基醚（例如，L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。In certain embodiments, the solid dosage forms provided herein comprise about 10% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 40% silicified microcrystalline cellulose (e.g., grade HD90) ; about 27% low-substituted cellulose hydroxypropyl ether (for example, L-HPC grade LH-B1); about 6% croscarmellose sodium (for example, AcDiSol); about 15% crospovidone (PVPP , for example, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate.

在某些實施方式中，本文提供的固體劑型包含約20%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約30%矽化微晶纖維素（例如，HD90級）；約27%低取代的纖維素羥丙基醚（例如，L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。In certain embodiments, the solid dosage forms provided herein comprise about 20% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 30% silicified microcrystalline cellulose (e.g., grade HD90) ; about 27% low-substituted cellulose hydroxypropyl ether (for example, L-HPC grade LH-B1); about 6% croscarmellose sodium (for example, AcDiSol); about 15% crospovidone (PVPP , for example, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate.

在某些實施方式中，本文提供的固體劑型包含約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約5%矽化微晶纖維素（例如，HD90級）；約32%低取代的纖維素羥丙基醚（例如，L-HPC級LH-B1）；約6%交聯羧甲基纖維素鈉（例如AcDiSol）；約15%交聚維酮（PVPP，例如，科利當CL-F）；約1%二氧化矽；和約1%硬脂酸鎂。在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約52%矽化微晶纖維素（例如，HD90級）；約20%交聚維酮（PVPP，例如，科利當CL-F）；約1%滑石粉；約1%二氧化矽；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 5% silicified microcrystalline cellulose (e.g., grade HD90) ; about 32% low-substituted cellulose hydroxypropyl ether (for example, L-HPC grade LH-B1); about 6% croscarmellose sodium (for example, AcDiSol); about 15% crospovidone (PVPP , for example, Corydon CL-F); about 1% silicon dioxide; and about 1% magnesium stearate. In certain embodiments, the solid dosage forms provided herein comprise about 25% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 52% silicified microcrystalline cellulose (e.g., grade HD90) about 20% crospovidone (PVPP, e.g., Corytan CL-F); about 1% talc; about 1% silicon dioxide; and about 1% sodium stearyl fumarate.

在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約47%矽化微晶纖維素（例如，HD90級）；約20%交聚維酮（PVPP，例如，科利當CL-F）；約5%交聚維酮（例如，PVP 64）；約1%滑石粉；約1%二氧化矽；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 25% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 47% silicified microcrystalline cellulose (e.g., grade HD90) ; about 20% crospovidone (PVPP, e.g., Corytan CL-F); about 5% crospovidone (e.g., PVP 64); about 1% talc; about 1% silicon dioxide; and about 1% Sodium stearyl fumarate.

在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約42%矽化微晶纖維素（例如，HD90級）；約20%交聚維酮（PVPP，例如，科利當CL-F）；約10%交聚維酮（例如PVP 64）；約1%滑石粉；約1%二氧化矽；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 25% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 42% silicified microcrystalline cellulose (e.g., grade HD90) ; about 20% crospovidone (PVPP, e.g., Corytan CL-F); about 10% crospovidone (e.g., PVP 64); about 1% talc; about 1% silicon dioxide; % Sodium Stearyl Fumarate.

在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約47%矽化微晶纖維素（例如，HD90級）；約20%交聚維酮（PVPP，例如，科利當CL-F）；約5%矽酸鋁鎂（例如，維格姆）；約1%滑石粉；約1%二氧化矽；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 25% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 47% silicified microcrystalline cellulose (e.g., grade HD90) about 20% crospovidone (PVPP, e.g., Corytan CL-F); about 5% magnesium aluminum silicate (e.g., Vigum); about 1% talc; about 1% silicon dioxide; and About 1% sodium stearyl fumarate.

在某些實施方式中，本文提供的固體劑型包含約25%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約42%矽化微晶纖維素（例如，HD90級）；約20%交聚維酮（PVPP，例如，科利當CL-F）；約10%矽酸鋁鎂（例如，維格姆）；約1%滑石粉；約1%二氧化矽；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 25% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 42% silicified microcrystalline cellulose (e.g., grade HD90) about 20% crospovidone (PVPP, e.g., Corytan CL-F); about 10% magnesium aluminum silicate (e.g., Vigum); about 1% talc; about 1% silicon dioxide; and About 1% sodium stearyl fumarate.

在某些實施方式中，本文提供的固體劑型包含約30%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約22%矽化微晶纖維素（例如，HD90）；約20%檸檬酸；約20%碳酸氫鈉；約5%交聚維酮（例如，PVPP）；約1.5%硬脂酸鎂；和約1.5%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 30% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 22% silicified microcrystalline cellulose (e.g., HD90); about 20% citric acid; about 20% sodium bicarbonate; about 5% crospovidone (eg, PVPP); about 1.5% magnesium stearate; and about 1.5% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約16%矽化微晶纖維素（例如，HD90）；約18%檸檬酸；約18%碳酸氫鈉；約5%交聚維酮（例如，PVPP）；約1.5%硬脂酸鎂；和約1.5%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 16% silicified microcrystalline cellulose (e.g., HD90); about 18% citric acid; about 18% sodium bicarbonate; about 5% crospovidone (eg, PVPP); about 1.5% magnesium stearate; and about 1.5% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約12%矽化微晶纖維素（例如，HD90）；約15%檸檬酸；約15%碳酸氫鈉；約5%交聚維酮（例如，PVPP）；約1.5%硬脂酸鎂；和約1.5%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 12% silicified microcrystalline cellulose (e.g., HD90); about 15% citric acid; about 15% sodium bicarbonate; about 5% crospovidone (eg, PVPP); about 1.5% magnesium stearate; and about 1.5% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約17%矽化微晶纖維素（例如，HD90）；約10%檸檬酸；約10%碳酸氫鈉；約10%交聚維酮（例如，PVPP）；約1.5%硬脂酸鎂；和約1.5%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 17% silicified microcrystalline cellulose (e.g., HD90); about 10% citric acid; about 10% sodium bicarbonate; about 10% crospovidone (eg, PVPP); about 1.5% magnesium stearate; and about 1.5% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約50%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約15%矽化微晶纖維素（例如，HD90）；約12%檸檬酸；約12%碳酸氫鈉；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約4%羧基乙酸澱粉鈉；約1.5%硬脂酸鎂；和約1.5%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 50% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 15% silicified microcrystalline cellulose (e.g., HD90); About 12% citric acid; about 12% sodium bicarbonate; about 4% croscarmellose sodium (such as AcDiSol); about 4% sodium starch glycolate; about 1.5% magnesium stearate; and about 1.5% colloid Silicon dioxide (for example, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約55%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約7.5%矽化微晶纖維素（例如，HD90）；約7.5%檸檬酸；約7.5%碳酸氫鈉；約20%交聚維酮（例如，PVPP）；約1%硬脂醯富馬酸鈉；和約1.5%膠體二氧化矽（例如，Aerosil 200）；其中藥劑的20%被包衣。In certain embodiments, the solid dosage forms provided herein comprise about 55% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 7.5% silicified microcrystalline cellulose (e.g., HD90); about 7.5% citric acid; about 7.5% sodium bicarbonate; about 20% crospovidone (eg, PVPP); about 1% sodium stearyl fumarate; and about 1.5% colloidal silicon dioxide (eg, Aerosil 200 ); wherein 20% of the medicament is coated.

在某些實施方式中，本文提供的固體劑型包含約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約25.5%矽化微晶纖維素（例如，HD90）；約5%檸檬酸；約6.5%碳酸氫鈉；約18%交聚維酮（例如，PVPP）；約2%羧基乙酸澱粉鈉；約1%硬脂醯富馬酸鈉；約1%滑石粉；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 25.5% silicified microcrystalline cellulose (e.g., HD90); About 5% citric acid; about 6.5% sodium bicarbonate; about 18% crospovidone (eg, PVPP); about 2% sodium starch glycolate; about 1% sodium stearyl fumarate; about 1% talc and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約40%藥劑（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末）；約22%矽化微晶纖維素（例如，HD90）；約5%檸檬酸；約6.5%碳酸氫鈉；約20%交聚維酮（例如，PVPP）；約3.5%交聚維酮（PVP 64）；約1%硬脂醯富馬酸鈉；約1%滑石粉；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 40% pharmaceutical agent (e.g., a powder comprising bacteria and/or agents of bacterial origin (e.g., mEV)); about 22% silicified microcrystalline cellulose (e.g., HD90); About 5% citric acid; about 6.5% sodium bicarbonate; about 20% crospovidone (eg, PVPP); about 3.5% crospovidone (PVP 64); about 1% sodium stearyl fumarate; 1% talc; and about 1% colloidal silicon dioxide (for example, Aerosil 200).

在一些實施方式中，藥劑的濕法製粒產生包含藥劑的顆粒（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末的藥物物質顆粒）。在一些實施方式中，顆粒進一步包含一種或多種賦形劑（例如，一種、兩種或三種）。在一些實施方式中，顆粒視需要與一種或多種（例如，一種、兩種或三種）賦形劑組合以製備藥物組成物（例如片劑、膠囊或固體劑型）。In some embodiments, wet granulation of the medicament produces granules comprising the medicament (eg, drug substance granules comprising a powder of bacteria and/or agents of bacterial origin (eg, mEV)). In some embodiments, the particles further comprise one or more excipients (eg, one, two, or three). In some embodiments, the granules are optionally combined with one or more (eg, one, two or three) excipients to prepare a pharmaceutical composition (eg, tablet, capsule or solid dosage form).

在本文提供的一些實施方式中，顆粒包含60%-100%的藥劑（例如粉末，包含細菌和/或細菌來源的試劑，例如mEV）。在一些實施方式中，顆粒包含約60%、65%、70%、75%、80%、85%、90%、95%或100%的藥劑。在其他實施方式中，顆粒占藥物組成物總質量的35%-85%。在本文提供的一些實施方式中，顆粒占藥物組成物總質量的約40%、50%、55%、60%、70%、75%、80%或85%。In some embodiments provided herein, the particles comprise 60%-100% agent (eg, powder comprising bacteria and/or agents of bacterial origin, eg, mEV). In some embodiments, the particles comprise about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the agent. In other embodiments, the particles account for 35%-85% of the total mass of the pharmaceutical composition. In some embodiments provided herein, the particles account for about 40%, 50%, 55%, 60%, 70%, 75%, 80% or 85% of the total mass of the pharmaceutical composition.

在某些實施方式中，本文提供的固體劑型包含約60%顆粒；約15%矽化微晶纖維素（例如，HD90）；約10%交聚維酮（例如，PVPP）；約9%低取代的纖維素羥丙基醚（例如L-HPC級LH-B1）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% granules; about 15% silicified microcrystalline cellulose (e.g., HD90); about 10% crospovidone (e.g., PVPP); about 9% low-substituted cellulose hydroxypropyl ether (such as L-HPC grade LH-B1); about 4% croscarmellose sodium (such as AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (for example, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約60%顆粒；約27%矽化微晶纖維素（例如，HD90）；約7%交聚維酮（例如，PVPP）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% granules; about 27% silicified microcrystalline cellulose (e.g., HD90); about 7% crospovidone (e.g., PVPP); about 4% cross-linked Sodium carboxymethylcellulose (eg, AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約60%顆粒；約27%矽化微晶纖維素（例如，HD90）；約13%交聚維酮（例如，PVPP）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% granules; about 27% silicified microcrystalline cellulose (e.g., HD90); about 13% crospovidone (e.g., PVPP); about 4% cross-linked Sodium carboxymethylcellulose (eg, AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約60%顆粒；約5%矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約14%低取代的纖維素羥丙基醚（例如L-HPC級LH-B1）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% granules; about 5% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone (e.g., PVPP); about 14% low-substituted cellulose hydroxypropyl ether (such as L-HPC grade LH-B1); about 4% croscarmellose sodium (such as AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (for example, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約60%顆粒；約17%交聚維酮（例如，PVPP）；約17%低取代的纖維素羥丙基醚（例如L-HPC級LH-B1）；約4%交聯羧甲基纖維素鈉（例如AcDiSol）；約1%硬脂酸鎂；和約1%膠體二氧化矽（例如，Aerosil 200）。In certain embodiments, the solid dosage forms provided herein comprise about 60% granules; about 17% crospovidone (e.g., PVPP); about 17% low-substituted cellulose hydroxypropyl ether (e.g., L-HPC grade LH -B1); about 4% croscarmellose sodium (eg, AcDiSol); about 1% magnesium stearate; and about 1% colloidal silicon dioxide (eg, Aerosil 200).

在某些實施方式中，本文提供的固體劑型包含約55%顆粒；約25%矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約1%膠體二氧化矽（例如，Aerosil 200）；約1%羧基乙酸澱粉鈉；和約1%硬脂醯富馬酸鈉。在某些實施方式中，本文提供的固體劑型包含約55%顆粒；約25%矽化微晶纖維素（例如，HD90）；約15%交聚維酮（例如，PVPP）；約1%膠體二氧化矽（例如，Aerosil 200）；約1%羧基乙酸澱粉鈉；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 55% granules; about 25% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone (e.g., PVPP); about 1% colloidal bismuth Silicon oxide (for example, Aerosil 200); about 1% sodium starch glycolate; and about 1% sodium stearyl fumarate. In certain embodiments, the solid dosage forms provided herein comprise about 55% granules; about 25% silicified microcrystalline cellulose (e.g., HD90); about 15% crospovidone (e.g., PVPP); about 1% colloidal bismuth Silicon oxide (for example, Aerosil 200); about 1% sodium starch glycolate; and about 1% sodium stearyl fumarate.

在某些實施方式中，本文提供的固體劑型包含約50%顆粒；約32%矽化微晶纖維素（例如，HD90）；約10%交聚維酮（例如，PVPP）；約3%交聚維酮（例如，PVP-64）；約2%交聯羧甲基纖維素鈉；約1%膠體二氧化矽（例如，Aerosil 200）；約1%滑石粉；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 50% granules; about 32% silicified microcrystalline cellulose (e.g., HD90); about 10% crospovidone (e.g., PVPP); about 3% cross-polymerized Povidone (eg, PVP-64); about 2% croscarmellose sodium; about 1% colloidal silicon dioxide (eg, Aerosil 200); about 1% talc; sodium maleate.

在某些實施方式中，本文提供的固體劑型包含約40%顆粒；約32%矽化微晶纖維素（例如，HD90）；約20%交聚維酮（例如，PVPP）；約3%交聚維酮（例如，PVP-64）；約2%交聯羧甲基纖維素鈉；約1%膠體二氧化矽（例如，Aerosil 200）；約1%滑石粉；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 40% granules; about 32% silicified microcrystalline cellulose (e.g., HD90); about 20% crospovidone (e.g., PVPP); about 3% cross-polymerized Povidone (eg, PVP-64); about 2% croscarmellose sodium; about 1% colloidal silicon dioxide (eg, Aerosil 200); about 1% talc; sodium maleate.

在某些實施方式中，本文提供的固體劑型包含約70%顆粒；約17%矽化微晶纖維素（例如，HD90）；約5%交聚維酮（例如，PVPP）；約3%交聚維酮（例如，PVP-64）；約2%交聯羧甲基纖維素鈉；約1%膠體二氧化矽（例如，Aerosil 200）；約1%滑石粉；和約1%硬脂醯富馬酸鈉。In certain embodiments, the solid dosage forms provided herein comprise about 70% granules; about 17% silicified microcrystalline cellulose (e.g., HD90); about 5% crospovidone (e.g., PVPP); about 3% cross-polymerized Povidone (eg, PVP-64); about 2% croscarmellose sodium; about 1% colloidal silicon dioxide (eg, Aerosil 200); about 1% talc; sodium maleate.

因此，在某些實施方式中，本文提供了包含含有細菌的藥劑的固體劑型。細菌可以是活細菌（例如，其粉末或生物質）；非活（死）細菌（例如，其粉末或生物質）；非複製型細菌（例如，其粉末或生物質）；經γ輻照的細菌（例如，其粉末或其生物質）；和/或凍乾細菌（例如，其粉末或生物質）。Accordingly, in certain embodiments, provided herein are solid dosage forms comprising a bacterium-containing agent. Bacteria can be live bacteria (for example, their powder or biomass); nonviable (dead) bacteria (for example, their powder or biomass); non-replicating bacteria (for example, their powder or biomass); gamma-irradiated Bacteria (eg, powder thereof or biomass thereof); and/or lyophilized bacteria (eg, powder or biomass thereof).

在某些實施方式中，本文提供了包含含有mEV的藥劑的固體劑型。mEV可來自培養基（例如，培養上清液）。mEV可來自活細菌（例如，其粉末或生物質）；mEV可來自非活（死）細菌（例如，其粉末或生物質）；mEV可來自非複製型細菌（例如其粉末或生物質）；mEV可來自經γ輻照的細菌（例如，其粉末或生物質）；和/或mEV可來自凍乾細菌（例如，其粉末或生物質）。In certain embodiments, provided herein are solid dosage forms comprising an mEV-containing medicament. mEVs can be derived from culture medium (eg, culture supernatant). mEVs can be derived from live bacteria (e.g., their powder or biomass); mEVs can be derived from nonviable (dead) bacteria (e.g., their powder or biomass); mEVs can be derived from non-replicating bacteria (e.g., their powder or biomass); mEVs can be from gamma-irradiated bacteria (eg, powder or biomass thereof); and/or mEVs can be from lyophilized bacteria (eg, powder or biomass thereof).

在一些實施方式中，藥劑包含基本上或完全不含細菌（例如，整個細菌）、細菌（例如，活細菌、死（例如，被殺死的）細菌、非複製型細菌、減毒細菌）的mEV。在一些實施方式中，藥物組成物包含mEV及細菌（例如，整個細菌）（例如，活細菌、被殺死的細菌、減毒細菌）兩者。在一些實施方式中，藥劑包含來自本文列舉的細菌菌株或物種或分類學組中的一種或多種（例如，1、2、3、4、5、6、7、8、9、10或更多）的細菌和/或mEV。在一些實施方式中，藥劑包含來自本文列舉的細菌菌株或物種或分類學組中的一種的細菌和/或mEV。在一些實施方式中，藥劑包含來自本文描述的細菌菌株或物種中的一種的細菌和/或mEV，例如乳球菌屬、普雷沃菌屬、雙歧桿菌屬、韋榮氏球菌屬、Fournierella屬、Harryflintia屬、巨型球菌屬； 例如，乳酸乳球菌乳脂亞種棲組織普雷沃菌；動物雙歧桿菌乳酸亞種；小韋榮氏球菌； Fournierella massiliensis ； Harryflintia acetispora ；或巨型球菌屬物種。 In some embodiments, the medicament comprises substantially or completely free of bacteria (e.g., whole bacteria), bacteria (e.g., live bacteria, dead (e.g., killed) bacteria, non-replicating bacteria, attenuated bacteria). mEV. In some embodiments, the pharmaceutical composition comprises both mEVs and bacteria (eg, whole bacteria) (eg, live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the medicament comprises one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) from the bacterial strains or species or taxonomic groups listed herein. ) bacteria and/or mEV. In some embodiments, the medicament comprises bacteria and/or mEVs from one of the bacterial strains or species or taxonomic groups listed herein. In some embodiments, the medicament comprises bacteria and/or mEVs from one of the bacterial strains or species described herein, e.g., Lactococcus, Prevotella, Bifidobacterium, Veillonella, Fournierella , Harryflintia spp., Macrococcus spp .; for example, Lactococcus lactis subsp. cremoris, Prevotella histoclidins; Bifidobacterium animalis subsp. lactis; Veillonella parvum; Fournierella massiliensis ; Harryflintia acetispora ;

在一些實施方式中，藥劑包含凍乾的棲組織普雷沃菌細菌。In some embodiments, the medicament comprises lyophilized Prevotella histotropes bacteria.

在一些實施方式中，藥劑包含凍乾的細菌和/或mEV。在一些實施方式中，藥劑包含經γ輻照的細菌和/或mEV。mEV（如smEV和/或pmEV）可以在mEV被分離（例如製備）之後進行γ輻照。In some embodiments, the medicament comprises lyophilized bacteria and/or mEVs. In some embodiments, the agent comprises gamma-irradiated bacteria and/or mEVs. mEVs (such as smEVs and/or pmEVs) can be gamma-irradiated after the mEVs are isolated (eg, prepared).

在一些實施方式中，為定量樣本中存在的mEV（如smEV和/或pmEV）和/或細菌的數量，可使用電子顯微術（例如，超薄冷凍切片的EM）以觀測mEV（如smEV和/或pmEV）和/或細菌並計數它們的相對數量。可替代地，可使用奈米顆粒跟蹤分析（NTA）、庫爾特計數或動態光散射（DLS）或該等技術的組合。NTA及庫爾特計數器計數顆粒並顯示它們的大小。DLS給出顆粒的大小分佈，而非濃度。細菌通常具有1-2 µm的直徑。完整範圍係0.2-20 µm。來自庫爾特計數及NTA的組合結果可揭示給定樣本中的細菌和/或mEV（如smEV和/或pmEV）數量。庫爾特計數揭示具有0.7至10 um的直徑的顆粒的數量。對於大多數細菌和/或mEV（如smEV和/或pmEV）樣本，僅庫爾特計數器就可以顯示樣本中細菌和/或mEV（如smEV和/或pmEV）的數量。pmEV的直徑係20 nm-600 nm。對於NTA，可以從瑪律文泛分析公司（Malvern Pananlytical）獲得Nanosight儀器。例如，NS300可以觀測並測量大小在10-2000 nm範圍內的懸浮顆粒。NTA允許計數例如直徑為50-1000 nm的顆粒的數量。DLS揭示具有於1 nm - 3 µm的近似範圍內的不同直徑的顆粒的分佈。In some embodiments, to quantify the number of mEVs (e.g., smEVs and/or pmEVs) and/or bacteria present in a sample, electron microscopy (e.g., EM of ultra-thin cryosections) can be used to visualize mEVs (e.g., smEVs and/or pmEV) and/or bacteria and count their relative numbers. Alternatively, nanoparticle tracking analysis (NTA), Coulter counting or dynamic light scattering (DLS) or a combination of these techniques can be used. NTA and Coulter counters count particles and display their size. DLS gives the size distribution of the particles, not the concentration. Bacteria typically have a diameter of 1-2 µm. The full range is 0.2-20 µm. Combined results from Coulter count and NTA can reveal the number of bacteria and/or mEVs (such as smEV and/or pmEV) in a given sample. Coulter counting revealed the number of particles with a diameter of 0.7 to 10 um. For most samples of bacteria and/or mEVs (such as smEV and/or pmEV), a Coulter counter alone will show the number of bacteria and/or mEVs (such as smEV and/or pmEV) in the sample. The diameter of pmEV is 20 nm-600 nm. For NTA, the Nanosight instrument is available from Malvern Pananlytical. For example, the NS300 can observe and measure suspended particles in the size range of 10-2000 nm. NTA allows counting the number of particles eg 50-1000 nm in diameter. DLS revealed a distribution of particles with different diameters in the approximate range of 1 nm - 3 µm.

mEV可以藉由本領域已知的分析方法（例如Jeppesen等人 Cell [細胞] 177:428 (2019)）來表徵。mEVs can be characterized by analytical methods known in the art (eg, Jeppesen et al. Cell 177:428 (2019)).

在一些實施方式中，可以基於顆粒計數來對細菌和/或mEV進行定量。例如，可以使用NTA測量細菌和/或mEV製劑的總顆粒計數。In some embodiments, bacteria and/or mEVs can be quantified based on particle counts. For example, total particle counts of bacterial and/or mEV preparations can be measured using NTA.

在一些實施方式中，可以基於蛋白質、脂質或碳水化合物的量來定量細菌和/或mEV。例如，可以使用布拉德福測定法或BCA來測量細菌和/或製劑的總蛋白含量。In some embodiments, bacteria and/or mEVs can be quantified based on the amount of protein, lipid, or carbohydrate. For example, the total protein content of bacteria and/or preparations can be measured using the Bradford assay or BCA.

在一些實施方式中，從源細菌或細菌培養物的一種或多種其他細菌組分中分離出mEV。在一些實施方式中，從源細菌培養物的一種或多種其他細菌組分中分離出細菌。在一些實施方式中，藥劑進一步包含其他細菌組分。In some embodiments, mEVs are isolated from the source bacterium or one or more other bacterial components of a bacterial culture. In some embodiments, the bacteria are isolated from one or more other bacterial components of the source bacterial culture. In some embodiments, the medicament further comprises other bacterial components.

在某些實施方式中，從源細菌獲得的mEV製劑可基於亞群的物理性質（例如，大小、密度、蛋白含量、結合親和力）被分級成亞群。然後可以將mEV亞群中的一個或多個併入到本文所述之藥劑中。In certain embodiments, mEV preparations obtained from source bacteria can be fractionated into subpopulations based on their physical properties (eg, size, density, protein content, binding affinity). One or more of the subpopulations of mEVs can then be incorporated into the agents described herein.

在某些方面，本文提供了包含藥劑（其包含細菌和/或mEV（例如smEV和/或pmEV））的固體劑型，可用於治療和/或預防疾病（例如，癌症、自體免疫性疾病、炎性疾病、代謝性疾病或生態失調）；或治療和/或預防細菌性敗血症性休克、細胞介素風暴和/或病毒感染（例如冠狀病毒感染、流感感染和/或呼吸道合胞病毒感染）；或降低炎性細胞介素表現（例如降低IL-8、IL-6、IL-1β和/或TNFα的表現水平），以及製造和/或鑒定此類細菌和/或mEV之方法，以及和單獨使用或與其他治療劑組合使用藥劑及其固體劑型之方法（例如，用於治療癌症、自體免疫性疾病、炎性疾病或代謝性疾病、生態失調、細菌性敗血症性休克、細胞介素風暴和/或病毒感染，或降低炎性細胞介素表現）。在一些實施方式中，藥劑包含mEV（如smEV和/或pmEV）及細菌（例如，整個細菌）（例如，活細菌、死（例如，被殺死的）細菌、非複製型細菌、減毒細菌）兩者。在一些實施方式中，藥劑包含在不存在mEV（如smEV和/或pmEV）的情況下的細菌。在一些實施方式中，藥劑包含在不存在細菌的情況下的mEV（如smEV和/或pmEV）。在一些實施方式中，藥劑包含來自表1、表2、表3和/或表4中列舉的細菌菌株或物種中的一種或多種的mEV（例如smEV和/或pmEV）和/或細菌。在一些實施方式中，藥物組成物包含來自本文列舉的細菌菌株或物種或分類學組中的一種的mEV（例如smEV和/或pmEV）和/或細菌。在一些實施方式中，藥劑包含來自本文描述的細菌菌株或物種中的一種的細菌和/或mEV，例如乳球菌屬、普雷沃菌屬、雙歧桿菌屬、韋榮氏球菌屬、Fournierella屬、Harryflintia屬、巨型球菌屬； 例如，乳酸乳球菌乳脂亞種棲組織普雷沃菌；動物雙歧桿菌乳酸亞種；小韋榮氏球菌； Fournierella massiliensis ； Harryflintia acetispora ；或巨型球菌屬物種。 In certain aspects, provided herein are solid dosage forms comprising a medicament comprising bacteria and/or mEVs (e.g., smEV and/or pmEV), useful for treating and/or preventing a disease (e.g., cancer, autoimmune disease, inflammatory disease, metabolic disease, or dysbiosis); or treatment and/or prevention of bacterial septic shock, cytokine storm, and/or viral infection (e.g., coronavirus infection, influenza infection, and/or respiratory syncytial virus infection) or reduce the expression of inflammatory cytokines (such as reducing the expression levels of IL-8, IL-6, IL-1β and/or TNFα), and methods of making and/or identifying such bacteria and/or mEVs, and and Methods of using medicaments and solid dosage forms thereof alone or in combination with other therapeutic agents (e.g., for the treatment of cancer, autoimmune, inflammatory or metabolic diseases, dysbiosis, bacterial septic shock, cytokine Storm and/or viral infection, or decreased expression of inflammatory cytokines). In some embodiments, the agent comprises mEV (e.g., smEV and/or pmEV) and bacteria (e.g., whole bacteria) (e.g., live bacteria, dead (e.g., killed) bacteria, non-replicating bacteria, attenuated bacteria ) both. In some embodiments, the agent comprises bacteria in the absence of mEV (eg, smEV and/or pmEV). In some embodiments, the agent comprises mEV (eg, smEV and/or pmEV) in the absence of bacteria. In some embodiments, the agent comprises mEV (eg, smEV and/or pmEV) and/or bacteria from one or more of the bacterial strains or species listed in Table 1, Table 2, Table 3, and/or Table 4. In some embodiments, the pharmaceutical composition comprises mEV (eg, smEV and/or pmEV) and/or bacteria from one of the bacterial strains or species or taxonomic groups listed herein. In some embodiments, the medicament comprises bacteria and/or mEVs from one of the bacterial strains or species described herein, e.g., Lactococcus, Prevotella, Bifidobacterium, Veillonella, Fournierella , Harryflintia spp., Macrococcus spp .; for example, Lactococcus lactis subsp. cremoris, Prevotella histoclidins; Bifidobacterium animalis subsp. lactis; Veillonella parvum; Fournierella massiliensis ; Harryflintia acetispora ;

在某些方面，提供了用於向受試者（例如人受試者）施用的藥劑。在一些實施方式中，藥劑與另外的活性和/或非活性材料組合以產生最終產品，其可呈單劑量單位或呈多劑量形式。在一些實施方式中，藥劑與佐劑如免疫佐劑（例如STING促効劑、TLR促効劑或NOD促効劑）組合。In certain aspects, medicaments for administration to a subject (eg, a human subject) are provided. In some embodiments, the medicament is combined with additional active and/or inactive materials to produce the final product, which may be presented as a single dosage unit or in multi-dose form. In some embodiments, the agent is combined with an adjuvant, such as an immune adjuvant (eg, a STING agonist, a TLR agonist, or a NOD agonist).

在一些實施方式中，固體劑型包含至少一種碳水化合物。In some embodiments, the solid dosage form comprises at least one carbohydrate.

在一些實施方式中，固體劑型包含至少一種脂質。在一些實施方式中，脂質包含至少一種選自以下的脂肪酸：月桂酸（12:0）、肉豆蔻酸（14:0）、棕櫚酸（16:0）、棕櫚油酸（16:1）、珍珠酸（17:0）、十七碳烯酸（17:1）、硬脂酸（18:0）、油酸（18:1）、亞油酸（18:2）、亞麻酸（18:3）、十八碳四烯酸（18:4）、花生酸（20:0）、二十碳烯酸（20:1）、二十碳二烯酸（20:2）、二十碳四烯酸（20:4）、二十碳五烯酸（20:5）（EPA）、二十二烷酸（22:0）、二十二碳烯酸（22:1）、二十二碳五烯酸（22:5）、二十二碳六烯酸（22:6）（DHA）及二十四烷酸（24:0）。In some embodiments, the solid dosage form comprises at least one lipid. In some embodiments, the lipid comprises at least one fatty acid selected from the group consisting of lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), Pearl Acid (17:0), Heptadecenoic Acid (17:1), Stearic Acid (18:0), Oleic Acid (18:1), Linoleic Acid (18:2), Linolenic Acid (18: 3), stearidonic acid (18:4), arachidic acid (20:0), eicosenoic acid (20:1), eicosadienoic acid (20:2), eicosatetra Acenoic acid (20:4), eicosapentaenoic acid (20:5) (EPA), docosanoic acid (22:0), docosanoic acid (22:1), docosanoic acid Pentaenoic acid (22:5), docosahexaenoic acid (22:6) (DHA) and tetracosanoic acid (24:0).

在一些實施方式中，固體劑型包含至少一種礦物質或礦物質源。礦物質的實例包括但不限於：氯化物、鈉、鈣、鐵、鉻、銅、碘、鋅、鎂、錳、鉬、磷、鉀及硒。任一前述礦物質的合適形式包括可溶性礦物質鹽、微溶性礦物質鹽、不溶性礦物質鹽、螯合礦物質、礦物質複合物、非反應性礦物質（例如羰基礦物質及經還原礦物質）及其組合。In some embodiments, the solid dosage form comprises at least one mineral or source of minerals. Examples of minerals include, but are not limited to: chloride, sodium, calcium, iron, chromium, copper, iodine, zinc, magnesium, manganese, molybdenum, phosphorus, potassium, and selenium. Suitable forms of any of the foregoing minerals include soluble mineral salts, slightly soluble mineral salts, insoluble mineral salts, chelated minerals, mineral complexes, non-reactive minerals (such as carbonyl minerals, and reduced minerals) ) and their combinations.

在一些實施方式中，固體劑型包含至少一種維生素。至少一種維生素可為脂肪可溶性或水可溶性維生素。合適維生素包括但不限於維生素C、維生素A、維生素E、維生素B12、維生素K、核黃素、菸酸（niacin）、維生素D、維生素B6、葉酸、吡哆醇（pyridoxine）、硫胺素、泛酸及生物素。任一前述物質的合適形式係維生素鹽、維生素衍生物、與維生素具有相同或類似活性的化合物及維生素代謝物。In some embodiments, the solid dosage form comprises at least one vitamin. At least one vitamin may be a fat-soluble or water-soluble vitamin. Suitable vitamins include, but are not limited to, vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, Pantothenic acid and biotin. Suitable forms of any of the foregoing are vitamin salts, vitamin derivatives, compounds having the same or similar activity as vitamins, and vitamin metabolites.

在一些實施方式中，固體劑型包含賦形劑。合適的賦形劑的非限制性實例包括稀釋劑、緩衝劑、防腐劑、穩定劑、黏合劑和/或黏結劑、壓實劑、潤滑劑和/或助流劑、分散增強劑、崩散劑、調味劑、甜味劑及著色劑。In some embodiments, solid dosage forms comprise excipients. Non-limiting examples of suitable excipients include diluents, buffers, preservatives, stabilizers, binders and/or binders, compacting agents, lubricants and/or glidants, dispersion enhancers, disintegrating agents , flavoring, sweetening and coloring agents.

可以包括在固體劑型中的合適的賦形劑可以是本領域已知的一種或多種藥學上可接受的賦形劑。例如，參見Rowe, Sheskey, 和Quinn編輯, Handbook of Pharmaceutical Excipients[ 藥物賦形劑手冊 ],第六版; 2009; Pharmaceutical Press and American Pharmacists Association [製藥出版社和美國藥劑師協會]。 固體劑型 Suitable excipients that may be included in the solid dosage form may be one or more pharmaceutically acceptable excipients known in the art. See, eg, Rowe, Sheskey, and Quinn, eds., Handbook of Pharmaceutical Excipients , Sixth Edition; 2009; Pharmaceutical Press and American Pharmacists Association. solid dosage form

本文所述之固體劑型可以是，例如片劑或微型片劑。此外，多個微型片劑可以處於（例如，裝入）膠囊中。The solid dosage forms described herein may be, for example, tablets or minitablets. Additionally, multiple mini-tablets may be in (eg, filled in) a capsule.

在一些實施方式中，固體劑型包含片劑（＞ 4 mm）（例如5 mm-17 mm）。例如，片劑係5 mm、5.5 mm、6 mm、6.5 mm、7 mm、7.5 mm、8 mm、8.5 mm、9 mm、9.5 mm、10 mm、11 mm、12 mm、13 mm、14 mm、15 mm、16 mm、17 mm或18 mm片劑。在一些實施方式中，片劑係13 mm、14 mm、15 mm、16 mm、17 mm或18 mm片劑。在一些實施方式中，片劑係17 mm片劑。如本領域中已知的，大小係指片劑的直徑。如本文所用，片劑的大小係指在應用腸溶衣之前的片劑的大小。In some embodiments, the solid dosage form comprises a tablet (>4 mm) (eg, 5 mm-17 mm). For example, tablets are 5 mm, 5.5 mm, 6 mm, 6.5 mm, 7 mm, 7.5 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm or 18 mm tablets. In some embodiments, the tablet is a 13 mm, 14 mm, 15 mm, 16 mm, 17 mm or 18 mm tablet. In some embodiments, the tablet is a 17 mm tablet. Size refers to the diameter of the tablet as known in the art. As used herein, tablet size refers to the size of the tablet before application of the enteric coating.

在一些實施方式中，固體劑型包含微型片劑。該微型片劑的大小範圍為1 mm-4 mm。例如，微型片劑可以是1 mm微型片劑、1.5 mm微型片劑、2 mm微型片劑、3 mm微型片劑或4 mm微型片劑。如本領域中已知的，大小係指微型片劑的直徑。如本文所用，微型片劑的大小係指在應用腸溶衣之前的微型片劑的大小。In some embodiments, the solid dosage form comprises minitablets. The minitablets range in size from 1 mm to 4 mm. For example, the minitablet can be a 1 mm minitablet, 1.5 mm minitablet, 2 mm minitablet, 3 mm minitablet or 4 mm minitablet. Size refers to the diameter of the minitablet as known in the art. As used herein, the size of the minitablet refers to the size of the minitablet before application of the enteric coating.

微型片劑可以是在膠囊中。該膠囊可以是00號、0號、1號、2號、3號、4號或5號膠囊。含有微型片劑的膠囊可以包含HPMC（羥丙基甲基纖維素）或明膠。微型片劑可以放在膠囊內：膠囊內的微型片劑的數量將取決於膠囊的大小和微型片劑的大小。例如，0號膠囊可容納31-35（平均33）個微型片劑，該等微型片劑係3 mm微型片劑。在一些實施方式中，膠囊在裝入後封口。在一些實施方式中，將膠囊用基於HPMC的封口溶液封口。 包衣 Mini-tablets may be in capsules. The capsule can be a No. 00, No. 0, No. 1, No. 2, No. 3, No. 4 or No. 5 capsule. Capsules containing minitablets may contain HPMC (hydroxypropylmethylcellulose) or gelatin. Microtablets can be placed inside a capsule: the number of microtablets inside a capsule will depend on the size of the capsule and the size of the microtablets. For example, a size 0 capsule holds 31-35 (average 33) microtablets, which are 3 mm microtablets. In some embodiments, the capsules are sealed after filling. In some embodiments, the capsules are capped with an HPMC-based capping solution. coating

本文所述之固體劑型（例如片劑或微型片劑）可以用例如一層腸溶衣或兩層腸溶衣（例如內部腸溶衣和外部腸溶衣）進行腸溶包衣。內層腸溶衣和外層腸溶衣不相同（例如，內層腸溶衣和外層腸溶衣不包含相同量的相同組分）。腸溶衣允許藥劑在例如小腸中（例如小腸上段，例如十二指腸和/或空腸）釋放。The solid dosage forms described herein (eg, tablets or minitablets) can be enteric-coated, eg, with one enteric coating or with two enteric coatings (eg, an inner enteric coat and an outer enteric coat). The inner and outer enteric coatings are not identical (eg, the inner and outer enteric coatings do not contain the same components in the same amount). The enteric coating allows release of the agent, for example in the small intestine (eg upper small intestine, eg duodenum and/or jejunum).

藥劑在小腸中（例如小腸上段，例如十二指腸或空腸中）的釋放允許藥劑靶向並影響位於該等特定的位置處的細胞（例如上皮細胞和/或免疫細胞），例如，這可以在小腸中引起局部作用和/或引起系統性作用（例如，胃腸道外的作用）。Release of the agent in the small intestine (e.g., the upper portion of the small intestine, such as the duodenum or jejunum) allows the agent to target and affect cells (e.g., epithelial and/or immune cells) located at those specific locations, for example, this can be in the small intestine Cause local effects and/or cause systemic effects (eg, parenteral effects).

EUDRAGIT係各種各樣聚甲基丙烯酸酯基共聚物的品牌名稱。它包括基於甲基丙烯酸和甲基丙烯酸/丙烯酸酯或其衍生物的陰離子、陽離子和中性共聚物。EUDRAGIT is the brand name for various polymethacrylate based copolymers. It includes anionic, cationic and neutral copolymers based on methacrylic acid and methacrylic acid/acrylates or their derivatives.

可用於腸溶衣（例如，一層腸溶衣或內層腸溶衣和/或外層腸溶衣）的其他材料的實例包括鄰苯二甲酸乙酸纖維素（CAP）、偏苯三酸乙酸纖維素（CAT）、聚(鄰苯二甲酸乙酸乙烯酯)（PVAP）、羥丙基甲基纖維素鄰苯二甲酸酯（HPMCP）、脂肪酸、蠟、蟲膠（紫膠桐酸的酯）、塑膠、植物纖維、玉米醇溶蛋白、AQUA-ZEIN®（不含醇的水性玉米醇溶蛋白配製物）、直鏈澱粉、澱粉衍生物、糊精、丙烯酸甲酯-甲基丙烯酸共聚物、乙酸琥珀酸纖維素、乙酸琥珀酸羥丙基甲基纖維素（乙酸琥珀酸羥丙甲纖維素）、甲基丙烯酸甲酯-甲基丙烯酸共聚物、和/或海藻酸鈉。Examples of other materials that can be used for enteric coatings (e.g., one layer or inner enteric coat and/or outer enteric coat) include cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), poly(vinyl acetate phthalate) (PVAP), hydroxypropyl methylcellulose phthalate (HPMCP), fatty acids, waxes, shellac (esters of laccarpus acid), Plastics, vegetable fibers, zein, AQUA-ZEIN® (alcohol-free aqueous zein formulation), amylose, starch derivatives, dextrin, methyl acrylate-methacrylic acid copolymer, acetic acid Cellulose succinate, hydroxypropylmethylcellulose acetate succinate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymer, and/or sodium alginate.

腸溶衣（例如，一層腸溶衣或內層腸溶衣和/或外層腸溶衣）可以包括甲基丙烯酸丙烯酸乙酯（MAE）共聚物（1:1）。The enteric coating (eg, one enteric coat or an inner enteric coat and/or an outer enteric coat) may include ethyl methacrylate (MAE) copolymer (1:1).

一層腸溶衣可以包括甲基丙烯酸丙烯酸乙酯（MAE）共聚物（1:1）（如Kollicoat MAE 100P）。An enteric coating may include ethyl methacrylate (MAE) copolymer (1:1) (eg Kollicoat MAE 100P).

一層腸溶衣可以包括Eudragit共聚物，例如，Eudragit L（例如，Eudragit L 100-55；Eudragit L 30 D-55）、Eudragit S、Eudragit RL、Eudragit RS、Eudragit E、或Eudragit FS（例如，Eudragit FS 30 D）。An enteric coating may comprise a Eudragit copolymer, e.g., Eudragit L (e.g., Eudragit L 100-55; Eudragit L 30 D-55), Eudragit S, Eudragit RL, Eudragit RS, Eudragit E, or Eudragit FS (e.g., Eudragit FS 30 D).

可以在腸溶衣（例如，一層腸溶衣或內層腸溶衣和/或外層腸溶衣）中使用的材料的其他實例包括在如下中描述的那些，例如U.S. 6312728；U.S. 6623759；U.S. 4775536；U.S. 5047258；U.S. 5292522；U.S. 6555124；U.S. 6638534；U.S. 2006/0210631；U.S. 2008/200482；U.S. 2005/0271778；U.S. 2004/0028737；WO 2005/044240。Other examples of materials that may be used in the enteric coating (e.g., one enteric coat or an inner enteric coat and/or an outer enteric coat) include those described in, for example, U.S. 6,312,728; U.S. 6,623,759; U.S. 4,775,536 U.S. 5047258; U.S. 5292522; U.S. 6555124; U.S. 6638534; U.S. 2006/0210631;

還參見，例如，U.S. 9233074，其提供了可與本文提供的固體劑型一起使用的pH依賴性腸溶聚合物，包括甲基丙烯酸共聚物、鄰苯二甲酸聚乙酸乙烯酯、乙酸琥珀酸羥丙基甲基纖維素、羥丙基甲基纖維素鄰苯二甲酸酯和鄰苯二甲酸乙酸纖維素；合適的甲基丙烯酸共聚物包括：聚(甲基丙烯酸，甲基丙烯酸甲酯)1:1固體，例如以尤特奇L100商品名出售；聚(甲基丙烯酸，丙烯酸乙酯)1:1固體，例如以尤特奇L100-55商品名出售；部分中和的聚(甲基丙烯酸，丙烯酸乙酯)1:1固體，例如以Kollicoat MAE-100P商品名出售；以及聚(甲基丙烯酸，甲基丙烯酸甲酯)1:2固體，例如以尤特奇S100商品名出售。See also, e.g., U.S. 9,233,074, which provides pH-dependent enteric polymers useful with the solid dosage forms provided herein, including methacrylic acid copolymers, polyvinyl acetate phthalate, hydroxypropyl acetate succinate, methylcellulose, hydroxypropylmethylcellulose phthalate, and cellulose acetate phthalate; suitable methacrylic acid copolymers include: poly(methacrylic acid, methyl methacrylate)1 :1 solids such as those sold under the Eudragit L100 tradename; poly(methacrylic acid, ethyl acrylate) 1:1 solids such as those sold under the Eudragit L100-55 tradename; partially neutralized poly(methacrylic acid , ethyl acrylate) 1:1 solid, such as sold under the trade name Kollicoat MAE-100P; and poly(methacrylic acid, methyl methacrylate) 1:2 solid, such as sold under the trade name Eudragit S100.

在某些方面，本文描述的固體劑型（例如片劑或微型片劑）還包含底衣。在一些實施方式中，固體劑型例如除了腸溶衣之外還包含底層包衣，例如，底層包衣在腸溶衣下面（例如，在固體劑型和腸溶衣之間）。在一些實施方式中，底層包衣包含歐巴代（Opadry）QX，例如歐巴代QX藍（Opadry QX Blue）。粉衣層可以例如用於視覺上掩蓋治療劑的外觀。 劑量 In certain aspects, the solid dosage forms (eg, tablets or minitablets) described herein further comprise a subcoat. In some embodiments, the solid dosage form comprises a subcoat, eg, in addition to the enteric coating, eg, the subcoat underlies the enteric coating (eg, between the solid dosage form and the enteric coating). In some embodiments, the base coat comprises Opadry QX, such as Opadry QX Blue. A sub-coat may, for example, be used to visually mask the appearance of the therapeutic agent. dose

藥劑的劑量（例如，對於人受試者）係按每膠囊或片劑計或按膠囊中使用的微型片劑的總數計的劑量。A dose of medicament (eg, for a human subject) is the dose per capsule or tablet or the total number of minitablets used in a capsule.

在藉由總細胞計數（TCC）確定劑量的實施方式中，可以藉由Coulter計數器確定的總細胞計數。In embodiments where the dose is determined by total cell count (TCC), the total cell count can be determined by a Coulter counter.

在一些實施方式中，藥劑包含細菌並且細菌的劑量為約1 x 10 7至約2 x 10 12（例如，約3 x 10 10或約1.5 x 10 11或約1.5 x 10 12）細胞（例如，其中藉由Coulter計數器確定的總細胞計數來確定細胞數），其中劑量係按每膠囊或片劑計或按膠囊中的微型片劑的總數計。在一些實施方式中，藥劑包含細菌並且細菌的劑量為約1 x 10 10至約2 x 10 12（例如，約1.6 x 10 11或約8 x 10 11或約9.6 x 10 11約12.8 x 10 11或約1.6 x 10 12）細胞（例如，其中藉由Coulter計數器確定的總細胞計數來確定細胞數），其中劑量係按每膠囊或片劑計或按膠囊中的微型片劑的總數計。 In some embodiments, the agent comprises bacteria and the dose of bacteria is about 1 x 10 7 to about 2 x 10 12 (eg, about 3 x 10 10 or about 1.5 x 10 11 or about 1.5 x 10 12 ) cells (eg, wherein the cell number is determined by total cell count determined by a Coulter counter), wherein the dosage is per capsule or tablet or the total number of minitablets in a capsule. In some embodiments, the medicament comprises bacteria and the dose of bacteria is about 1 x 10 10 to about 2 x 10 12 (eg, about 1.6 x 10 11 or about 8 x 10 11 or about 9.6 x 10 11 about 12.8 x 10 11 or about 1.6 x 10 12 ) cells (eg, where cell number is determined by total cell count determined by a Coulter counter), where the dose is per capsule or tablet or the total number of minitablets in a capsule.

在一些實施方式中，藥劑包含細菌並且細菌的劑量為約1 x 10 9、約3 x 10 9、約5 x 10 9、約1.5 x 10 10、約3 x 10 10、約5 x 10 10、約1.5 x 10 11、約1.5 x 10 12或約2 x 10 12細胞，其中劑量係按每膠囊或片劑計或按膠囊中的微型片劑的總數計。 In some embodiments, the agent comprises bacteria and the dose of bacteria is about 1 x 10 9 , about 3 x 10 9 , about 5 x 10 9 , about 1.5 x 10 10 , about 3 x 10 10 , about 5 x 10 10 , About 1.5 x 1011 , about 1.5 x 1012 , or about 2 x 1012 cells, where the dosage is per capsule or tablet or the total number of minitablets in a capsule.

在一些實施方式中，藥劑包含mEV並且mEV的劑量為約1 x 10 5至約7 x 10 13個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中該劑量按每膠囊或片劑計或按膠囊中微型片劑的總數計。在一些實施方式中，藥劑包含mEV並且mEV的劑量為約1 x 10 10至約7 x 10 13個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中該劑量按每膠囊或片劑計或按膠囊中微型片劑的總數計。 In some embodiments, the medicament comprises mEV and the dose of mEV is about 1 x 10 5 to about 7 x 10 13 particles (eg, where the particle count is determined by NTA (Nanoparticle Tracking Analysis)), wherein the dose is expressed as Per capsule or tablet or total number of minitablets in a capsule. In some embodiments, the medicament comprises mEV and the dose of mEV is about 1 x 1010 to about 7 x 1013 particles (eg, where the particle count is determined by NTA (Nanoparticle Tracking Analysis)), wherein the dose is expressed as Per capsule or tablet or total number of minitablets in a capsule.

在其中藥劑包含mEV的一些實施方式中，mEV的劑量為約2 x 10 6至約2 x 10 16個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中劑量按每膠囊或片劑計或按膠囊中的微型片劑的總數計。 In some embodiments where the agent comprises mEV, the dose of mEV is about 2 x 106 to about 2 x 1016 particles (e.g., where the particle count is determined by NTA (Nanoparticle Tracking Analysis)), wherein the dose is Per capsule or tablet or total number of mini-tablets in a capsule.

在一些方面，本揭露提供了治療受試者（例如人）（例如需要治療的受試者）之方法，該方法包括向受試者施用本文提供的固體劑型。In some aspects, the present disclosure provides methods of treating a subject (eg, a human), eg, a subject in need of treatment, comprising administering to the subject a solid dosage form provided herein.

在一些方面，本揭露提供了本文提供的固體劑型在製備用於治療受試者（例如人）（例如需要治療的受試者）的藥物中的用途。In some aspects, the disclosure provides use of a solid dosage form provided herein in the manufacture of a medicament for treating a subject (eg, a human), eg, a subject in need of treatment.

在一些實施方式中，固體劑型經口服施用（例如用於口服施用）。In some embodiments, the solid dosage form is administered orally (eg, for oral administration).

在一些實施方式中，固體劑型被施用（例如，用於施用）每天1、2、3或4次。在一些實施方式中，1、2、3、4或5個固體劑型（例如，片劑）被施用（例如，用於施用）每天1、2、3或4次。在一些實施方式中，2、4、6、8或10個固體劑型（例如，片劑）被施用（例如，用於施用）每天1、2、3或4次。在一些實施方式中，1個固體劑型（例如，片劑）被施用（例如，用於施用）每天1或2次。在一些實施方式中，2個固體劑型（例如，片劑）被施用（例如，用於施用）每天1或2次。在一些實施方式中，3個固體劑型（例如，片劑）被施用（例如，用於施用）每天1或2次。在一些實施方式中，4個固體劑型（例如，片劑）被施用（例如，用於施用）每天1或2次。在一些實施方式中，5個固體劑型（例如，片劑）被施用（例如，用於施用）每天1或2次。In some embodiments, the solid dosage form is administered (eg, for administration) 1, 2, 3, or 4 times per day. In some embodiments, 1, 2, 3, 4, or 5 solid dosage forms (eg, tablets) are administered (eg, for administration) 1, 2, 3, or 4 times per day. In some embodiments, 2, 4, 6, 8, or 10 solid dosage forms (eg, tablets) are administered (eg, for administration) 1, 2, 3, or 4 times per day. In some embodiments, 1 solid dosage form (eg, tablet) is administered (eg, for administration) 1 or 2 times per day. In some embodiments, 2 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day. In some embodiments, 3 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day. In some embodiments, 4 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day. In some embodiments, 5 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day.

在一些實施方式中，1個固體劑型（例如，片劑）被施用（例如，用於施用）每天1或2次，其中該固體劑型包含約3.2 × 10 11個細胞的細菌劑量。在一些實施方式中，2個固體劑型（例如，片劑）被施用（例如，用於施用）每天1或2次，其中該固體劑型包含約3.2 × 10 11個細胞的細菌劑量。在一些實施方式中，3個固體劑型（例如，片劑）被施用（例如，用於施用）每天1或2次，其中該固體劑型包含約3.2 × 10 11個細胞的細菌劑量。在一些實施方式中，4個固體劑型（例如，片劑）被施用（例如，用於施用）每天1或2次，其中該固體劑型包含約3.2 × 10 11個細胞的細菌劑量。在一些實施方式中，5個固體劑型（例如，片劑）被施用（例如，用於施用）每天1或2次，其中該固體劑型包含約3.2 × 10 11個細胞的細菌劑量。 In some embodiments, 1 solid dosage form (eg, tablet) is administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage form comprises a bacterial dose of about 3.2 x 1011 cells. In some embodiments, 2 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 1011 cells. In some embodiments, 3 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 1011 cells. In some embodiments, 4 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 1011 cells. In some embodiments, 5 solid dosage forms (eg, tablets) are administered (eg, for administration) 1 or 2 times per day, wherein the solid dosage forms comprise a bacterial dose of about 3.2 x 1011 cells.

在一些實施方式中，1個固體劑型（例如，片劑）被每天施用（例如，用於施用），其中該固體劑型包含約3.2 × 10 11個細胞的細菌劑量（例如，導致總共約3.2 x 10 11個細胞被施用）。在一些實施方式中，2個固體劑型（例如，片劑）被每天施用（例如，用於施用），其中該固體劑型包含約3.2 × 10 11個細胞的細菌劑量（例如，導致在2個片劑情況下總共約6.4 x 10 11個細胞被施用）。在一些實施方式中，3個固體劑型（例如，片劑）被每天施用（例如，用於施用），其中該固體劑型包含約3.2 × 10 11個細胞的細菌劑量（例如，導致在3個片劑情況下總共約9.6 x 10 11個細胞被施用）。在一些實施方式中，4個固體劑型（例如，片劑）被每天施用（例如，用於施用），其中該固體劑型包含約3.2 × 10 11個細胞的細菌劑量（例如，導致在4個片劑情況下總共約12.8 x 10 11個細胞被施用）。在一些實施方式中，5個固體劑型（例如，片劑）被每天施用（例如，用於施用），其中該固體劑型包含約3.2 × 10 11個細胞的細菌劑量（例如，導致在5個片劑情況下總共約16 x 10 11個細胞被施用）。 In some embodiments, 1 solid dosage form (eg, tablet) is administered (eg, for administration) per day, wherein the solid dosage form comprises a bacterial dose of about 3.2 x 10 cells (eg, resulting in a total of about 3.2 x 10 of 11 cells were administered). In some embodiments, 2 solid dosage forms (e.g., tablets) are administered (e.g., for administration) per day, wherein the solid dosage forms contain a bacterial dose of about 3.2 x 1011 cells (e.g., resulting in A total of approximately 6.4 x 10 11 cells were administered for each dose). In some embodiments, 3 solid dosage forms (eg, tablets) are administered (eg, for administration) per day, wherein the solid dosage form comprises a bacterial dose of about 3.2 x 1011 cells (eg, resulting in A total of approximately 9.6 x 1011 cells were administered with each dose). In some embodiments, 4 solid dosage forms (e.g., tablets) are administered (e.g., for administration) per day, wherein the solid dosage form comprises a bacterial dose of about 3.2 x 1011 cells (e.g., resulting in A total of about 12.8 x 1011 cells were administered for each dose). In some embodiments, 5 solid dosage forms (e.g., tablets) are administered (e.g., for administration) per day, wherein the solid dosage form comprises a bacterial dose of about 3.2 x 1011 cells (e.g., resulting in A total of about 16 x 1011 cells were administered in each dose).

在一些實施方式中，藥劑劑量可以是按藥劑（例如，包含細菌和/或細菌來源的試劑（如mEV）的粉末）的重量確定的毫克（mg）劑量。藥劑的劑量按每膠囊或片劑計或按例如膠囊中的微型片劑的總數計。In some embodiments, the dosage of the agent can be a milligram (mg) dose determined by weight of the agent (eg, a powder comprising bacteria and/or an agent of bacterial origin (eg, mEV)). The dosage of the medicament is per capsule or tablet or as the total number of mini-tablets in eg a capsule.

例如，為了施用約400 mg的1x劑量的藥劑，每膠囊存在約200 mg的藥劑並且施用兩個膠囊，則產生約400 mg的劑量。這兩個膠囊可以例如每天1次或2次施用。For example, to administer a 1x dose of about 400 mg of medicament, about 200 mg of medicament is present per capsule and two capsules are administered, resulting in a dose of about 400 mg. The two capsules can be administered, for example, once or twice a day.

例如，對於微型片劑：每微型片劑可以包含約0.1至約3.5 mg（0.1、0.35、1.0、3.5 mg）的藥劑。微型片劑可以放在膠囊內：膠囊內的微型片劑的數量將取決於膠囊的大小和微型片劑的大小。例如，平均33（範圍為31-35）個3 mm微型片劑裝於0號膠囊內。例如，每微型片劑0.1- 3.5 mg的藥劑，劑量範圍將為每膠囊3.3 mg-115.5 mg（針對0號膠囊中33個微型片劑）（針對0號膠囊中31個微型片劑，為3.1 mg-108.5 mg）（針對0號膠囊中35個微型片劑，為3.5 mg- 122.5 mg）。可以施用多個膠囊和/或一個或多個更大的膠囊以增加施用的劑量和/或可以每天施用一次或多次以增加施用的劑量。For example, for minitablets: each minitablet may contain from about 0.1 to about 3.5 mg (0.1, 0.35, 1.0, 3.5 mg) of the agent. Microtablets can be placed inside a capsule: the number of microtablets inside a capsule will depend on the size of the capsule and the size of the microtablets. For example, an average of 33 (range 31-35) 3 mm minitablets were contained in size 0 capsules. For example, for a dose of 0.1-3.5 mg per microtablet, the dose range would be 3.3 mg-115.5 mg per capsule (for 33 microtablets in size 0 capsule) (for 31 microtablets in size 0 capsule, 3.1 mg-108.5 mg) (3.5 mg-122.5 mg for 35 microtablets in a size 0 capsule). Multiple capsules and/or one or more larger capsules may be administered to increase the dose administered and/or may be administered one or more times per day to increase the dose administered.

在一些實施方式中，劑量可以為按每膠囊或片劑計或按例如膠囊中的微型片劑的總數計的約3 mg至約125 mg的藥劑。In some embodiments, the dosage may be from about 3 mg to about 125 mg of the medicament per capsule or tablet or the total number of mini-tablets, eg, in a capsule.

在一些實施方式中，劑量可以為約35 mg至約1200 mg（例如，約35 mg、約125 mg、約350 mg或約1200 mg）的藥劑。In some embodiments, the dose can be from about 35 mg to about 1200 mg (eg, about 35 mg, about 125 mg, about 350 mg, or about 1200 mg) of the medicament.

在一些實施方式中，藥劑包括粉末，該粉末包含細菌和/或mEV，並且該藥劑（例如，包含細菌和/或mEV的粉末）的劑量為約10 mg至約1500 mg，其中該劑量按每膠囊或片劑計或按膠囊中微型片劑的總數計。In some embodiments, the medicament comprises a powder comprising bacteria and/or mEV, and the dose of the medicament (eg, powder comprising bacteria and/or mEV) is from about 10 mg to about 1500 mg, wherein the dose is Capsules or tablets or the total number of microtablets in a capsule.

在一些實施方式中，藥劑的劑量可以是約30 mg至約3500 mg（約25、約50、約75、約100、約150、約250、約300、約350、約400、約500、約600、約750、約1000、約1250、約1300、約2000、約2500、約3000或約3500 mg）。In some embodiments, the dosage of the medicament may be from about 30 mg to about 3500 mg (about 25, about 50, about 75, about 100, about 150, about 250, about 300, about 350, about 400, about 500, about 600, about 750, about 1000, about 1250, about 1300, about 2000, about 2500, about 3000 or about 3500 mg).

可以基於對模型生物（例如，小鼠）施用的劑量的異速比例（allometric scaling）來適當地計算人劑量。Human doses can be appropriately calculated based on allometric scaling of doses administered to model organisms (eg, mice).

在一些實施方式中，一個或兩個片劑膠囊可以一天施用一次或兩次。In some embodiments, one or two tablet capsules may be administered once or twice a day.

在一些實施方式中，可以每天施用一個或兩個片劑。In some embodiments, one or two tablets may be administered per day.

在一些實施方式中，可以每天一次或兩次施用3、4或5個片劑。In some embodiments, 3, 4 or 5 tablets may be administered once or twice per day.

在一些實施方式中，可以每天施用3、4或5個片劑。In some embodiments, 3, 4, or 5 tablets may be administered per day.

在一些實施方式中，可以每天一次或兩次施用4個片劑。In some embodiments, 4 tablets may be administered once or twice daily.

在一些實施方式中，可以每天施用4個片劑。In some embodiments, 4 tablets may be administered per day.

藥劑包含細菌和/或細菌來源的試劑（如mEV），或包含含有細菌和/或細菌來源的試劑（如mEV）的粉末，並且還可以包含一種或多種另外的組分，如冷凍保護劑等。Medicaments containing bacteria and/or agents of bacterial origin (such as mEV), or powders containing bacteria and/or agents of bacterial origin (such as mEV), and may also contain one or more additional components, such as cryoprotectants, etc. .

在一些實施方式中，藥劑的mg（按重量計）劑量為按每膠囊或每片劑計或按例如膠囊中使用的微型片劑的總數計的例如約1 mg至約500 mg。 使用方法 In some embodiments, the dose in mg (by weight) of the agent is, for example, from about 1 mg to about 500 mg per capsule or per tablet, or the total number of minitablets used, for example, in a capsule. Instructions

例如，本文描述的固體劑型允許口服施用其中包含的藥劑。For example, the solid dosage forms described herein allow oral administration of the agents contained therein.

本文描述的固體劑型可用於治療和/或預防癌症、炎症、自體免疫、代謝病症或生態失調。The solid dosage forms described herein are useful for treating and/or preventing cancer, inflammation, autoimmunity, metabolic disorders or dysbiosis.

本文描述的固體劑型可用於治療和/或預防細菌性敗血症性休克、細胞介素風暴和/或病毒感染（例如冠狀病毒感染、流感感染和/或呼吸道合胞病毒感染）。The solid dosage forms described herein are useful for the treatment and/or prevention of bacterial septic shock, cytokine storm, and/or viral infection (eg, coronavirus infection, influenza infection, and/or respiratory syncytial virus infection).

本文描述的固體劑型可用於降低炎性細胞介素表現（例如降低IL-8、IL-6、IL-1β和/或TNFα表現水平）。The solid dosage forms described herein can be used to reduce the expression of inflammatory cytokines (eg, reduce the expression level of IL-8, IL-6, IL-1β and/or TNFα).

本文描述了使用包含藥劑（例如其治療有效量）的固體劑型（例如用於口服施用）（例如用於製藥用途）之方法，其中該藥劑包含細菌和/或微生物胞外囊泡（mEV），並且其中該固體劑型還包含揭露的賦形劑。Described herein are methods of using a solid dosage form (e.g. for oral administration) (e.g. for pharmaceutical use) comprising a medicament (e.g. a therapeutically effective amount thereof), wherein the medicament comprises bacteria and/or microbial extracellular vesicles (mEVs), And wherein the solid dosage form further comprises the disclosed excipients.

例如，本文描述之方法和施用的固體劑型允許口服施用其中包含的藥劑。固體劑型可施用給處於進食或禁食狀態的受試者。固體劑型可以例如空腹（例如，進食前一小時或進食後兩小時）施用。固體劑型可在進食前一小時施用。固體劑型可在進食後兩小時施用。For example, the methods and solid dosage forms of administration described herein allow oral administration of the agents contained therein. Solid dosage forms can be administered to a subject in a fed or fasted state. Solid dosage forms can be administered, for example, on an empty stomach (eg, one hour before or two hours after a meal). Solid dosage forms can be administered one hour before eating. Solid dosage forms can be administered two hours after eating.

本文提供了用於治療和/或預防癌症、炎症、自體免疫、代謝病症或生態失調的固體劑型。Provided herein are solid dosage forms for use in the treatment and/or prevention of cancer, inflammation, autoimmunity, metabolic disorders or dysbiosis.

本文提供了用於治療和/或預防細菌性敗血症性休克、細胞介素風暴和/或病毒感染（例如冠狀病毒感染、流感感染和/或呼吸道合胞病毒感染）的固體劑型。Provided herein are solid dosage forms for the treatment and/or prevention of bacterial septic shock, cytokine storm, and/or viral infection (eg, coronavirus infection, influenza infection, and/or respiratory syncytial virus infection).

本文提供了用於降低炎性細胞介素表現（例如降低IL-8、IL-6、IL-1β和/或TNFα表現水平）的固體劑型。Provided herein are solid dosage forms for reducing the expression of inflammatory cytokines (eg, reducing the expression levels of IL-8, IL-6, IL-1β, and/or TNFα).

本文提供了固體劑型在製備用於治療和/或預防癌症、炎症、自體免疫、代謝病症或生態失調的藥物中的用途。Provided herein is the use of a solid dosage form for the manufacture of a medicament for the treatment and/or prevention of cancer, inflammation, autoimmunity, metabolic disorders or dysbiosis.

本文提供了固體劑型用於製備用於治療和/或預防細菌性感染性休克、細胞介素風暴和/或病毒感染（例如冠狀病毒感染、流感感染和/或呼吸道合胞病毒感染）的藥物的用途。Provided herein is a solid dosage form for the preparation of a medicament for the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection (such as coronavirus infection, influenza infection and/or respiratory syncytial virus infection) use.

本文提供了固體劑型用於製備用於治療和/或預防細菌性感染性休克、細胞介素風暴和/或病毒感染（例如冠狀病毒感染、流感感染和/或呼吸道合胞病毒感染）的藥物的用途。 製備固體劑型之方法 Provided herein is a solid dosage form for the preparation of a medicament for the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection (such as coronavirus infection, influenza infection and/or respiratory syncytial virus infection) use. Method for preparing solid dosage form

在某些方面，本文提供了製備藥物組成物的固體劑型之方法，該方法包括將藥劑（例如，本文公開的細菌和/或細菌來源的試劑，例如本文公開的mEV）和一種或多種（例如一種、兩種或三種）賦形劑組合成藥物組成物。在某些實施方式中，藥劑總質量係藥物組成物總質量的至少5%、10%、15%、20%、25%、30%、35%、40%、45%、50%、55%、60%、65%或70%。在一些實施方式中，藥劑總質量不超過藥物組成物總質量的70%、65%、60%、55%、50%、45%、40%、35%、30%或25%。在一些實施方式中，一種或多種賦形劑的總質量為藥物組成物總質量的至少5%、至少10%、至少20%、至少30%、至少35%、至少40%、至少45%或至少50%。在一些實施方式中，一種或多種賦形劑的總質量不超過藥物組成物總質量的90%、85%、80%、75%、70%、65%、60%或55%。In certain aspects, provided herein is a method of preparing a solid dosage form of a pharmaceutical composition, the method comprising combining an agent (e.g., a bacterium disclosed herein and/or a bacterial-derived agent, such as an mEV disclosed herein) and one or more (e.g., One, two or three) excipients are combined into a pharmaceutical composition. In certain embodiments, the total mass of the medicament is at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55% of the total mass of the pharmaceutical composition , 60%, 65% or 70%. In some embodiments, the total mass of the medicament does not exceed 70%, 65%, 60%, 55%, 50%, 45%, 40%, 35%, 30% or 25% of the total mass of the pharmaceutical composition. In some embodiments, the total mass of one or more excipients is at least 5%, at least 10%, at least 20%, at least 30%, at least 35%, at least 40%, at least 45%, or At least 50%. In some embodiments, the total mass of one or more excipients does not exceed 90%, 85%, 80%, 75%, 70%, 65%, 60% or 55% of the total mass of the pharmaceutical composition.

在一些實施方式中，一種或多種賦形劑包含矽化微晶纖維素。在一些實施方式中，一種或多種賦形劑包括交聚維酮（PVPP）。在某些實施方式中，本文提供的固體劑型包含矽化微晶纖維素。在一些實施方式中，矽化微晶纖維素為HD90級。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的至少15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%。在某些實施方式中，矽化微晶纖維素總質量不超過藥物組成物總質量的15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%。在某些實施方式中，矽化微晶纖維素總質量為藥物組成物總質量的約15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%或42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%。在某些實施方式中，本文提供的固體劑型包含交聚維酮。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聚維酮總質量不超過藥物組成物總質量的5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。在某些實施方式中，交聚維酮總質量係藥物組成物總質量的約5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%或25%。In some embodiments, the one or more excipients comprise silicified microcrystalline cellulose. In some embodiments, the one or more excipients include crospovidone (PVPP). In certain embodiments, the solid dosage forms provided herein comprise silicified microcrystalline cellulose. In some embodiments, the silicified microcrystalline cellulose is grade HD90. In certain embodiments, the total mass of silicified microcrystalline cellulose is at least 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% of the total mass of the pharmaceutical composition. %, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57% , 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72%, 73%, 74%, 75% %, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%. In some embodiments, the total mass of silicified microcrystalline cellulose does not exceed 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% of the total mass of the pharmaceutical composition %, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57% , 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72%, 73%, 74%, 75% %, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%. In some embodiments, the total mass of silicified microcrystalline cellulose is about 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% of the total mass of the pharmaceutical composition %, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41% or 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57% , 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72%, 73%, 74%, 75% %, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%. In certain embodiments, the solid dosage forms provided herein comprise crospovidone. In certain embodiments, the total mass of crospovidone is at least 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crospovidone does not exceed 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%. In some embodiments, the total mass of crospovidone is about 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14% of the total mass of the pharmaceutical composition , 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24% or 25%.

在某些實施方式中，本文提供的固體劑型包含：(i) 藥劑，藥劑總質量為藥物組成物總質量的至少5%且不超過70%，(ii) 矽化微晶纖維素，矽化微晶纖維素總質量為藥物組成物總質量的至少為15%（例如 ，至少15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、25%、26%、27%、28%、29%、30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%、43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%）且不超過90%（例如不超過30%、31%、32%、33%、34%、35%、36%、37%、38%、39%、40%、41%、42%,43%、44%、45%、46%、47%、48%、49%、50%、51%、52%、53%、54%、55%、56%、57%、58%、59%、60%、61%、62%、63%、64%、65%、66%、67%、68%、70%、71%、72%、73%、74%、75%、76%、77%、78%、79%、80%、81%、82%、83%、84%、85%、86%、87%、88%、89%或90%）。在某些實施方式中，固體劑型進一步包含交聚維酮，其具有的交聚維酮總質量係藥物組成物總質量的至少5%（例如，至少5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、或25%）且不超過藥物組成物總質量的25%（例如，不超過5%、6%、7%、8%、9%、10%、11%、12%、13%、14%、15%、16%、17%、18%、19%、20%、21%、22%、23%、24%、或25%）。在某些實施方式中，矽化微晶纖維素總質量加上交聚維酮總質量為藥物組成物總質量的至少60%、70%、80%或90%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約50%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約76.4%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約72.5%，交聚維酮總質量為藥物組成物總質量的約15%。在一些實施方式中，固體劑型包含：矽化微晶纖維素總質量為藥物組成物總質量的約20%，交聚維酮總質量為藥物組成物總質量的約15%。 In some embodiments, the solid dosage form provided herein comprises: (i) medicament, the total mass of the medicament is at least 5% and no more than 70% of the total mass of the pharmaceutical composition, (ii) silicified microcrystalline cellulose, silicified microcrystalline The total mass of cellulose is at least 15% (e.g. , at least 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25% of the total mass of the pharmaceutical composition) %, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58% , 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72%, 73%, 74%, 75%, 76 %, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%) and not more than 90% ( For example, no more than 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45% , 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62 %, 63%, 64%, 65%, 66%, 67%, 68%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89% or 90%). In certain embodiments, the solid dosage form further comprises crospovidone having a total mass of crospovidone of at least 5% (e.g., at least 5%, 6%, 7%, 8% of the total mass of the pharmaceutical composition) , 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%) and not more than 25% of the total mass of the pharmaceutical composition (for example, not more than 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15% %, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, or 25%). In some embodiments, the total mass of silicified microcrystalline cellulose plus the total mass of crospovidone is at least 60%, 70%, 80% or 90% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 50% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is approximately 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 76.4% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is about 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 72.5% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is approximately 15% of the total mass of the pharmaceutical composition. In some embodiments, the solid dosage form comprises: the total mass of silicified microcrystalline cellulose is about 20% of the total mass of the pharmaceutical composition, and the total mass of crospovidone is approximately 15% of the total mass of the pharmaceutical composition.

在一些實施方式中，固體劑型包含一定量（例如，劑量）的活性成分（例如，細菌和細菌來源的試劑（例如，組分）（例如，微生物胞外囊泡或mEV））。在一些實施方式中，可以根據在藥劑的給定製劑（例如批次）中包含的活性成分的量來調節摻入固體劑型中的藥劑（包含活性成分）的量。在一些實施方式中，然後相應地調節稀釋劑（例如甘露醇）的量。在一些實施方式中，當藥劑的量增加時，稀釋劑的量減少；並且反之亦然。在一些實施方式中，可以對藥劑和稀釋劑的量進行調整，但一種或多種賦形劑（例如，一種、兩種或三種賦形劑）的量保持不變，例如，對於給定的固體劑型配方的批次之間。在一些實施方式中，硬脂酸鎂和膠體二氧化矽的量也可以保持恒定，例如，對於給定的固體劑型配方的批次之間。In some embodiments, solid dosage forms comprise an amount (eg, dose) of an active ingredient (eg, bacteria and bacterially derived agents (eg, components) (eg, microbial extracellular vesicles or mEVs)). In some embodiments, the amount of medicament (comprising an active ingredient) incorporated into a solid dosage form can be adjusted according to the amount of active ingredient contained in a given formulation (eg, batch) of medicament. In some embodiments, the amount of diluent (eg, mannitol) is then adjusted accordingly. In some embodiments, when the amount of agent is increased, the amount of diluent is decreased; and vice versa. In some embodiments, the amount of agent and diluent can be adjusted, but the amount of one or more excipients (e.g., one, two, or three excipients) remains constant, e.g., for a given solid Between batches of dosage formulations. In some embodiments, the amounts of magnesium stearate and colloidal silicon dioxide can also be kept constant, eg, between batches for a given solid dosage form formulation.

在某些實施方式中，該方法進一步包括壓製藥物組成物，從而形成片劑或微型片劑。在一些實施方式中，該方法進一步包括對片劑或微型片劑進行腸溶包衣，從而製備經腸溶包衣的片劑。在某些實施方式中，該方法進一步包括將微型片劑裝載到膠囊中。In certain embodiments, the method further comprises compressing the pharmaceutical composition, thereby forming a tablet or minitablet. In some embodiments, the method further comprises enteric coating the tablet or mini-tablet, thereby preparing an enteric coated tablet. In certain embodiments, the method further comprises loading the mini-tablets into a capsule.

在某些實施方式中，該方法包括在將藥劑（例如，細菌（例如，本文揭露的細菌）和/或細菌來源的試劑，例如mEV（例如，本文揭露的mEV））（例如，藥劑可以是粉末，該粉末包含細菌和/或細菌來源的試劑，例如mEV）和一種或多種（例如，一種、兩種或三種）賦形劑組合成藥物組成物之前對藥劑進行濕法製粒。在一些實施方式中，濕法製粒包括將藥劑與製粒流體（例如，水、乙醇或異丙醇，單獨或組合）混合以製備混合組成物。在一些實施方式中，製粒流體包含水。在一些實施方式中，製粒流體由水組成。在一些實施方式中，濕法製粒還包括乾燥混合的組成物（例如，在流化床乾燥器上乾燥）以製備乾燥的組成物。在一些實施方式中，濕法製粒還包括研磨乾燥的組成物以製備經研磨的組成物。經研磨的組成物可以視需要與一種或多種（例如，一種、兩種或三種）賦形劑組合以製備藥物組成物。在一些實施方式中，藥劑的濕法製粒產生包含藥劑的顆粒（例如包含細菌和/或細菌來源的試劑（例如mEV）的粉末的藥物物質顆粒）。在一些實施方式中，顆粒進一步包含一種或多種賦形劑（例如，一種、兩種或三種）。在一些實施方式中，顆粒視需要與一種或多種（例如，一種、兩種或三種）賦形劑組合以製備藥物組成物（例如片劑、膠囊或固體劑型）。In certain embodiments, the method comprises adding an agent (e.g., a bacterium (e.g., a bacterium disclosed herein) and/or an agent of bacterial origin, such as an mEV (e.g., a mEV disclosed herein)) (e.g., the agent can be Powders comprising bacteria and/or agents of bacterial origin, such as mEV) and one or more (eg, one, two or three) excipients are wet granulated prior to combination into a pharmaceutical composition. In some embodiments, wet granulation involves mixing the agent with a granulation fluid (eg, water, ethanol, or isopropanol, alone or in combination) to prepare a mixed composition. In some embodiments, the granulation fluid comprises water. In some embodiments, the granulation fluid consists of water. In some embodiments, wet granulation further includes drying the blended composition (eg, drying on a fluid bed dryer) to produce a dried composition. In some embodiments, wet granulation further includes milling the dried composition to produce a milled composition. The milled composition can be optionally combined with one or more (eg, one, two or three) excipients to prepare a pharmaceutical composition. In some embodiments, wet granulation of the medicament produces granules comprising the medicament (eg, drug substance granules comprising a powder of bacteria and/or agents of bacterial origin (eg, mEV)). In some embodiments, the particles further comprise one or more excipients (eg, one, two, or three). In some embodiments, the granules are optionally combined with one or more (eg, one, two or three) excipients to prepare a pharmaceutical composition (eg, tablet, capsule or solid dosage form).

在本文提供的一些實施方式中，顆粒包含60%-100%的藥劑（例如粉末，包含細菌和/或細菌來源的試劑，例如mEV）。在一些實施方式中，顆粒包含約60%、65%、70%、75%、80%、85%、90%、95%或100%的藥劑。在其他實施方式中，顆粒占藥物組成物總質量的35%-85%。在本文提供的一些實施方式中，顆粒占藥物組成物總質量的約40%、50%、55%、60%、70%、75%、80%或85%。 顆粒和濕法製粒 In some embodiments provided herein, the particles comprise 60%-100% agent (eg, powder comprising bacteria and/or agents of bacterial origin, eg, mEV). In some embodiments, the particles comprise about 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100% of the agent. In other embodiments, the particles account for 35%-85% of the total mass of the pharmaceutical composition. In some embodiments provided herein, the particles account for about 40%, 50%, 55%, 60%, 70%, 75%, 80% or 85% of the total mass of the pharmaceutical composition. Granules and wet granulation

在一些方面，本文提供包含藥劑的顆粒，例如，其中藥劑包含細菌（例如，本文揭露的細菌）和/或細菌來源的試劑，例如mEV（例如，本文揭露的mEV）（例如，藥劑可以是。該粉末包含細菌和/或細菌來源的試劑，例如mEV）。顆粒包含藥劑的團聚（例如，比藥劑顆粒大（例如，比粉末的顆粒大）的顆粒）。顆粒的直徑比藥劑（例如，粉末，例如粉末顆粒）的直徑（例如，平均直徑）大於（例如，約1.5倍至超過4倍）。顆粒可以藉由濕法製粒產生。In some aspects, provided herein are particles comprising an agent, e.g., wherein the agent comprises a bacterium (e.g., a bacterium disclosed herein) and/or an agent of bacterial origin, such as an mEV (e.g., an mEV disclosed herein) (e.g., the agent can be. The powder contains bacteria and/or reagents of bacterial origin, such as mEV). Particles comprise agglomerates of medicament (eg, particles that are larger than particles of a medicament (eg, larger than particles of a powder)). The diameter of the particles is larger (eg, about 1.5 times to more than 4 times) than the diameter (eg, average diameter) of the medicament (eg, powder, eg, powder particles). Granules can be produced by wet granulation.

例如，對於棲組織普雷沃菌菌株B smEV，濕法製粒後的顆粒直徑比DS粉末的直徑大約1.5倍至4倍以上： 棲組織普雷沃菌smEV D 10（µm） D 50（µm） D 90（µm） HS DS顆粒 8.22 110 386 HS DS粉末 5.61 25.4 95.3 For example, for the Prevotella histotropes strain B smEV, the particle diameter after wet granulation was approximately 1.5 to more than 4 times that of the DS powder: Prevotella smEV D 10 (µm) D50 (µm) D90 (µm) HS DS particles 8.22 110 386 HS DS powder 5.61 25.4 95.3

製粒係藉由團聚使顆粒增大的過程。製粒可以將細粉末轉化為易於壓縮的自由流動、無塵顆粒。在製粒過程中，小的細顆粒或粗顆粒被轉化為較大的團聚物，稱為顆粒體。參見例如Shanmugam, Bioimpacts[生物影響] 5:55-63 (2015)。濕法製粒涉及藉由將液體黏合劑（例如製粒流體）添加到粉末（例如，其包含藥劑，例如包含細菌（例如，本文揭露的細菌）和/或細菌來源的試劑，例如mEV（例如，本文揭露的mEV））來產生顆粒。Granulation is the process of enlarging particles by agglomeration. Granulation converts fine powders into free-flowing, dust-free granules that are easily compressed. During granulation, small fine or coarse particles are converted into larger agglomerates called granules. See, eg, Shanmugam, Bioimpacts 5:55-63 (2015). Wet granulation involves adding a liquid binder (e.g., a granulation fluid) to a powder (e.g., comprising a pharmaceutical agent, e.g., comprising bacteria (e.g., the bacteria disclosed herein) and/or an agent of bacterial origin, such as mEV (e.g., mEVs disclosed herein)) to generate particles.

製粒，例如濕法製粒，可以允許將更高劑量的細菌（例如，本文揭露的細菌）和/或細菌來源的試劑，例如mEV（例如，本文揭露的mEV）配製成固體劑型（例如、片劑、迷你片劑或膠囊）。例如，藉由對包含mEV的粉末進行濕法製粒，0號膠囊中的mEV劑量增加了3倍。Granulation, such as wet granulation, can allow higher doses of bacteria (e.g., the bacteria disclosed herein) and/or bacteria-derived agents, such as mEVs (e.g., the mEVs disclosed herein), to be formulated into solid dosage forms (e.g., tablets, mini-tablets or capsules). For example, the mEV dose in size 0 capsules was increased 3-fold by wet granulation of mEV-containing powder.

在某些方面，本文提供了對藥劑例如進行濕法製粒之方法，例如，其中藥劑包含細菌（例如，本文揭露的細菌）和/或細菌來源的試劑，例如mEV（例如，本文揭露的mEV）（例如，藥劑可以是。該粉末包含細菌和/或細菌來源的試劑，例如mEV）。In certain aspects, provided herein are methods of, e.g., wet granulating a medicament, e.g., wherein the medicament comprises a bacterium (e.g., a bacterium disclosed herein) and/or an agent of bacterial origin, e.g., an mEV (e.g., a mEV disclosed herein) (For example, the medicament can be. The powder contains bacteria and/or agents of bacterial origin, such as mEV).

在一些實施方式中，濕法製粒包括將藥劑與製粒流體（例如，水、乙醇或異丙醇，單獨或組合）混合以製備混合組成物。在一些實施方式中，製粒流體包含水。在一些實施方式中，製粒流體由水組成。在一些實施方式中，濕法製粒包括乾燥混合的組成物（例如，在流化床乾燥器上乾燥）以製備乾燥的組成物。在一些實施方式中，濕法製粒包括研磨乾燥的組成物以製備經研磨的組成物。然後經研磨的組成物可以視需要與一種或多種（例如，一種、兩種或三種）賦形劑組合以製備藥物組成物。濕法製粒方法可以生產顆粒。In some embodiments, wet granulation involves mixing the agent with a granulation fluid (eg, water, ethanol, or isopropanol, alone or in combination) to prepare a mixed composition. In some embodiments, the granulation fluid comprises water. In some embodiments, the granulation fluid consists of water. In some embodiments, wet granulation includes drying the blended composition (eg, drying on a fluid bed dryer) to produce a dried composition. In some embodiments, wet granulation includes milling a dried composition to produce a milled composition. The milled composition can then be combined with one or more (eg, one, two or three) excipients as desired to prepare a pharmaceutical composition. The wet granulation method can produce granules.

在一些實施方式中，濕法製粒包括 (i) 將藥劑與製粒流體（例如，水、乙醇或異丙醇，單獨或組合）混合以製備混合組成物和 (ii) 乾燥混合的組成物（例如，在流化床乾燥器上乾燥）以製備乾燥的組成物。In some embodiments, wet granulation involves (i) mixing the agent with a granulation fluid (e.g., water, ethanol, or isopropanol, alone or in combination) to prepare a blend composition and (ii) dry blending the composition ( For example, drying on a fluid bed drier) to prepare a dry composition.

在一些實施方式中，濕法製粒包括 (i) 將藥劑與製粒流體（例如，水、乙醇或異丙醇，單獨或組合）混合以製備混合組成物；(ii) 乾燥混合的組成物（例如，在流化床乾燥器上乾燥）以製備乾燥的組成物；以及 (iii) 研磨乾燥的組成物以製備經研磨的組成物。In some embodiments, wet granulation involves (i) mixing the agent with a granulation fluid (e.g., water, ethanol, or isopropanol, alone or in combination) to prepare a blended composition; (ii) drying the blended composition ( For example, drying on a fluid bed drier) to produce a dried composition; and (iii) grinding the dried composition to produce a milled composition.

在一些實施方式中，濕法製粒包括 (i) 將藥劑與製粒流體（例如，水、乙醇或異丙醇，單獨或組合）混合以製備混合組成物；(ii) 乾燥混合的組成物（例如，在流化床乾燥器上乾燥）以製備乾燥的組成物；(iii) 研磨乾燥的組成物以製備經研磨的組成物；以及 (iv) 將研磨的組成物與一種或多種（例如，一種、兩種或三種）賦形劑組合成藥物組成物。In some embodiments, wet granulation involves (i) mixing the agent with a granulation fluid (e.g., water, ethanol, or isopropanol, alone or in combination) to prepare a blended composition; (ii) drying the blended composition ( For example, drying on a fluid bed drier) to prepare a dried composition; (iii) grinding the dried composition to prepare a milled composition; and (iv) combining the milled composition with one or more (e.g., One, two or three) excipients are combined into a pharmaceutical composition.

在一些實施方式中，本文提供的是藉由濕法製粒生產的顆粒。In some embodiments, provided herein are granules produced by wet granulation.

在一些方面，本文提供的是混合組成物，例如，其包含藥劑和製粒流體（例如水、乙醇或異丙醇，單獨或組合）。In some aspects, provided herein are mixed compositions, eg, comprising a medicament and a granulation fluid (eg, water, ethanol, or isopropanol, alone or in combination).

在某些方面，本文提供乾燥的組成物，例如，其包含已乾燥的混合組成物。In certain aspects, provided herein are dried compositions, eg, comprising dried mixed compositions.

在某些方面，本文提供研磨的組成物，例如，其包含已研磨的乾燥組成物。 固體劑型的另外方面 In certain aspects, provided herein are milled compositions, eg, comprising milled dry compositions. Additional Aspects of Solid Dosage Forms

例如，如本文描述的包含藥劑（例如，其治療有效量）的固體劑型（其中藥劑包含細菌和/或微生物胞外囊泡（mEV），並且其中固體劑型還包含所描述的賦形劑）可以向受試者例如人提供治療有效量的藥劑。For example, a solid dosage form as described herein comprising an agent (e.g., a therapeutically effective amount thereof) (wherein the agent comprises bacterial and/or microbial extracellular vesicles (mEVs) and wherein the solid dosage form further comprises the described excipients) may A therapeutically effective amount of the agent is provided to a subject, eg, a human.

例如，如本文描述的包含藥劑（例如，其治療有效量）的固體劑型（其中藥劑包含細菌和/或微生物胞外囊泡（mEV），並且其中固體劑型還包含所描述的賦形劑）可以向受試者例如人提供非天然量的治療有效組分（例如，存在於藥劑中）。For example, a solid dosage form as described herein comprising an agent (e.g., a therapeutically effective amount thereof) (wherein the agent comprises bacterial and/or microbial extracellular vesicles (mEVs) and wherein the solid dosage form further comprises the described excipients) may A non-natural amount of a therapeutically effective component (eg, present in a medicament) is provided to a subject, eg, a human.

例如，如本文描述的包含藥劑（例如，其治療有效量）的固體劑型（其中藥劑包含細菌和/或微生物胞外囊泡（mEV），並且其中固體劑型還包含所描述的賦形劑）可以向受試者例如人提供非天然數量的治療有效組分（例如，存在於藥劑中）。For example, a solid dosage form as described herein comprising an agent (e.g., a therapeutically effective amount thereof) (wherein the agent comprises bacterial and/or microbial extracellular vesicles (mEVs) and wherein the solid dosage form further comprises the described excipients) may A therapeutically effective component is provided to a subject, such as a human, in an unnatural amount (eg, present in a medicament).

例如，如本文描述的包含藥劑（例如，其治療有效量）的固體劑型（其中藥劑包含細菌和/或微生物胞外囊泡（mEV），並且其中固體劑型還包含所描述的賦形劑）可以給受試者例如人帶來一個或多個變化，例如治療或預防疾病或健康失調。For example, a solid dosage form as described herein comprising an agent (e.g., a therapeutically effective amount thereof) (wherein the agent comprises bacterial and/or microbial extracellular vesicles (mEVs) and wherein the solid dosage form further comprises the described excipients) may To bring about one or more changes in a subject, eg, a human, eg, to treat or prevent a disease or health disorder.

例如，如本文描述的包含藥劑（例如，其治療有效量）的固體劑型（其中藥劑包含細菌和/或微生物胞外囊泡（mEV），並且其中固體劑型還包含所描述的賦形劑）具有潛在的重大效用，例如影響受試者（例如人），例如治療或預防疾病或健康失調。For example, a solid dosage form comprising a medicament (e.g., a therapeutically effective amount thereof) as described herein (where the medicament comprises bacteria and/or microbial extracellular vesicles (mEVs), and wherein the solid dosage form further comprises the described excipients) has Potentially significant utility, such as affecting a subject (eg, a human), such as treating or preventing a disease or health disorder.

如本文所述，固體劑型例如的崩散測試以每分鐘30次扣籃的速率進行，例如使用DT50無浴崩散儀（SOTAX集團（SOTAX Group））。 另外的治療劑 Disintegration testing of solid dosage forms, eg, as described herein, is performed at a rate of 30 dunks per minute, eg, using the DT50 Bathless Disintegration Apparatus (SOTAX Group). additional therapeutic agent

在某些方面，本文提供之方法包括向受試者單獨地或與另外的治療劑組合地施用本文描述的固體劑型。在一些實施方式中，另外的治療劑係免疫抑制劑、抗炎劑、類固醇和/或癌症治療劑。In certain aspects, the methods provided herein comprise administering to a subject a solid dosage form described herein, alone or in combination with an additional therapeutic agent. In some embodiments, the additional therapeutic agent is an immunosuppressant, an anti-inflammatory agent, a steroid, and/or a cancer therapeutic.

在一些實施方式中，在施用另外的治療劑之前（例如之前至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小時或之前至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天）向受試者施用固體劑型。在一些實施方式中，在施用另外的治療劑之後（例如之後至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小時或之後至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天）向受試者施用固體劑型。在一些實施方式中，同時或接近同時（例如，彼此在一小時內施用）向受試者施用固體劑型及另外的治療劑。In some embodiments, prior to (eg, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days) to administer the solid dosage form to the subject. In some embodiments, after (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17 , 18, 19, 20, 21, 22, 23, or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days) to administer the solid dosage form to the subject. In some embodiments, the solid dosage form and the additional therapeutic agent are administered to the subject at or near the same time (eg, administered within one hour of each other).

在一些實施方式中，在向受試者施用固體劑型之前（例如之前至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小時或之前至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天）向受試者施用抗生素。在一些實施方式中，在向受試者施用固體劑型之後（例如之前至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23或24小時或之後至少1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22、23、24、25、26、27、28、29或30天）向受試者施用抗生素。在一些實施方式中，向受試者同時或接近同時施用（例如，彼此在一小時內施用）固體劑型及抗生素。In some embodiments, prior to (eg, at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days) to administer antibiotics to the subject. In some embodiments, after (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 , 17, 18, 19, 20, 21, 22, 23, or 24 hours or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 days) to administer antibiotics to the subject. In some embodiments, the solid dosage form and the antibiotic are administered to the subject at or near the same time (eg, within one hour of each other).

在一些實施方式中，另外的治療劑係癌症治療劑。在一些實施方式中，癌症治療劑係化學治療劑。該等化學治療劑的實例包含（但不限於）烷基化劑，例如噻替哌（thiotepa）及環磷醯胺（cyclosphosphamide）；磺酸烷基酯，例如白消安（busulfan）、英丙舒凡（improsulfan）及哌泊舒凡（piposulfan）；氮丙啶，例如苯并多巴（benzodopa）、卡波醌（carboquone）、米得哌（meturedopa）及烏得哌（uredopa）；乙撐亞胺及甲基密胺，包含六甲密胺（altretamine）、三乙撐密胺（triethylenemelamine）、三乙撐磷醯胺、三乙撐硫化磷醯胺及三羥甲基密胺（trimethylolomelamine）；番荔枝內酯（acetogenin）（尤其布拉他辛（bullatacin）及布拉他辛酮（bullatacinone））；喜樹鹼（camptothecin）（包含合成類似物托泊替康（topotecan））；苔蘚蟲素（bryostatin）；卡利抑制素（callystatin）；CC-1065（包含其合成類似物阿多來新（adozelesin）、卡折來新（carzelesin）及比折來新（bizelesin））；念珠藻素（cryptophycin）（尤其念珠藻素1及念珠藻素8）；朵拉司他汀（dolastatin）；多卡米星（duocarmycin）（包含合成類似物KW-2189及CB1-TM1）；艾榴塞洛素（eleutherobin）；水鬼蕉鹼（pancratistatin）；匍枝珊瑚醇（sarcodictyin）；海綿抑制素（spongistatin）；氮芥（nitrogen mustard），例如苯丁酸氮芥（chlorambucil）、萘氮芥（chlornaphazine）、氯磷醯胺（cholophosphamide）、雌氮芥（estramustine）、異環磷醯胺（ifosfamide）、氮芥（mechlorethamine）、鹽酸甲氧氮芥、美法侖（melphalan）、新氮芥（novembichin）、苯乙酸氮芥膽甾醇酯（phenesterine）、潑尼莫司汀（prednimustine）、曲磷胺（trofosfmaide）、尿嘧啶氮芥；亞硝基脲，例如卡莫司汀（carmustine）、氯脲菌素（chlorozotocin）、福莫司汀（fotemustine）、洛莫司汀（lomustine）、尼莫司汀（nimustine）及雷莫司汀（ranimnustine）；抗生素，例如烯二炔抗生素（例如卡奇黴素（calicheamicin），尤其卡奇黴素γlI及卡奇黴素Ωl1；達內黴素（dynemicin），包含達內黴素A；雙膦酸鹽類，例如氯膦酸鹽（clodronate）；埃斯培拉黴素（esperamicin）；以及新製癌菌素發色團（neocarzinostatin chromophore）及相關色蛋白烯二炔抗生素發色團）、阿克拉黴素（aclacinomysin）、放線菌素（actinomycin）、安麯黴素（authramycin）、氮雜絲胺酸、博來黴素（bleomycin）、放線菌素C（cactinomycin）、卡拉黴素（carabicin）、洋紅黴素（caminomycin）、嗜癌素（carzinophilin）、色黴素（chromomycin）、放線菌素D（dactinomycin）、柔紅黴素（daunorubicin）、地托比星（detorubicin）、6-重氮基-5-側氧基-L-正白胺酸、多柔比星（doxorubicin）（包含𠰌啉基-多柔比星、氰𠰌啉基-多柔比星、2-吡咯啉基-多柔比星及去氧多柔比星）、表柔比星（epirubicin）、依索比星（esorubicin）、伊達比星（idarubicin）、麻西羅黴素（marcellomycin）、絲裂黴素（mitomycin）（例如絲裂黴素C）、黴酚酸（mycophenolic acid）、諾拉黴素（nogalamycin）、橄欖黴素（olivomycin）、培洛黴素（peplomycin）、泊非黴素（potfiromycin）、嘌呤黴素（puromycin）、三鐵阿黴素（quelamycin）、羅多比星（rodorubicin）、鏈黑菌素（streptonigrin）、鏈脲菌素（streptozocin）、殺結核菌素（tubercidin）、烏苯美司（ubenimex）、淨司他丁（zinostatin）、佐柔比星（zorubicin）；抗代謝物，例如胺甲喋呤和5-氟尿嘧啶（5-FU）；葉酸類似物，例如二甲葉酸（denopterin）、胺甲喋呤、蝶羅呤（pteropterin）、曲美沙特（trimetrexate）；嘌呤類似物，例如氟達拉濱（fludarabine）、6-巰基嘌呤、硫咪嘌呤（thiamiprine）、硫鳥嘌呤；嘧啶類似物，例如安西他濱（ancitabine）、阿紮胞苷（azacitidine）、6-阿紮尿苷（6-azauridine）、卡莫氟（carmofur）、阿糖胞苷（cytarabine）、二去氧尿苷、去氧氟尿苷（doxifluridine）、依諾他濱（enocitabine）、氟尿苷（floxuridine）；雄激素，例如卡普睪酮（calusterone）、丙酸屈他雄酮（dromostanolone propionate）、環硫雄醇（epitiostanol）、美雄烷（mepitiostane）、睪內酯酮（testolactone）；抗腎上腺素，例如胺魯米特（aminoglutethimide）、米托坦（mitotane）、曲洛司坦（trilostane）；葉酸補充劑，例如亞葉酸；乙醯葡醛酸內酯（aceglatone）；醛磷醯胺糖苷（aldophosphamide glycoside）；胺基乙醯丙酸（aminolevulinic acid）；恩尿嘧啶（eniluracil）；安吖啶（amsacrine）；百思布希（bestrabucil）；比生群（bisantrene）；依達曲沙（edatraxate）；地磷醯胺（defofamine）；秋水仙胺（demecolcine）；地吖醌（diaziquone）；依氟鳥胺酸（eflornithine）；依利乙銨（elliptinium acetate）；埃博黴素（epothilone）；依託格魯（etoglucid）；硝酸鎵；羥基脲；蘑菇多糖（lentinan）；氯尼達明（lonidainine）；類美坦辛（maytansinoid），例如美坦辛（maytansine）及柄型菌素（ansamitocin）；米托胍腙（mitoguazone）；米托蒽醌（mitoxantrone）；莫哌達醇（mopidanmol）；尼群克林（nitraerine）；噴托他汀（pentostatin）；蛋胺氮芥（phenamet）；吡柔比星（pirarubicin）；洛索蒽醌（losoxantrone）；鬼臼酸（podophyllinic acid）；2-乙基醯肼；丙卡巴肼（procarbazine）；PSK多糖複合物）；雷佐生（razoxane）；根黴素（rhizoxin）；西佐喃（sizofuran）；鍺螺胺（spirogermanium）；細交鏈孢菌酮酸（tenuazonic acid）；三亞胺醌（triaziquone）；2,2',2''-三氯三乙胺；單端孢黴烯（trichothecene）（尤其T-2毒素、疣皰菌素（verrucarin）A、桿孢菌素（roridin）A及蛇形菌素（anguidine））；烏拉坦（urethan）；長春地辛（vindesine）；達卡巴𠯤（dacarbazine）；甘露莫司汀（mannomustine）；二溴甘露醇（mitobronitol）；二溴衛矛醇（mitolactol）；哌泊溴烷（pipobroman）；噶薩托辛（gacytosine）；阿拉伯糖苷（arabinoside）（「Ara-C」）；環磷醯胺；噻替派；紫杉烷（taxoid），例如，太平洋紫杉醇（paclitaxel）及多西紫杉醇（doxetaxel）；苯丁酸氮芥；吉西他濱（gemcitabine）；6-硫鳥嘌呤；巰基嘌呤；胺甲喋呤；鉑配位錯合物，例如順鉑（cisplatin）、奧沙利鉑（oxaliplatin）及卡鉑（carboplatin）；長春花鹼（vinblastine）；鉑；依託泊苷（etoposide）（VP-16）；異環磷醯胺；米托蒽醌（mitoxantrone）；長春新鹼（vincristine）；長春瑞濱（vinorelbine）；諾安托（novantrone）；替尼泊苷（teniposide）；依達曲沙；道諾黴素（daunomycin）；胺蝶呤（aminopterin）；希羅達（xeloda）；伊班膦酸鹽（ibandronate）；伊立替康（irinotecan）（例如，CPT-11）；拓撲異構酶抑制劑RFS 2000；二氟甲基鳥胺酸（DMFO）；類視黃醇，例如視黃酸；卡培他濱（capecitabine）；以及上述任何一種的藥學上可接受的鹽、酸或衍生物。In some embodiments, the additional therapeutic agent is a cancer therapeutic. In some embodiments, the cancer therapeutic agent is a chemotherapeutic agent. Examples of such chemotherapeutic agents include, but are not limited to, alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, Improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylene Imines and methylmelamines, including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenephosphoramide sulfide, and trimethylolomelamine; acetogenin (especially bullatacin and bullatacinone); camptothecin (including the synthetic analog topotecan); bryostatin (bryostatin); callystatin; CC-1065 (including its synthetic analogs adozelesin, carzelesin, and bizelesin); nodocin ( cryptophycin) (especially nodocin 1 and nodocin 8); dolastatin (dolastatin); duocarmycin (including synthetic analogues KW-2189 and CB1-TM1); eleutherobin; pancratistatin; sarcodictyn; spongistatin; nitrogen mustards such as chlorambucil, chlornaphazine, Cholophosphamide, etramustine, ifosfamide, mechlorethamine, methoxymustine, melphalan, novembichin, Cholesteryl phenylacetate mustard (phenesterine), prednimustine, trofosfamide (trofosfmaide), uracil mustard; nitrosoureas such as carmustine, chlorurecin (chlorozotocin), fotemustine, lomustine, nimustine (nimustine) and ramustine (ranimnustine); antibiotics, such as enediyne antibiotics (such as calicheamicin (calicheamicin), especially calicheamicin γlI and calicheamicin Ωl1; dynemicin (dynemicin), Contains danemycin A; bisphosphonates such as clodronate; esperamicin; and neocarzinostatin chromophore and related chromoprenes Diacetylene antibiotic chromophore), aclacinomysin, actinomycin, athramycin, azaserine, bleomycin, cactinomycin ), carabicin, caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin (detorubicin), 6-diazo-5-oxo-L-norleucine, doxorubicin (including ? , 2-pyrrolinyl-doxorubicin and deoxydoxorubicin), epirubicin, esorubicin, idarubicin, marcellomycin ), mitomycin (such as mitomycin C), mycophenolic acid (mycophenolic acid), nogalamycin (nogalamycin), olivomycin (olivomycin), peplomycin (peplomycin), pomol Potfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin, tuberculosis tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate and 5-fluorouracil (5-FU); folic acid similar Drugs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiomethopurine (thiamipri ne), thioguanine; pyrimidine analogs such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine (cytarabine), dideoxyuridine, doxifluridine, enocitabine, floxuridine; androgens such as calusterone, drotasterone propionate Dromostanolone propionate, epitiostanol, mepitiostane, testolactone; anti-epinephrines such as aminoglutethimide, mitotane, trirolactone Trilostane; folic acid supplements such as folinic acid; aceglatone; aldophosphamide glycoside; aminolevulinic acid; eniluracil ( eniluracil; amsacrine; bestrabucil; bisantrene; edatraxate; defofamine; demecolcine; deacridine Diaziquone; eflornithine; elliptinium acetate; epothilone; etoglucid; gallium nitrate; hydroxyurea; lentinan; chloride lonidainine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopedadol (mopidanmol); nitraerine; pentostatin; phenamet; pirarubicin; losoxantrone; podophyllinic acid ; 2-ethylhydrazine; procarbazine; PSK polysaccharide complex); razoxane; rhizoxin; sizofuran; germanspiramine (spirog ermanium); tenuazonic acid; triaziquone; 2,2',2''-trichlorotriethylamine; trichothecene (especially T-2 toxin, verrucarin A, roridin A, and anguidine); urethan; vindesine; dacarbazine; manna Mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C ”); cyclophosphamide; thiotepa; taxoids such as paclitaxel and doxetaxel; chlorambucil; gemcitabine; 6-thioguanine ; mercaptopurine; methotrexate; platinum coordination complexes such as cisplatin, oxaliplatin, and carboplatin; vinblastine; platinum; etoposide ( etoposide) (VP-16); ifosfamide; mitoxantrone; vincristine; vinorelbine; novantrone; teniposide ; edatrexate; daunomycin; aminopterin; xeloda; ibandronate; irinotecan (eg, CPT-11) ; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid; capecitabine; and pharmaceutically acceptable salts of any of the foregoing , acids or derivatives.

在一些實施方式中，癌症治療劑係癌症免疫療法藥劑。免疫療法係指使用受試者的免疫系統來治療癌症的治療，例如，檢查點抑制劑、癌症疫苗、細胞介素、細胞療法、CAR-T細胞及樹突細胞療法。檢查點抑制劑免疫療法的非限制性實例包含尼沃魯單抗（Nivolumab）（BMS，抗PD-1）、派姆單抗（Pembrolizumab）（Merck，抗PD-1）、伊匹單抗（Ipilimumab）（BMS，抗CTLA-4）、MEDI4736（阿斯利康公司（AstraZeneca），抗PD-L1）及MPDL3280A（羅氏公司（Roche），抗PD-L1）。其他免疫療法可為腫瘤疫苗，例如Gardail、Cervarix、BCG、西普賽爾-T（sipulencel-T）、Gp100:209-217、AGS-003、DCVax-L、阿爾土賽爾-L（Algenpantucel-L）、特爾土賽爾-L（Tergenpantucel-L）、TG4010、ProstAtak、Prostvac-V/R-TRICOM、林多莫爾（Rindopepimul）、E75乙酸肽、IMA901、POL-103A、貝拉土賽爾-L（Belagenpumatucel-L）、GSK1572932A、MDX-1279、GV1001及替西泰德（Tecemotide）。免疫療法藥劑可經由注射（例如經靜脈內、經腫瘤內、經皮下或注射至淋巴結中）來施用，但還可經口、經局部或經由氣溶膠來施用。免疫療法可包括佐劑（例如細胞介素）。In some embodiments, the cancer therapeutic agent is a cancer immunotherapy agent. Immunotherapy refers to treatments that use a subject's immune system to treat cancer, for example, checkpoint inhibitors, cancer vaccines, cytokines, cell therapy, CAR-T cell and dendritic cell therapy. Non-limiting examples of checkpoint inhibitor immunotherapy include Nivolumab (BMS, anti-PD-1 ), Pembrolizumab (Merck, anti-PD-1 ), ipilimumab ( Ipilimumab) (BMS, anti-CTLA-4), MEDI4736 (AstraZeneca, anti-PD-L1) and MPDL3280A (Roche, anti-PD-L1). Other immunotherapies can be tumor vaccines, such as Gardail, Cervarix, BCG, Sipulencel-T (sipulencel-T), Gp100:209-217, AGS-003, DCVax-L, Algenpantucel-L (Algenpantucel- L), Tergenpantucel-L (Tergenpantucel-L), TG4010, ProstAtak, Prostvac-V/R-TRICOM, Rindopepimul, E75 Acetate Peptide, IMA901, POL-103A, Beiratusai Belagenpumatucel-L, GSK1572932A, MDX-1279, GV1001 and Tecemotide. Immunotherapy agents can be administered via injection (eg, intravenously, intratumorally, subcutaneously, or into lymph nodes), but can also be administered orally, topically, or via aerosol. Immunotherapy can include adjuvants such as cytokines.

在一些實施方式中，免疫療法藥劑係免疫檢查點抑制劑。免疫檢查點抑制在廣義上係指抑制癌細胞可產生的檢查點以預防或下調免疫應答。免疫檢查點蛋白的實例包括但不限於CTLA4、PD-1、PD-L1、PD-L2、A2AR、B7-H3、B7-H4、BTLA、KIR、LAG3、TIM-3或VISTA。免疫檢查點抑制劑可為結合至並抑制免疫檢查點蛋白的抗體或其抗原結合片段。免疫檢查點抑制劑的實例包括但不限於尼沃魯單抗、派姆單抗、匹利珠單抗（pidilizumab）、AMP-224、AMP-514、STI-A1110、TSR-042、RG-7446、BMS-936559、MEDI-4736、MSB-0020718C、AUR-012及STI-A1010。In some embodiments, the immunotherapy agent is an immune checkpoint inhibitor. Immune checkpoint inhibition broadly refers to the inhibition of checkpoints that cancer cells can produce to prevent or downregulate the immune response. Examples of immune checkpoint proteins include, but are not limited to, CTLA4, PD-1, PD-L1, PD-L2, A2AR, B7-H3, B7-H4, BTLA, KIR, LAG3, TIM-3, or VISTA. An immune checkpoint inhibitor can be an antibody or antigen-binding fragment thereof that binds to and inhibits an immune checkpoint protein. Examples of immune checkpoint inhibitors include, but are not limited to, nivolumab, pembrolizumab, pidilizumab, AMP-224, AMP-514, STI-A1110, TSR-042, RG-7446 , BMS-936559, MEDI-4736, MSB-0020718C, AUR-012 and STI-A1010.

在一些實施方式中，本文提供之方法包括施用本文描述的藥物組成物與一種或多種另外的治療劑的組合。在一些實施方式中，本文揭露之方法包括施用兩種免疫療法藥劑（例如，免疫檢查點抑制劑）。例如，本文提供之方法包括將本文所述之藥物組成物與PD-1抑制劑（例如派姆單抗或尼沃魯單抗或匹利珠單抗）或CLTA-4抑制劑（例如伊匹單抗）或PD-L1抑制劑組合施用。In some embodiments, the methods provided herein comprise administering a pharmaceutical composition described herein in combination with one or more additional therapeutic agents. In some embodiments, the methods disclosed herein include administering two immunotherapy agents (eg, immune checkpoint inhibitors). For example, the methods provided herein include combining a pharmaceutical composition described herein with a PD-1 inhibitor (such as pembrolizumab or nivolumab or pilizumab) or a CLTA-4 inhibitor (such as ipilimumab monoclonal antibody) or a combination of PD-L1 inhibitors.

在一些實施方式中，免疫療法藥劑係（例如）結合至癌症相關抗原的抗體或其抗原結合片段。癌症相關抗原的實例包括但不限於親脂素（adipophilin）、AIM-2、ALDH1A1、α-輔肌動蛋白-4、α-胎蛋白（「AFP」）、ARTC1、B-RAF、BAGE-1、BCLX（L）、BCR-ABL融合蛋白b3a2、β-鏈蛋白、BING-4、CA-125、CALCA、癌胚抗原（「CEA」）、CASP-5、CASP-8、CD274、CD45、Cdc27、CDK12、CDK4、CDKN2A、CEA、CLPP、COA-1、CPSF、CSNK1A1、CTAG1、CTAG2、週期蛋白D1、週期蛋白-A1、dek-can融合蛋白、DKK1、EFTUD2、延長因子2、ENAH（hMena）、Ep-CAM、EpCAM、EphA3、上皮腫瘤抗原（「ETA」）、ETV6-AML1融合蛋白、EZH2、FGF5、FLT3-ITD、FN1、G250/MN/CAIX、GAGE-1,2,8、GAGE-3,4,5,6,7、GAS7、磷脂醯肌醇蛋白聚糖-3、GnTV、gp100/Pmel17、GPNMB、HAUS3、海普森（Hepsin）、HER-2/neu、HERV-K-MEL、HLA-A11、HLA-A2、HLA-DOB、hsp70-2、IDO1、IGF2B3、IL13Rα2、腸羧基酯酶、K-ras、激肽釋放素4、KIF20A、KK-LC-1、KKLC1、KM-HN-1、KMHN1（又稱為CCDC110）、LAGE-1、LDLR-岩藻糖基轉移酶AS融合蛋白、萊格西因（Lengsin）、M-CSF、MAGE-A1、MAGE-A10、MAGE-A12、MAGE-A2、MAGE-A3、MAGE-A4、MAGE-A6、MAGE-A9、MAGE-C1、MAGE-C2、蘋果酸酶、乳腺珠蛋白-A、MART2、MATN、MC1R、MCSP、mdm-2、ME1、Melan-A/MART-1、Meloe、中期因子、MMP-2、MMP-7、MUC1、MUC5AC、黏蛋白、MUM-1、MUM-2、MUM-3、肌凝蛋白、I類肌凝蛋白、N-raw、NA88-A、新-PAP、NFYC、NY-BR-1、NY-ESO-1/LAGE-2、OA1、OGT、OS-9、P多肽、p53、PAP、PAX5、PBF、pml-RARα融合蛋白、多態上皮黏蛋白（「PEM」）、PPP1R3B、PRAME、PRDX5、PSA、PSMA、PTPRK、RAB38/NY-MEL-1、RAGE-1、RBAF600、RGS5、RhoC、RNF43、RU2AS、SAGE、分離蛋白1、SIRT2、SNRPD1、SOX10、Sp17、SPA17、SSX-2、SSX-4、STEAP1、存活蛋白、SYT-SSX1或-SSX2融合蛋白、TAG-1、TAG-2、端粒酶、TGF-βRII、TPBG、TRAG-3、磷酸丙糖異構酶、TRP-1/gp75、TRP-2、TRP2-INT2、酪胺酸酶、酪胺酸酶（「TYR」）、VEGF、WT1、XAGE-1b/GAGED2a。在一些實施方式中，抗原係新抗原。In some embodiments, the immunotherapy agent is, for example, an antibody or antigen-binding fragment thereof that binds to a cancer-associated antigen. Examples of cancer-associated antigens include, but are not limited to, adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTC1, B-RAF, BAGE-1 , BCLX(L), BCR-ABL fusion protein b3a2, β-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen (“CEA”), CASP-5, CASP-8, CD274, CD45, Cdc27 , CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin D1, cyclin-A1, dek-can fusion protein, DKK1, EFTUD2, elongation factor 2, ENAH (hMena) , Ep-CAM, EpCAM, EphA3, Epithelial Tumor Antigen (“ETA”), ETV6-AML1 Fusion Protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE- 3,4,5,6,7, GAS7, Glypican-3, GnTV, gp100/Pmel17, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL , HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDO1, IGF2B3, IL13Rα2, intestinal carboxylesterase, K-ras, kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM- HN-1, KMHN1 (also known as CCDC110), LAGE-1, LDLR-fucosyltransferase AS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE-A10, MAGE- A12, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm- 2. ME1, Melan-A/MART-1, Meloe, midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, myosin, class I Myosin, N-raw, NA88-A, Neo-PAP, NFYC, NY-BR-1, NY-ESO-1/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5 , PBF, pml-RARα fusion protein, polymorphic epithelial mucin (“PEM”), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTP RK, RAB38/NY-MEL-1, RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, Isolate 1, SIRT2, SNRPD1, SOX10, Sp17, SPA17, SSX-2, SSX-4, STEAP1, Survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, telomerase, TGF-βRII, TPBG, TRAG-3, triose phosphate isomerase, TRP-1/gp75, TRP-2 , TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1, XAGE-1b/GAGED2a. In some embodiments, the antigen is a neoantigen.

在一些實施方式中，免疫療法藥劑係癌症疫苗和/或癌症疫苗的組分（例如，抗原性肽和/或蛋白質）。癌症疫苗可為蛋白質疫苗、核酸疫苗或其組合。例如，在一些實施方式中，癌症疫苗包括含有癌症相關抗原的表位的多肽。在一些實施方式中，癌症疫苗包括編碼癌症相關抗原的表位的核酸（例如，DNA或RNA（例如mRNA））。癌症相關抗原的實例包括但不限於親脂素（adipophilin）、AIM-2、ALDH1A1、α-輔肌動蛋白-4、α-胎蛋白（「AFP」）、ARTC1、B-RAF、BAGE-1、BCLX（L）、BCR-ABL融合蛋白b3a2、β-鏈蛋白、BING-4、CA-125、CALCA、癌胚抗原（「CEA」）、CASP-5、CASP-8、CD274、CD45、Cdc27、CDK12、CDK4、CDKN2A、CEA、CLPP、COA-1、CPSF、CSNK1A1、CTAG1、CTAG2、週期蛋白D1、週期蛋白-A1、dek-can融合蛋白、DKK1、EFTUD2、延長因子2、ENAH（hMena）、Ep-CAM、EpCAM、EphA3、上皮腫瘤抗原（「ETA」）、ETV6-AML1融合蛋白、EZH2、FGF5、FLT3-ITD、FN1、G250/MN/CAIX、GAGE-1,2,8、GAGE-3,4,5,6,7、GAS7、磷脂醯肌醇蛋白聚糖-3、GnTV、gp100/Pmel17、GPNMB、HAUS3、海普森（Hepsin）、HER-2/neu、HERV-K-MEL、HLA-A11、HLA-A2、HLA-DOB、hsp70-2、IDO1、IGF2B3、IL13Rα2、腸羧基酯酶、K-ras、激肽釋放素4、KIF20A、KK-LC-1、KKLC1、KM-HN-1、KMHN1（又稱為CCDC110）、LAGE-1、LDLR-岩藻糖基轉移酶AS融合蛋白、萊格西因（Lengsin）、M-CSF、MAGE-A1、MAGE-A10、MAGE-A12、MAGE-A2、MAGE-A3、MAGE-A4、MAGE-A6、MAGE-A9、MAGE-C1、MAGE-C2、蘋果酸酶、乳腺珠蛋白-A、MART2、MATN、MC1R、MCSP、mdm-2、ME1、Melan-A/MART-1、Meloe、中期因子、MMP-2、MMP-7、MUC1、MUC5AC、黏蛋白、MUM-1、MUM-2、MUM-3、肌凝蛋白、I類肌凝蛋白、N-raw、NA88-A、新-PAP、NFYC、NY-BR-1、NY-ESO-1/LAGE-2、OA1、OGT、OS-9、P多肽、p53、PAP、PAX5、PBF、pml-RARα融合蛋白、多態上皮黏蛋白（「PEM」）、PPP1R3B、PRAME、PRDX5、PSA、PSMA、PTPRK、RAB38/NY-MEL-1、RAGE-1、RBAF600、RGS5、RhoC、RNF43、RU2AS、SAGE、分離蛋白1、SIRT2、SNRPD1、SOX10、Sp17、SPA17、SSX-2、SSX-4、STEAP1、存活蛋白、SYT-SSX1或-SSX2融合蛋白、TAG-1、TAG-2、端粒酶、TGF-βRII、TPBG、TRAG-3、磷酸丙糖異構酶、TRP-1/gp75、TRP-2、TRP2-INT2、酪胺酸酶、酪胺酸酶（「TYR」）、VEGF、WT1、XAGE-1b/GAGED2a。在一些實施方式中，抗原係新抗原。在一些實施方式中，將癌症疫苗與佐劑一起施用。佐劑的實例包括但不限於免疫調節蛋白、佐劑65、α-GalCer、磷酸鋁、氫氧化鋁、磷酸鈣、β-葡聚糖肽、CpG ODN DNA、GPI-0100、脂質A、脂多糖、利波夫（Lipovant）、蒙塔尼（Montanide）、N-乙醯基-胞壁醯基-L-丙胺醯基-D-異麩醯胺酸、Pam3CSK4、quil A、霍亂毒素（CT）及來自腸毒性大腸桿菌（ Escherichia coli）的不耐熱毒素（LT），包括這類的衍生物（CTB、mmCT、CTA1-DD、LTB、LTK63、LTR72、dmLT）及海藻糖二黴菌酸酯。 In some embodiments, the immunotherapy agent is a cancer vaccine and/or a component of a cancer vaccine (eg, an antigenic peptide and/or protein). Cancer vaccines can be protein vaccines, nucleic acid vaccines, or combinations thereof. For example, in some embodiments, a cancer vaccine includes a polypeptide comprising an epitope of a cancer-associated antigen. In some embodiments, a cancer vaccine includes a nucleic acid (eg, DNA or RNA (eg, mRNA)) encoding an epitope of a cancer-associated antigen. Examples of cancer-associated antigens include, but are not limited to, adipophilin, AIM-2, ALDH1A1, alpha-actinin-4, alpha-fetoprotein ("AFP"), ARTC1, B-RAF, BAGE-1 , BCLX(L), BCR-ABL fusion protein b3a2, β-catenin, BING-4, CA-125, CALCA, carcinoembryonic antigen (“CEA”), CASP-5, CASP-8, CD274, CD45, Cdc27 , CDK12, CDK4, CDKN2A, CEA, CLPP, COA-1, CPSF, CSNK1A1, CTAG1, CTAG2, cyclin D1, cyclin-A1, dek-can fusion protein, DKK1, EFTUD2, elongation factor 2, ENAH (hMena) , Ep-CAM, EpCAM, EphA3, Epithelial Tumor Antigen (“ETA”), ETV6-AML1 Fusion Protein, EZH2, FGF5, FLT3-ITD, FN1, G250/MN/CAIX, GAGE-1,2,8, GAGE- 3,4,5,6,7, GAS7, Glypican-3, GnTV, gp100/Pmel17, GPNMB, HAUS3, Hepsin, HER-2/neu, HERV-K-MEL , HLA-A11, HLA-A2, HLA-DOB, hsp70-2, IDO1, IGF2B3, IL13Rα2, intestinal carboxylesterase, K-ras, kallikrein 4, KIF20A, KK-LC-1, KKLC1, KM- HN-1, KMHN1 (also known as CCDC110), LAGE-1, LDLR-fucosyltransferase AS fusion protein, Lengsin, M-CSF, MAGE-A1, MAGE-A10, MAGE- A12, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A9, MAGE-C1, MAGE-C2, malic enzyme, mammaglobin-A, MART2, MATN, MC1R, MCSP, mdm- 2. ME1, Melan-A/MART-1, Meloe, midkine, MMP-2, MMP-7, MUC1, MUC5AC, mucin, MUM-1, MUM-2, MUM-3, myosin, class I Myosin, N-raw, NA88-A, Neo-PAP, NFYC, NY-BR-1, NY-ESO-1/LAGE-2, OA1, OGT, OS-9, P polypeptide, p53, PAP, PAX5 , PBF, pml-RARα fusion protein, polymorphic epithelial mucin (“PEM”), PPP1R3B, PRAME, PRDX5, PSA, PSMA, PTP RK, RAB38/NY-MEL-1, RAGE-1, RBAF600, RGS5, RhoC, RNF43, RU2AS, SAGE, Isolate 1, SIRT2, SNRPD1, SOX10, Sp17, SPA17, SSX-2, SSX-4, STEAP1, Survivin, SYT-SSX1 or -SSX2 fusion protein, TAG-1, TAG-2, telomerase, TGF-βRII, TPBG, TRAG-3, triose phosphate isomerase, TRP-1/gp75, TRP-2 , TRP2-INT2, tyrosinase, tyrosinase ("TYR"), VEGF, WT1, XAGE-1b/GAGED2a. In some embodiments, the antigen is a neoantigen. In some embodiments, the cancer vaccine is administered with an adjuvant. Examples of adjuvants include, but are not limited to, immunomodulatory proteins, Adjuvant 65, α-GalCer, aluminum phosphate, aluminum hydroxide, calcium phosphate, β-glucan peptide, CpG ODN DNA, GPI-0100, lipid A, lipopolysaccharide , Lipovant, Montanide, N-acetyl-muramidyl-L-alanyl-D-isoglutamine, Pam3CSK4, quil A, cholera toxin (CT) and heat-labile toxins (LT) from enterotoxic Escherichia coli ( Escherichia coli ), including derivatives of this class (CTB, mmCT, CTA1-DD, LTB, LTK63, LTR72, dmLT) and trehalose dipycolate.

在一些實施方式中，免疫療法藥劑係用於受試者的免疫調節蛋白。在一些實施方式中，該免疫調節蛋白係細胞介素或趨化因子。免疫調節蛋白的實例包括但不限於B淋巴細胞化學引誘物（「BLC」）、C-C模體趨化因子11（「嗜酸性粒細胞趨化因子（Eotaxin）-1」）、嗜酸性粒細胞趨化蛋白2（「嗜酸性粒細胞趨化因子-2」）、粒細胞群落刺激因子（「G-CSF」）、粒細胞巨噬細胞群落刺激因子（「GM-CSF」）、1-309、細胞間黏附分子1（「ICAM-1」）、干擾素α（「IFN-α」）、干擾素β（「IFN-β」）、干擾素γ（「IFN-γ」）、白細胞介素-1α（「IL-1α」）、白細胞介素-1β（「IL-1β」）、白細胞介素1受體拮抗劑（「IL-1 ra」）、白細胞介素-2（「IL-2」）、白細胞介素-4（「IL-4」）、白細胞介素-5（「IL-5」）、白細胞介素-6（「IL-6」）、白細胞介素-6可溶性受體（「IL-6 sR」）、白細胞介素-7（「IL-7」）、白細胞介素-8（「IL-8」）、白細胞介素-10（「IL-10」）、白細胞介素-11（「IL-11」）、白細胞介素-12的亞基β（「IL-12 p40」或「IL-12 p70」）、白細胞介素-13（「IL-13」）、白細胞介素-15（「IL-15」）、白細胞介素-16（「IL-16」）、白細胞介素17A-F（「IL-17A-F」）、白細胞介素-18（「IL-18」）、白細胞介素-21（「IL-21」）、白細胞介素-22（「IL-22」）、白細胞介素-23（「IL-23」）、白細胞介素-33（「IL-33」）、趨化因子（C-C模體）配位基2（「MCP-1」）、巨噬細胞群落刺激因子（「M-CSF」）、由γ干擾素誘導的單核因子（「MIG」）、趨化因子（C-C模體）配位基2（「MIP-1α」）、趨化因子（C-C模體）配位基4（「MIP-1β」）、巨噬細胞炎症蛋白- 1 -δ（「MIP-1δ」）、血小板源生長因子亞基B（「PDGF-BB」）、趨化因子（C-C模體）配位基5、調控活化正常T細胞表現及分泌蛋白（「RANTES」）、TIMP金屬肽酶抑制劑1（「TIMP-1」）、TIMP金屬肽酶抑制劑2（「TIMP-2」）、腫瘤壞死因子、淋巴毒素-α（「TNFα」）、腫瘤壞死因子、淋巴毒素-β（「TNFβ」）、1型可溶性TNF受體（「sTNFRI」）、sTNFRIIAR、腦源神經營養因子（「BDNF」）、鹼性成纖維細胞生長因子（「bFGF」）、骨成形性蛋白4（「BMP-4」）、骨成形性蛋白5（「BMP-5」）、骨成形性蛋白7（「BMP-7」）、神經生長因子（「b-NGF」）、表皮生長因子（「EGF」）、表皮生長因子受體（「EGFR」）、內分泌腺源血管內皮生長因子（「EG-VEGF」）、成纖維細胞生長因子4（「FGF-4」）、角質細胞生長因子（「FGF-7」）、生長分化因子15（「GDF-15」）、神經膠細胞源神經營養因子（「GDNF」）、生長激素、結合肝素的EGF樣生長因子（「HB-EGF」）、肝細胞生長因子（「HGF」）、胰島素樣生長因子結合蛋白1（「IGFBP-1」）、胰島素樣生長因子結合蛋白2（「IGFBP-2」）、胰島素樣生長因子結合蛋白3（「IGFBP-3」）、胰島素樣生長因子結合蛋白4（「IGFBP-4」）、胰島素樣生長因子結合蛋白6（「IGFBP-6」）、胰島素樣生長因子1（「IGF-1」）、胰島素、巨噬細胞群落刺激因子（「M-CSF R」）、神經生長因子受體（「NGF R」）、神經營養因子-3（「NT-3」）、神經營養因子-4（「NT-4」）、破骨細胞發生抑制因子（「護骨素（Osteoprotegerin）」）、血小板源生長因子受體（「PDGF-AA」）、磷脂醯肌醇-聚糖生物合成蛋白（「PIGF」）、Skp、Cullin、含有F-盒的複合物（「SCF」）、幹細胞介素受體（「SCF R」）、轉形生長因子α（「TGFα」）、轉形生長因子β-1（「TGFβ 1」）、轉形生長因子β-3（「TGFβ 3」）、血管內皮生長因子（「VEGF」）、血管內皮生長因子受體2（「VEGFR2」）、血管內皮生長因子受體3（「VEGFR3」）、VEGF-D 6Ckine、酪胺酸蛋白激酶受體UFO（「Axl」）、β細胞素（Betacellulin）（「BTC」）、黏膜相關上皮趨化因子（「CCL28」）、趨化因子（C-C模體）配位基27（「CTACK」）、趨化因子（C-X-C模體）配位基16（「CXCL16」）、C-X-C模體趨化因子5（「ENA-78」）、趨化因子（C-C模體）配位基26（「嗜酸性粒細胞趨化因子-3」）、粒細胞趨化蛋白2（「GCP-2」）、GRO、趨化因子（C-C模體）配位基14（「HCC-l」）、趨化因子（C-C模體）配位基16（「HCC-4」）、白細胞介素-9（「IL-9」）、白細胞介素-17 F（「IL-17F」）、白細胞介素- 18結合蛋白（「IL-18 BPa」）、白細胞介素-28 A（「IL-28A」）、白細胞介素29（「IL-29」）、白細胞介素31（「IL-31」）、C-X-C模體趨化因子10（「IP-10」）、趨化因子受體CXCR3（「I-TAC」）、白血病抑制因子（「LIF」）、Light、趨化因子（C模體）配位基（「淋巴細胞趨化因子（Lymphotactin）」）、單核細胞化學吸引蛋白2（「MCP-2」）、單核細胞化學吸引蛋白3（「MCP-3」）、單核細胞化學吸引蛋白4（「MCP-4」）、巨噬細胞源趨化因子（「MDC」）、巨噬細胞遷移抑制因子（「MIF」）、趨化因子（C-C模體）配位基20（「MIP-3α」）、C-C模體趨化因子19（「MIP-3β」）、趨化因子（C-C模體）配位基23（「MPIF-1」）、巨噬細胞刺激蛋白α鏈（「MSPα」）、核小體組裝蛋白1樣4（「NAP-2」）、分泌磷蛋白1（「骨橋蛋白（Osteopontin）」）、肺及活化調控細胞介素（「PARC」）、血小板因子4（「PF4」）、基質細胞源因子- 1α（「SDF-1α」）、趨化因子（C-C模體）配位基17（「TARC」）、胸腺表現的趨化因子（「TECK」）、胸腺基質淋巴生成素（「TSLP 4- IBB」）、CD 166抗原（「ALCAM」）、分化簇80（「B7-1」）、腫瘤壞死因子受體超家族成員17（「BCMA」）、分化簇14（「CD14」）、分化簇30（「CD30」）、分化簇40（「CD40配位基」）、癌胚抗原相關細胞黏附分子1（膽管糖蛋白）（「CEACAM-1」）、死亡受體6（「DR6」）、去氧胸苷激酶（「Dtk」）、1型膜糖蛋白（「內皮糖蛋白（Endoglin）」）、受體酪胺酸蛋白激酶erbB-3（「ErbB3」）、內皮-白血球黏附分子1（「E-選擇素（Selectin）」）、細胞凋亡抗原1（「Fas」）、Fms樣酪胺酸激酶3（「Flt-3L」）、腫瘤壞死因子受體超家族成員1（「GITR」）、腫瘤壞死因子受體超家族成員14（「HVEM」）、細胞間黏附分子3（「ICAM-3」）、IL-1 R4、IL-1 RI、IL-10 Rβ、IL-17R、IL-2Rγ、IL-21R、溶酶體膜蛋白2（「LIMPII」）、中性粒細胞明膠酶相關脂質運載蛋白（「脂質運載蛋白-2」）、CD62L（「L-選擇素」）、淋巴內皮（「LYVE-1」）、I類MHC多肽相關序列A（「MICA」）、I類MHC多肽相關序列B（「MICB」）、NRGl-βl、β-型血小板源生長因子受體（「PDGF Rβ」）、血小板內皮細胞黏附分子（「PECAM-1」）、RAGE、A型肝炎病毒細胞受體1（「TIM-1」）、腫瘤壞死因子受體超家族成員IOC（「TRAIL R3」）、特拉平（Trappin）蛋白轉麩醯胺酸酶結合結構域（「特拉平-2」）、尿激酶受體（「uPAR」）、血管細胞黏附蛋白1（「VCAM-1」）、XEDAR活化素A、野鼠色相關蛋白（「AgRP」）、核糖核酸酶5（「血管生成素（Angiogenin）」）、血管生成素（Angiopoietin）1、血管抑素（Angiostatin）、卡層析因（Catheprin）S、CD40、隱藏家族蛋白IB（「Cripto-1」）、DAN、Dickkopf相關蛋白1（「DKK-1」）、E-鈣黏蛋白、上皮細胞黏附分子（「EpCAM」）、Fas配位基（FasL或CD95L）、Fcg RIIB/C、卵泡抑素、半乳糖凝集素-7、細胞間黏附分子2（「ICAM-2」）、IL-13 Rl、IL-13R2、IL-17B、IL-2 Ra、IL-2 Rb、IL-23、LAP、神經元細胞黏附分子（「NrCAM」）、纖維蛋白溶酶原活化抑制劑- 1（「PAI-1」）、血小板源生長因子受體（「PDGF-AB」）、抵抗素（Resistin）、基質細胞源因子1（「SDF-1β」）、sgpl30、分泌型捲曲相關蛋白2（「ShhN」）、唾液酸結合免疫球蛋白型凝集素（「Siglec-5」）、ST2、轉形生長因子-β2（「TGFβ 2」）、Tie-2、血小板生成素（「TPO」）、腫瘤壞死因子受體超家族成員10D（「TRAIL R4」）、表現於骨髓性細胞上的觸發受體1（「TREM-1」）、血管內皮生長因子C（「VEGF-C」）、VEGFRl脂聯素、脂素（Adipsin）（「AND」）、α-胎蛋白（「AFP」）、血管生成素樣4（「ANGPTL4」）、β-2-微球蛋白（「B2M」）、基底細胞黏附分子（「BCAM」）、碳水化合物抗原125（「CA125」）、癌症抗原15-3（「CA15-3」）、癌胚抗原（「CEA」）、cAMP受體蛋白（「CRP」）、人表皮生長因子受體2（「ErbB2」）、濾泡抑素、濾泡刺激素（「FSH」）、趨化因子（C-X-C模體）配位基1（「GROα」）、人絨毛膜促性腺激素（「βHCG」）、胰島素樣生長因子1受體（「IGF-1 sR」）、IL-1 sRII、IL-3、IL-18 Rb、IL-21、瘦素（Leptin）、基質金屬蛋白酶-1（「MMP-1」）、基質金屬蛋白酶-2（「MMP-2」）、基質金屬蛋白酶-3（「MMP-3」）、基質金屬蛋白酶-8（「MMP-8」）、基質金屬蛋白酶-9（「MMP-9」）、基質金屬蛋白酶-10（「MMP-10」）、基質金屬蛋白酶-13（「MMP-13」）、神經細胞黏附分子（「NCAM-1」）、巢蛋白（Entactin）（「巢蛋白（Nidogen）-1」）、神經元特異性烯醇酶（「NSE」）、抑瘤素（Oncostatin） M（「OSM」）、原降鈣素（Procalcitonin）、泌乳素（Prolactin）、前列腺特異性抗原（「PSA」）、結合唾液酸的Ig樣凝集素9（「Siglec-9」）、ADAM 17內肽酶（「TACE」）、甲狀腺球蛋白（Thyroglobulin）、金屬蛋白酶抑制劑4（「TIMP-4」）、TSH2B4、含有去整合素（Disintegrin）及金屬蛋白酶結構域的蛋白質9（「ADAM-9」）、血管生成素2、腫瘤壞死因子配位基超家族成員13/富酸性白胺酸核磷蛋白32家族成員B（「APRIL」）、骨成形性蛋白2（「BMP-2」）、骨成形性蛋白9（「BMP-9」）、補體組分5a（「C5a」）、細胞自溶酶L、CD200、CD97、趨化素（Chemerin）、腫瘤壞死因子受體超家族成員6B（「DcR3」）、脂肪酸結合蛋白2（「FABP2」）、成纖維細胞活化蛋白、α（「FAP」）、成纖維細胞生長因子19（「FGF-19」）、半乳糖凝集素-3、肝細胞生長因子受體（「HGF R」）、IFN-γα/β R2、胰島素樣生長因子2（「IGF-2」）、胰島素樣生長因子2受體（「IGF-2 R」）、白細胞介素-1受體6（「IL-1R6」）、白細胞介素24（「IL-24」）、白細胞介素33（「IL-33」）、激肽釋放素（Kallikrein） 14、天門冬醯胺醯基內肽酶（「天門冬醯胺內肽酶（Legumain）」）、氧化型低密度脂蛋白受體1（「LOX-1」）、甘露糖結合凝集素（「MBL」）、腦啡肽酶（Neprilysin）（「NEP」）、Notch同系物1、易位相關（果蠅（Drosophila））（「Notch-1」）、腎胚細胞瘤過度表現的蛋白（「NOV」）、骨活化素（Osteoactivin）、計劃性細胞死亡蛋白1（「PD-1」）、N-乙醯基胞壁醯基-L-丙胺酸醯胺酶（「PGRP-5」）、絲胺酸蛋白酶抑制劑（Serpin） A4、分泌型捲曲相關蛋白3（「sFRP-3」）、血栓調節蛋白（Thrombomodulin）、Toll樣受體2（「TLR2」）、腫瘤壞死因子受體超家族成員10A（「TRAIL Rl」）、運鐵蛋白（「TRF」）、WIF-lACE-2、白蛋白、AMICA、血管生成素4、B細胞活化因子（「BAFF」）、碳水化合物抗原19-9（「CA19-9」）、CD 163、叢生蛋白（Clusterin）、CRT AM、趨化因子（C-X-C模體）配位基14（「CXCL14」）、胱抑素（Cystatin）C、核心蛋白聚糖（Decorin）（「DCN」）、Dickkopf相關蛋白3（「Dkk-3」）、δ樣蛋白質1（「DLL1」）、胎球蛋白（Fetuin）A、肝素結合生長因子1（「aFGF」）、葉酸受體α（「FOLR1」）、弗林蛋白酶（Furin）、GPCR相關分選蛋白1（「GASP-1」）、GPCR相關分選蛋白2（「GASP-2」）、粒細胞群落刺激因子受體（「GCSF R」）、絲胺酸蛋白酶海普森（「HAI-2」）、白細胞介素-17B受體（「IL-17B R」）、白細胞介素27（「IL-27」）、淋巴細胞活化基因3（「LAG-3」）、缺脂脂蛋白A-V（「LDL R」）、胃蛋白酶原I、視黃醇結合蛋白4（「RBP4」）、SOST、類肝素硫酸蛋白聚糖（「共結合蛋白聚糖-1（Syndecan-1）」）、腫瘤壞死因子受體超家族成員13B（「TACI」）、組織因子通路抑制劑（「TFPI」）、TSP-1、腫瘤壞死因子受體超家族成員10b（「TRAIL R2」）、TRANCE、肌鈣蛋白I（Troponin I）、尿激酶纖維蛋白溶酶原活化劑（「uPA」）、鈣黏蛋白5、2型或VE-鈣黏蛋白（血管內皮）（還稱為CD144，「VE-鈣黏蛋白」）、WNTl可誘導型信號傳導通路蛋白1（「WISP-1」）及核因子κ B的受體活化劑（「RANK」）。In some embodiments, the immunotherapy agent is an immunomodulatory protein for the subject. In some embodiments, the immunomodulatory protein is a cytokine or a chemokine. Examples of immunomodulatory proteins include, but are not limited to, B-lymphocyte chemoattractant ("BLC"), C-C motif chemokine 11 ("Eotaxin-1"), eotaxin-1 EG protein 2 ("eotaxin-2"), granulocyte colony-stimulating factor ("G-CSF"), granulocyte-macrophage colony-stimulating factor ("GM-CSF"), 1-309, Intercellular adhesion molecule 1 (“ICAM-1”), interferon alpha (“IFN-α”), interferon beta (“IFN-β”), interferon gamma (“IFN-γ”), interleukin- 1α ("IL-1α"), Interleukin-1β ("IL-1β"), Interleukin 1 Receptor Antagonist ("IL-1 ra"), Interleukin-2 ("IL-2" ), interleukin-4 (“IL-4”), interleukin-5 (“IL-5”), interleukin-6 (“IL-6”), interleukin-6 soluble receptor ( "IL-6 sR"), interleukin-7 ("IL-7"), interleukin-8 ("IL-8"), interleukin-10 ("IL-10"), interleukin -11 ("IL-11"), subunit beta of interleukin-12 ("IL-12 p40" or "IL-12 p70"), interleukin-13 ("IL-13"), interleukin-12 Interleukin-15 (“IL-15”), Interleukin-16 (“IL-16”), Interleukin 17A-F (“IL-17A-F”), Interleukin-18 (“IL-18 ”), Interleukin-21 (“IL-21”), Interleukin-22 (“IL-22”), Interleukin-23 (“IL-23”), Interleukin-33 (“IL-23”) -33"), chemokine (C-C motif) ligand 2 ("MCP-1"), macrophage colony-stimulating factor ("M-CSF"), monokine induced by gamma interferon (" MIG"), chemokine (C-C motif) ligand 2 ("MIP-1α"), chemokine (C-C motif) ligand 4 ("MIP-1β"), macrophage inflammatory protein- 1-δ ("MIP-1δ"), platelet-derived growth factor subunit B ("PDGF-BB"), chemokine (C-C motif) ligand 5, regulates the expression and secretion of activated normal T cells (" RANTES"), TIMP metallopeptidase inhibitor 1 ("TIMP-1"), TIMP metallopeptidase inhibitor 2 ("TIMP-2"), tumor necrosis factor, lymphotoxin-alpha ("TNFα"), tumor necrosis factor, lymphotoxin-β (“TNFβ”), soluble TNF receptor type 1 (“sTNFRI”), sTNFRIIAR, brain-derived neurotrophic factor (“BDNF”), basic fibroblast growth factor (“bFGF”), bone morphogenic protein 4 (“BMP-4”), bone morphogenic protein 5 (“BMP-5”), bone morphogenic protein 7 (“BMP-7”), nerve growth factor (“b-NGF”), epidermal growth factor ( "EGF"), epidermal growth factor receptor ("EGFR"), endocrine gland-derived vascular endothelial growth factor ("EG-VEGF"), fibroblast growth factor 4 ("FGF-4"), keratinocyte growth factor ( "FGF-7"), growth differentiation factor 15 ("GDF-15"), glial cell-derived neurotrophic factor ("GDNF"), growth hormone, heparin-bound EGF-like growth factor ("HB-EGF"), Hepatocyte Growth Factor (“HGF”), Insulin-like Growth Factor Binding Protein 1 (“IGFBP-1”), Insulin-like Growth Factor Binding Protein 2 (“IGFBP-2”), Insulin-like Growth Factor Binding Protein 3 (“IGFBP-1”) -3"), insulin-like growth factor binding protein 4 ("IGFBP-4"), insulin-like growth factor binding protein 6 ("IGFBP-6"), insulin-like growth factor 1 ("IGF-1"), insulin, Macrophage Colony Stimulating Factor (“M-CSF R”), Nerve Growth Factor Receptor (“NGF R”), Neurotrophic Factor-3 (“NT-3”), Neurotrophic Factor-4 (“NT-4”) ”), osteoclastogenesis inhibitory factor (“Osteoprotegerin”), platelet-derived growth factor receptor (“PDGF-AA”), phosphatidylinositol-glycan biosynthetic protein (“PIGF”), Skp, Cullin, F-box-containing complex ("SCF"), stem cell interleukin receptor ("SCF R"), transforming growth factor alpha ("TGFα"), transforming growth factor beta-1 ("TGFβ 1"), transforming growth factor beta-3 ("TGFβ 3"), vascular endothelial growth factor ("VEGF"), vascular endothelial growth factor receptor 2 ("VEGFR2"), vascular endothelial growth factor receptor 3 (" VEGFR3"), VEGF-D 6Ckine, receptor tyrosine protein kinase UFO ("Axl"), Betacellulin ("BTC"), mucosa-associated epithelial chemokine ("CCL28"), chemokines (C-C motif) ligand 27 ("CTACK"), chemokine (C-X-C motif) ligand 16 ("CXCL16"), C-X-C motif chemokine 5 ("ENA-78"), chemokine Factor (C-C motif) ligand 26 (“eotaxin-3”), granulotaxin protein 2 (“GCP-2”), GRO, chemokine (C-C motif) ligand base 14 (“HCC-1”), chemokine (C-C motif) ligand 16 (“HCC-4”), interleukin-9 (“IL-9”), interleukin-17F ( "IL-1 7F"), interleukin-18 binding protein ("IL-18 BPa"), interleukin-28 A ("IL-28A"), interleukin 29 ("IL-29"), interleukin 31 ("IL-31"), C-X-C motif chemokine 10 ("IP-10"), chemokine receptor CXCR3 ("I-TAC"), leukemia inhibitory factor ("LIF"), Light, chemokine Factor (C motif) ligand ("Lymphotactin"), Monocyte chemoattractant protein 2 ("MCP-2"), Monocyte chemoattractant protein 3 ("MCP-3" ), monocyte chemoattractant protein 4 (“MCP-4”), macrophage-derived chemokine (“MDC”), macrophage migration inhibitory factor (“MIF”), chemokine (C-C motif) Ligand 20 (“MIP-3α”), C-C motif chemokine 19 (“MIP-3β”), chemokine (C-C motif) ligand 23 (“MPIF-1”), macrophage Stimulatory protein alpha chain ("MSPα"), nucleosome assembly protein 1-like 4 ("NAP-2"), secreted phosphoprotein 1 ("Osteopontin"), lung and activation regulatory cytokines (" PARC"), platelet factor 4 ("PF4"), stromal cell-derived factor-1α ("SDF-1α"), chemokine (C-C motif) ligand 17 ("TARC"), thymus-expressed chemotaxis Thymic stromal lymphopoietin ("TSLP 4-IBB"), CD 166 antigen ("ALCAM"), cluster of differentiation 80 ("B7-1"), tumor necrosis factor receptor superfamily member 17 ("BCMA"), cluster of differentiation 14 ("CD14"), cluster of differentiation 30 ("CD30"), cluster of differentiation 40 ("CD40 ligand"), carcinoembryonic antigen-related cell adhesion molecule 1 (cholangioglycoprotein) ( "CEACAM-1"), death receptor 6 ("DR6"), deoxythymidine kinase ("Dtk"), type 1 membrane glycoprotein ("Endoglin"), receptor tyrosine protein Kinase erbB-3 (“ErbB3”), endothelial-leukocyte adhesion molecule 1 (“E-Selectin”), apoptosis antigen 1 (“Fas”), Fms-like tyrosine kinase 3 (“Flt- 3L"), tumor necrosis factor receptor superfamily member 1 ("GITR"), tumor necrosis factor receptor superfamily member 14 ("HVEM"), intercellular adhesion molecule 3 ("ICAM-3"), IL-1 R4, IL-1 RI, IL-10 Rβ, IL-17R, IL-2Rγ, IL-21R, lysosomal membrane protein 2 (“LIMPII”), neutrophil gelatinase-associated lipocalin (“lipocalin”) protein-2"), CD62L (" L-selectin"), lymphatic endothelium ("LYVE-1"), MHC class I polypeptide-related sequence A ("MICA"), MHC class I polypeptide-related sequence B ("MICB"), NRG1-β1, β-type Platelet-derived growth factor receptor (“PDGF Rβ”), platelet endothelial cell adhesion molecule (“PECAM-1”), RAGE, hepatitis A virus cellular receptor 1 (“TIM-1”), tumor necrosis factor receptor super Family members IOC (“TRAIL R3”), Trappin protein transglutaminase-binding domain (“Trapin-2”), urokinase receptor (“uPAR”), vascular cell adhesion protein 1 ( "VCAM-1"), XEDAR Activin A, Violet-related protein ("AgRP"), ribonuclease 5 ("Angiogenin"), Angiopoietin 1, Angiostatin ), Catheprin S, CD40, cryptic family protein IB (“Cripto-1”), DAN, Dickkopf-related protein 1 (“DKK-1”), E-cadherin, epithelial cell adhesion molecule ( "EpCAM"), Fas ligand (FasL or CD95L), Fcg RIIB/C, follistatin, galectin-7, intercellular adhesion molecule 2 ("ICAM-2"), IL-13 Rl, IL -13R2, IL-17B, IL-2 Ra, IL-2 Rb, IL-23, LAP, Neuronal Cell Adhesion Molecule ("NrCAM"), Plasminogen Activation Inhibitor-1 ("PAI-1") ), platelet-derived growth factor receptor ("PDGF-AB"), resistin (Resistin), stromal cell-derived factor 1 ("SDF-1β"), sgpl30, secreted frizzled-related protein 2 ("ShhN"), salivary Acid-binding immunoglobulin-type lectin ("Siglec-5"), ST2, transforming growth factor-β2 ("TGFβ2"), Tie-2, thrombopoietin ("TPO"), tumor necrosis factor receptor super Family member 10D ("TRAIL R4"), triggering receptor expressed on myeloid cells 1 ("TREM-1"), vascular endothelial growth factor C ("VEGF-C"), VEGFRl adiponectin, adiponectin ( Adipsin) ("AND"), alpha-fetoprotein ("AFP"), angiopoietin-like 4 ("ANGPTL4"), beta-2-microglobulin ("B2M"), basal cell adhesion molecule ("BCAM") ), Carbohydrate Antigen 125 (“CA125”), Cancer Antigen 15-3 (“CA15-3”), Carcinoembryonic Antigen (“CEA”), cAMP Receptor Protein (“CRP”), Human Epidermal Growth Factor Receptor 2 ("ErbB2"), follicle Statin, follicle stimulating hormone ("FSH"), chemokine (C-X-C motif) ligand 1 ("GROα"), human chorionic gonadotropin ("βHCG"), insulin-like growth factor 1 receptor ("IGF-1 sR"), IL-1 sRII, IL-3, IL-18 Rb, IL-21, Leptin, Matrix Metalloproteinase-1 ("MMP-1"), Matrix Metalloproteinase- 2 (“MMP-2”), matrix metalloproteinase-3 (“MMP-3”), matrix metalloproteinase-8 (“MMP-8”), matrix metalloproteinase-9 (“MMP-9”), matrix metalloproteinase Protease-10 (“MMP-10”), Matrix Metalloproteinase-13 (“MMP-13”), Neural Cell Adhesion Molecule (“NCAM-1”), Entactin (“Nidogen-1”) "), neuron-specific enolase ("NSE"), Oncostatin M ("OSM"), procalcitonin (Procalcitonin), prolactin (Prolactin), prostate-specific antigen ("PSA ”), sialic acid-binding Ig-like lectin 9 (“Siglec-9”), ADAM 17 endopeptidase (“TACE”), Thyroglobulin, inhibitor of metalloproteinase 4 (“TIMP-4”) , TSH2B4, disintegrin (Disintegrin) and metalloproteinase domain-containing protein 9 ("ADAM-9"), angiopoietin 2, tumor necrosis factor ligand superfamily member 13/acid-rich leucine nucleophosmin 32 family member B ("APRIL"), bone morphogenic protein 2 ("BMP-2"), bone morphogenic protein 9 ("BMP-9"), complement component 5a ("C5a"), autolysozyme L, CD200, CD97, Chemerin, tumor necrosis factor receptor superfamily member 6B ("DcR3"), fatty acid binding protein 2 ("FABP2"), fibroblast activation protein, alpha ("FAP") , Fibroblast Growth Factor 19 (“FGF-19”), Galectin-3, Hepatocyte Growth Factor Receptor (“HGF R”), IFN-γα/β R2, Insulin-like Growth Factor 2 (“IGF -2"), insulin-like growth factor 2 receptor ("IGF-2 R"), interleukin-1 receptor 6 ("IL-1R6"), interleukin 24 ("IL-24"), leukocyte Interlein 33 (“IL-33”), Kallikrein 14, Asparaginyl Endopeptidase (“Asparaginyl Endopeptidase (Legumain)”), Oxidized Low Density Lipoprotein receptor 1 (“LOX-1”), mannose-binding lectin (“MBL”), neprilysin (Neprilys in) ("NEP"), Notch homolog 1, translocation-associated (Drosophila) ("Notch-1"), nephroblastoma overexpressed protein ("NOV"), osteoactivin (Osteoactivin ), programmed cell death protein 1 ("PD-1"), N-acetylmurayl-L-alanine amidase ("PGRP-5"), serine protease inhibitor (Serpin) A4. Secreted Frizzled-Related Protein 3 ("sFRP-3"), Thrombomodulin, Toll-like Receptor 2 ("TLR2"), Tumor Necrosis Factor Receptor Superfamily Member 10A ("TRAIL Rl"), Transferrin (“TRF”), WIF-lACE-2, Albumin, AMICA, Angiopoietin 4, B Cell Activating Factor (“BAFF”), Carbohydrate Antigen 19-9 (“CA19-9”), CD 163. Clusterin, CRT AM, Chemokine (C-X-C Motif) Ligand 14 (“CXCL14”), Cystatin C, Decorin (“DCN”), Dickkopf-related protein 3 (“Dkk-3”), delta-like protein 1 (“DLL1”), fetuin A, heparin-binding growth factor 1 (“aFGF”), folate receptor alpha (“FOLR1”) , Furin, GPCR-associated sorting protein 1 (“GASP-1”), GPCR-associated sorting protein 2 (“GASP-2”), granulocyte colony-stimulating factor receptor (“GCSFR”), Serine protease hempson ("HAI-2"), interleukin-17B receptor ("IL-17B R"), interleukin 27 ("IL-27"), lymphocyte activation gene 3 (" LAG-3"), lipoprotein A-V ("LDL R"), pepsinogen I, retinol-binding protein 4 ("RBP4"), SOST, heparan sulfate proteoglycan ("conjugated proteoglycan -1 (Syndecan-1)"), tumor necrosis factor receptor superfamily member 13B ("TACI"), tissue factor pathway inhibitor ("TFPI"), TSP-1, tumor necrosis factor receptor superfamily member 10b ( "TRAIL R2"), TRANCE, Troponin I, urokinase plasminogen activator ("uPA"), cadherin 5, type 2, or VE-cadherin (vascular endothelium) ( Also known as CD144, "VE-cadherin"), WNT1 inducible signaling pathway protein 1 ("WISP-1"), and receptor activator of nuclear factor kappa B ("RANK").

在一些實施方式中，癌症治療劑係抗癌症化合物。示例性抗癌症化合物包括但不限於阿侖單抗（Campath®）、阿利維A酸（Panretin®）、阿那曲唑（Arimidex®）、貝伐單抗（Avastin®）、貝沙羅汀（Targretin®）、硼替佐米（Velcade®）、博舒替尼（Bosulif®）、本妥昔單抗（Adcetris®）、卡巴坦尼（Cometriq™）、卡菲佐米（Kyprolis™）、西妥昔單抗（Erbitux®）、克裡唑蒂尼（Xalkori®）、達沙替尼（Sprycel®）、地尼介白素（Ontak®）、鹽酸埃羅替尼（Tarceva®）、依維莫司（Afinitor®）、依西美坦（Aromasin®）、氟維司群（Faslodex®）、吉非替尼（Iressa®）、替坦異貝莫單抗（Zevalin®）、甲磺酸伊馬替尼（Gleevec®）、伊匹單抗（Yervoy™）、二對甲苯磺酸拉帕替尼（Tykerb®）、來曲唑（Femara®）、尼洛替尼（Tasigna®）、奧法木單抗（Arzerra®）、帕尼單抗（Vectibix®）、鹽酸帕唑帕尼（Votrient®）、帕妥珠單抗（Perjeta™）、普拉曲沙（Folotyn®）、瑞戈非尼（Stivarga®）、利妥昔單抗（Rituxan®）、羅米地辛（Istodax®）、甲苯磺酸索拉非尼（Nexavar®）、蘋果酸舒尼替尼（Sutent®）、他莫昔芬、西羅莫司（Torisel®）、托瑞米芬（Fareston®）、托西莫單抗及131I-托西莫單抗（Bexxar®）、曲妥珠單抗（Herceptin®）、維甲酸（Vesanoid®）、凡德他尼（Caprelsa®）、威羅菲尼（Zelboraf®）、伏立諾他（Zolinza®）及阿柏西普（Zaltrap®）。In some embodiments, the cancer therapeutic agent is an anti-cancer compound. Exemplary anticancer compounds include, but are not limited to, alemtuzumab (Campath®), alitretinoin (Panretin®), anastrozole (Arimidex®), bevacizumab (Avastin®), bexarotene (Targretin® ), Bortezomib (Velcade®), Bosutinib (Bosulif®), Bentuximab (Adcetris®), Cabatatinib (Cometriq™), Carfilzomib (Kyprolis™), Cetuximab Anti-(Erbitux®), Crizotinib (Xalkori®), Dasatinib (Sprycel®), Denileukin (Ontak®), Erlotinib Hydrochloride (Tarceva®), Everolimus ( Afinitor®), exemestane (Aromasin®), fulvestrant (Faslodex®), gefitinib (Iressa®), isobembomumab (Zevalin®), imatinib mesylate ( Gleevec®), ipilimumab (Yervoy™), lapatinib ditosylate (Tykerb®), letrozole (Femara®), nilotinib (Tasigna®), ofatumumab ( Arzerra®), panitumumab (Vectibix®), pazopanib hydrochloride (Votrient®), pertuzumab (Perjeta™), pralatrexate (Folotyn®), regorafenib (Stivarga®) , rituximab (Rituxan®), romidepsin (Istodax®), sorafenib tosylate (Nexavar®), sunitinib malate (Sutent®), tamoxifen, ciprofloxacin Limus (Torisel®), toremifene (Fareston®), tositumomab and 131I-tositumomab (Bexxar®), trastuzumab (Herceptin®), retinoic acid (Vesanoid®) , vandetanib (Caprelsa®), vemurafenib (Zelboraf®), vorinostat (Zolinza®), and aflibercept (Zaltrap®).

修飾調節基因表現及其他細胞功能的蛋白質的功能的示例性抗癌症化合物（例如，HDAC抑制劑，類視黃醇受體配位基）係伏立諾他（Zolinza®）、貝沙羅汀（Targretin®）及羅米地辛（Istodax®）、阿利維A酸（Panretin®）及維甲酸（Vesanoid®）。Exemplary anticancer compounds that modify the function of proteins that regulate gene expression and other cellular functions (e.g., HDAC inhibitors, retinoid receptor ligands) are vorinostat (Zolinza®), bexarotene (Targretin ®) and romidepsin (Istodax®), alitretinoin (Panretin®) and tretinoin (Vesanoid®).

誘導細胞凋亡的示例性抗癌症化合物（例如，蛋白酶體抑制劑，葉酸拮抗劑）係硼替佐米（Velcade®）、卡菲佐米（Kyprolis™）及普拉曲沙（Folotyn®）。Exemplary anti-cancer compounds (eg, proteasome inhibitors, folate antagonists) that induce apoptosis are bortezomib (Velcade®), kafizomib (Kyprolis™), and pralatrexate (Folotyn®).

增加抗腫瘤免疫應答的示例性抗癌化合物（例如抗CD20、抗CD52；抗細胞毒性T淋巴細胞相關抗原-4）為利妥昔單抗（Rituxan®）、阿侖單抗（Campath®）、奧法木單抗（Arzerra®）及伊匹單抗（Yervoy™）。Exemplary anti-cancer compounds (e.g. anti-CD20, anti-CD52; anti-cytotoxic T-lymphocyte-associated antigen-4) that increase anti-tumor immune responses are rituximab (Rituxan®), alemtuzumab (Campath®), Ofatumumab (Arzerra®) and ipilimumab (Yervoy™).

將毒劑遞送至癌細胞的示例性抗癌症化合物（例如，抗CD20-放射性核素融合物；IL-2-白喉毒素融合物；抗CD30-單甲基澳瑞他汀E（MMAE）-融合物）係托西莫單抗及131I-托西莫單抗（Bexxar®）及替坦異貝莫單抗（Zevalin®）、地尼介白素（Ontak®）及本妥昔單抗（Adcetris®）。Exemplary anti-cancer compounds that deliver toxic agents to cancer cells (e.g., anti-CD20-radionuclide fusion; IL-2-diphtheria toxin fusion; anti-CD30-monomethylauristatin E (MMAE)-fusion) Tositumomab and 131I-tositumomab (Bexxar®) and Tetan isobembolomab (Zevalin®), denileukin (Ontak®) and ventuximab (Adcetris®) .

其他示例性抗癌症化合物係小分子抑制劑及其結合物，例如，Janus激酶、ALK、Bcl-2、PARP、PI3K、VEGF受體、Braf、MEK、CDK及HSP90。Other exemplary anticancer compounds are small molecule inhibitors and conjugates thereof, eg, Janus kinase, ALK, Bcl-2, PARP, PI3K, VEGF receptor, Braf, MEK, CDK, and HSP90.

示例性基於鉑的抗癌症化合物包括（例如）順鉑、卡鉑、奧沙利鉑、賽特鉑、吡鉑、奈達鉑、三鉑（Triplatin）及脂鉑（Lipoplatin）。適用於治療的其他基於金屬的藥物包括但不限於基於釕的化合物、二茂鐵衍生物、基於鈦的化合物及基於鎵的化合物。Exemplary platinum-based anticancer compounds include, for example, cisplatin, carboplatin, oxaliplatin, satraplatin, picoplatin, nedaplatin, Triplatin, and Lipoplatin. Other metal-based drugs suitable for therapy include, but are not limited to, ruthenium-based compounds, ferrocene derivatives, titanium-based compounds, and gallium-based compounds.

在一些實施方式中，癌症治療劑係包括放射性核素的放射性部分。示例性放射性核素包括但不限於Cr-51、Cs-131、Ce-134、Se-75、Ru-97、I-125、Eu-149、Os-189m、Sb-119、I-123、Ho-161、Sb-117、Ce-139、In-111、Rh-103m、Ga-67、Tl-201、Pd-103、Au-195、Hg-197、Sr-87m、Pt-191、P-33、Er-169、Ru-103、Yb-169、Au-199、Sn-121、Tm-167、Yb-175、In-113m、Sn-113、Lu-177、Rh-105、Sn-117m、Cu-67、Sc-47、Pt-195m、Ce-141、I-131、Tb-161、As-77、Pt-197、Sm-153、Gd-159、Tm-173、Pr-143、Au-198、Tm-170、Re-186、Ag-111、Pd-109、Ga-73、Dy-165、Pm-149、Sn-123、Sr-89、Ho-166、P-32、Re-188、Pr-142、Ir-194、In-114m/In-114及Y-90。In some embodiments, the cancer therapeutic agent comprises a radioactive moiety of a radionuclide. Exemplary radionuclides include, but are not limited to, Cr-51, Cs-131, Ce-134, Se-75, Ru-97, I-125, Eu-149, Os-189m, Sb-119, I-123, Ho -161, Sb-117, Ce-139, In-111, Rh-103m, Ga-67, Tl-201, Pd-103, Au-195, Hg-197, Sr-87m, Pt-191, P-33 , Er-169, Ru-103, Yb-169, Au-199, Sn-121, Tm-167, Yb-175, In-113m, Sn-113, Lu-177, Rh-105, Sn-117m, Cu -67, Sc-47, Pt-195m, Ce-141, I-131, Tb-161, As-77, Pt-197, Sm-153, Gd-159, Tm-173, Pr-143, Au-198 , Tm-170, Re-186, Ag-111, Pd-109, Ga-73, Dy-165, Pm-149, Sn-123, Sr-89, Ho-166, P-32, Re-188, Pr -142, Ir-194, In-114m/In-114 and Y-90.

在一些實施方式中，額外治療劑係抗生素。例如，如果檢測疾病相關細菌和/或疾病相關微生物組特徵存在，則可施用抗生素例如以從受試者消除疾病相關細菌。在一些實施方式中，癌症治療劑係抗生素。例如，如果根據本文提供之方法來檢測癌症相關細菌和/或癌症相關微生物組特徵的存在，則可施用抗生素以從受試者消除癌症相關細菌。「抗生素」在廣義上係指能夠抑制或預防細菌感染的化合物。抗生素可以諸多方式（包含根據其用於特定感染的用途、其作用機制、其生物可用性或其靶微生物範圍（例如革蘭氏陰性細菌對革蘭氏陽性細菌、好氧細菌對厭氧細菌等））進行分類且可使用該等方式來殺死宿主的特定區域（「生態位」）中的特定細菌（Leekha等人, 2011.General Principles of Antimicrobial Therapy[抗微生物療法的一般原則].Mayo Clin Proc.[梅歐醫院院刊] 86(2): 156-167）。在某些實施方式中，可使用抗生素來選擇性靶向特定生態位的細菌。在一些實施方式中，可使用已知治療包括疾病（例如癌症）生態位的特定感染的抗生素來靶向疾病相關微生物（包括該生態位中的疾病相關細菌）。在其他實施方式中，在固體劑型之後施用抗生素。在一些實施方式中，在固體劑型之前施用抗生素。In some embodiments, the additional therapeutic agent is an antibiotic. For example, if a disease-associated bacterium is detected and/or a disease-associated microbiome signature is present, an antibiotic may be administered, eg, to eliminate the disease-associated bacterium from the subject. In some embodiments, the cancer therapeutic agent is an antibiotic. For example, if the presence of cancer-associated bacteria and/or a cancer-associated microbiome signature is detected according to the methods provided herein, an antibiotic can be administered to eliminate the cancer-associated bacteria from the subject. "Antibiotic" refers broadly to compounds capable of inhibiting or preventing bacterial infections. Antibiotics can be administered in a number of ways (including based on their use for a particular infection, their mechanism of action, their bioavailability, or their range of target microorganisms (e.g. Gram-negative versus Gram-positive, aerobic versus anaerobic, etc.) ) and can be used to kill specific bacteria in specific regions ("niches") of the host (Leekha et al., 2011. General Principles of Antimicrobial Therapy [General Principles of Antimicrobial Therapy]. Mayo Clin Proc .[Mayo Hospital Proceedings] 86(2): 156-167). In certain embodiments, antibiotics can be used to selectively target bacteria in specific niches. In some embodiments, disease-associated microbes (including disease-associated bacteria in that niche) can be targeted using antibiotics known to treat specific infections in a niche including a disease (eg, cancer). In other embodiments, the antibiotic is administered after the solid dosage form. In some embodiments, the antibiotic is administered prior to the solid dosage form.

在一些方面，可基於殺細菌或細菌抑制性質來選擇抗生素。殺細菌抗生素包含破壞細胞壁（例如β-內醯胺）、細胞膜（例如達托黴素（daptomycin））或細菌DNA（例如氟喹諾酮（fluoroquinolone））的作用機制。細菌抑制劑抑制細菌複製且包含磺醯胺、四環素（tetracycline）及巨環內酯並藉由抑制蛋白質合成來發揮作用。另外，儘管一些藥物可在某些生物體中具有殺細菌性且在其他生物體中具有細菌抑制性，但知曉靶生物體使得熟悉該項技術者可選擇具有適當性質的抗生素。在某些治療條件中，細菌抑制抗生素抑制殺細菌抗生素的活性。因此，在某些實施方式中，並不組合殺細菌抗生素及細菌抑制抗生素。In some aspects, antibiotics can be selected based on bactericidal or bacteriostatic properties. Bactericidal antibiotics involve mechanisms of action that disrupt cell walls (eg beta-lactams), cell membranes (eg daptomycin) or bacterial DNA (eg fluoroquinolones). Bacterial inhibitors inhibit bacterial replication and include sulfonamides, tetracyclines, and macrolides and act by inhibiting protein synthesis. Additionally, although some drugs may be bactericidal in some organisms and bacteriostatic in others, knowledge of the target organism allows one skilled in the art to select an antibiotic with appropriate properties. In certain therapeutic conditions, bacteriostatic antibiotics inhibit the activity of bactericidal antibiotics. Thus, in certain embodiments, bactericidal and bacteriostatic antibiotics are not combined.

抗生素包括但不限於胺基糖苷、安莎黴素（ansamycin）、碳頭孢烯（carbacephem）、碳青黴烯（carbapenem）、頭孢菌素（cephalosporin）、糖肽、林可醯胺（lincosamide）、脂肽、巨環內酯、單醯胺菌素（monobactam）、硝基呋喃、㗁唑烷酮、青黴素（penicillin）、多肽抗生素、喹諾酮（quinolone）、氟喹諾酮、磺醯胺、四環素及抗分枝桿菌化合物及其組合。Antibiotics include, but are not limited to, aminoglycosides, ansamycin, carbacephem, carbapenem, cephalosporin, glycopeptide, lincosamide, lipid Peptides, macrolides, monobactams, nitrofurans, oxazolidinones, penicillins, peptide antibiotics, quinolones, fluoroquinolones, sulfonamides, tetracyclines, and anti-branching Bacillus compounds and combinations thereof.

胺基糖苷包括但不限於阿米卡星（Amikacin）、建它黴素（Gentamicin）、康黴素（Kanamycin）、新黴素（Neomycin）、奈替米星（Netilmicin）、妥布黴素（Tobramycin）、巴龍黴素（Paromomycin）及大觀黴素（Spectinomycin）。胺基糖苷可有效抵抗例如革蘭氏陰性細菌（例如大腸桿菌、克雷伯氏菌屬、銅綠假單胞菌（ Pseudomonas aeruginosa）及土倫病法蘭西斯氏菌（ Francisella tularensis））且抵抗某些需氧細菌，但對於專性/兼性厭氧菌具有較小有效性。據信，胺基糖苷結合至細菌30S或50S核糖體亞基，由此抑制細菌蛋白合成。 Aminoglycosides include, but are not limited to, Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin ( Tobramycin), Paromomycin, and Spectinomycin. Aminoglycosides are effective against, for example, Gram-negative bacteria (such as Escherichia coli, Klebsiella, Pseudomonas aeruginosa and Francisella tularensis ) and against certain Aerobic bacteria, but less effective against obligate/facultative anaerobes. Aminoglycosides are believed to bind to bacterial 30S or 50S ribosomal subunits, thereby inhibiting bacterial protein synthesis.

安莎黴素包括但不限於格爾德黴素（Geldanamycin）、除莠黴素（Herbimycin）、利福黴素（Rifamycin）及曲張鏈菌素（Streptovaricin）。據信，格爾德黴素及除莠黴素抑制或改變熱休克蛋白90的功能。Ansamycins include, but are not limited to, Geldanamycin, Herbimycin, Rifamycin, and Streptovaricin. Geldanamycin and herbimycin are believed to inhibit or alter heat shock protein 90 function.

碳頭孢烯包括但不限於氯碳頭孢（Loracarbef）。據信，碳頭孢烯抑制細菌細胞壁合成。Carbacephems include, but are not limited to, Loracarbef. Carbacephems are believed to inhibit bacterial cell wall synthesis.

碳青黴烯包括但不限於厄他培南（Ertapenem）、多尼培南（Doripenem）、亞胺培南（Imipenem）/西司他丁（Cilastatin）及美羅培南（Meropenem）。碳青黴烯作為寬譜抗生素對革蘭氏陽性細菌及革蘭氏陰性細菌均具有殺細菌性。據信，碳青黴烯抑制細菌細胞壁合成。Carbapenems include, but are not limited to, Ertapenem, Doripenem, Imipenem/Cilastatin, and Meropenem. Carbapenems are broad-spectrum antibiotics that are bactericidal against both Gram-positive and Gram-negative bacteria. Carbapenems are believed to inhibit bacterial cell wall synthesis.

頭孢菌素包括但不限於頭孢羥胺苄（Cefadroxil）、頭孢唑啉（Cefazolin）、頭孢噻吩（Cefalotin）、頭孢金素（Cefalothin）、頭孢胺苄（Cefalexin）、頭孢克洛（Cefaclor）、頭孢孟多（Cefamandole）、頭孢西丁（Cefoxitin）、頭孢丙烯（Cefprozil）、頭孢呋辛（Cefuroxime）、頭孢克肟（Cefixime）、頭孢地尼（Cefdinir）、頭孢托侖（Cefditoren）、頭孢哌酮（Cefoperazone）、頭孢噻肟（Cefotaxime）、頭孢泊肟（Cefpodoxime）、頭孢他啶（Ceftazidime）、頭孢布烯（Ceftibuten）、頭孢唑肟（Ceftizoxime）、頭孢曲松（Ceftriaxone）、頭孢吡肟（Cefepime）、頭孢他洛林酯（Ceftaroline fosamil）及頭孢比普（Ceftobiprole）。所選頭孢菌素可效抵抗（例如）革蘭氏陰性細菌及革蘭氏陽性細菌（包含假單胞菌（ Pseudomonas）），某些頭孢菌素可有效抵抗甲氧西林（methicillin）抗性金黃色葡萄球菌（ Staphylococcus aureus）（MRSA）。據信，頭孢菌素藉由破壞細菌細胞壁的肽聚糖層的合成來抑制細菌細胞壁合成。 Cephalosporins include, but are not limited to, Cefadroxil, Cefazolin, Cefalotin, Cefalothin, Cefalexin, Cefaclor, Cefamangan Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone ( Cefoperazone), Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil and Ceftobiprole. Selected cephalosporins are effective against, for example, Gram-negative bacteria as well as Gram-positive bacteria (including Pseudomonas ), some cephalosporins are effective against methicillin-resistant gold Staphylococcus aureus (MRSA). Cephalosporins are believed to inhibit bacterial cell wall synthesis by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall.

糖肽包括但不限於替考拉寧（Teicoplanin）、萬古黴素（Vancomycin）及特拉萬星（Telavancin）。糖肽可有效抵抗（例如）好氧及厭氧革蘭氏陽性細菌（包含MRSA及艱難梭菌（ Clostridium difficile））。據信，糖肽藉由破壞細菌細胞壁的肽聚糖層的合成來抑制細菌細胞壁合成。 Glycopeptides include, but are not limited to, Teicoplanin, Vancomycin, and Telavancin. Glycopeptides are effective against, for example, aerobic and anaerobic Gram-positive bacteria including MRSA and Clostridium difficile . Glycopeptides are believed to inhibit bacterial cell wall synthesis by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall.

林可醯胺包括但不限於克林達黴素（Clindamycin）及林可黴素（Lincomycin）。林可醯胺可有效抵抗（例如）厭氧細菌以及葡萄球菌屬（ Staphylococcus）及鏈球菌屬（ Streptococcus）。據信，林可醯胺結合至細菌50S核糖體亞基，由此抑制細菌蛋白合成。 Lincosamides include, but are not limited to, Clindamycin and Lincomycin. Lincosamide is effective against, for example, anaerobic bacteria as well as Staphylococcus and Streptococcus species. It is believed that lincosamide binds to the bacterial 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

脂肽包括但不限於達托黴素。脂肽可有效抵抗（例如）革蘭氏陽性細菌。據信，脂肽結合至細菌膜並引起快速去極化。Lipopeptides include, but are not limited to, daptomycin. Lipopeptides are effective against, for example, Gram-positive bacteria. It is believed that lipopeptides bind to bacterial membranes and cause rapid depolarization.

巨環內酯包括但不限於阿奇黴素（Azithromycin）、克拉黴素（Clarithromycin）、地紅黴素（Dirithromycin）、紅黴素（Erythromycin）、羅紅黴素（Roxithromycin）、醋竹桃黴素（Troleandomycin）、泰利黴素（Telithromycin）及螺旋黴素（Spiramycin）。巨環內酯可有效抵抗例如鏈球菌屬及支原體屬（ Mycoplasma）。據信，巨環內酯結合至細菌或50S核糖體亞基，由此抑制細菌蛋白合成。 Macrolides include but are not limited to Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin ), Telithromycin and Spiramycin. Macrolides are effective against eg Streptococcus and Mycoplasma . It is believed that macrolides bind to the bacterial or 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

單醯胺菌素包括但不限於胺曲南（Aztreonam）。單醯胺菌素可有效抵抗例如革蘭氏陰性細菌。據信，單醯胺菌素藉由破壞細菌細胞壁的肽聚糖層的合成來抑制細菌細胞壁合成。Monoamidocins include, but are not limited to, Aztreonam. Amamicin is effective against, for example, Gram-negative bacteria. Amamidocin is believed to inhibit bacterial cell wall synthesis by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall.

硝基呋喃包括但不限於呋喃唑酮（Furazolidone）及呋喃妥因（Nitrofurantoin）。Nitrofurans include, but are not limited to, Furazolidone and Nitrofurantoin.

㗁唑烷酮包括但不限於利奈唑胺（Linezolid）、潑斯唑來（Posizolid）、雷得唑來（Radezolid）及特地唑胺（Torezolid）。據信，㗁唑烷酮係蛋白質合成抑制劑。Ozolidinones include, but are not limited to, Linezolid, Posizolid, Radezolid, and Torezolid. Zazolidinones are believed to be inhibitors of protein synthesis.

青黴素包括但不限於阿莫西林（Amoxicillin）、安比西林（Ampicillin）、阿洛西林（Azlocillin）、羧苄青黴素（Carbenicillin）、氯噻青黴素（Cloxacillin）、二氯噻青黴素（Dicloxacillin）、氟氯西林（Flucloxacillin）、美洛西林（Mezlocillin）、甲氧西林、萘夫西林（Nafcillin）、苯唑西林（Oxacillin）、青黴素G、青黴素V、哌拉西林（Piperacillin）、替莫西林（Temocillin）及替凱西林（Ticarcillin）。青黴素可有效抵抗例如革蘭氏陽性細菌、兼性厭氧菌（例如鏈球菌屬、包柔氏螺旋體屬（ Borrelia）及密螺旋體屬（ Treponema））。據信，青黴素藉由破壞細菌細胞壁的肽聚糖層的合成來抑制細菌細胞壁合成。 Penicillins include, but are not limited to, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin (Flucloxacillin), Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin and Temocillin Ticarcillin. Penicillin is effective against, for example, Gram-positive bacteria, facultative anaerobes (eg Streptococcus, Borrelia and Treponema ). Penicillin is believed to inhibit bacterial cell wall synthesis by disrupting the synthesis of the peptidoglycan layer of the bacterial cell wall.

青黴素組合包括但不限於阿莫西林/克拉維酸鹽（clavulanate）、安比西林/舒巴坦（sulbactam）、哌拉西林/三唑巴坦（tazobactam）及替凱西林/克拉維酸鹽。Penicillin combinations include, but are not limited to, amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, and tikacillin/clavulanate.

多肽抗生素包括但不限於桿菌肽（Bacitracin）、黏菌素（Colistin）及多黏菌素（Polymyxin）B及E。多肽抗生素可有效抵抗例如革蘭氏陰性細菌。據信，某些多肽抗生素抑制涉及細菌細胞壁的肽聚糖層的合成的焦磷酸異戊二烯基酯，而其他多肽抗生素藉由置換細菌相對離子來去穩定細菌外膜。Polypeptide antibiotics include, but are not limited to, Bacitracin, Colistin, and Polymyxin B and E. Polypeptide antibiotics are effective against, for example, Gram-negative bacteria. It is believed that some polypeptide antibiotics inhibit the synthesis of prenyl pyrophosphate involved in the peptidoglycan layer of the bacterial cell wall, while others destabilize the bacterial outer membrane by displacing bacterial counter ions.

喹諾酮及氟喹諾酮包括但不限於環丙沙星（Ciprofloxacin）、依諾沙星（Enoxacin）、加替沙星（Gatifloxacin）、吉米沙星（Gemifloxacin）、左氧氟沙星（Levofloxacin）、洛美沙星（Lomefloxacin）、莫西沙星（Moxifloxacin）、萘啶酮酸（Nalidixic acid）、諾氟沙星（Norfloxacin）、氧氟沙星（Ofloxacin）、曲伐沙星（Trovafloxacin）、格帕沙星（Grepafloxacin）、司帕沙星（Sparfloxacin）及替馬沙星（Temafloxacin）。喹諾酮/氟喹諾酮可有效抵抗（例如）鏈球菌及奈瑟菌（ Neisseria）。據信，喹諾酮/氟喹諾酮抑制細菌DNA旋轉酶或拓撲異構酶IV，由此抑制DNA複製及轉錄。 Quinolones and fluoroquinolones include but are not limited to Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin , Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Division Pafloxacin (Sparfloxacin) and Temafloxacin (Temafloxacin). Quinolones/fluoroquinolones are effective against eg Streptococcus and Neisseria . It is believed that quinolones/fluoroquinolones inhibit bacterial DNA gyrase or topoisomerase IV, thereby inhibiting DNA replication and transcription.

磺醯胺包括但不限於磺胺米隆（Mafenide）、磺胺醋醯（Sulfacetamide）、磺胺嘧啶（Sulfadiazine）、磺胺嘧啶銀、磺胺地索辛（Sulfadimethoxine）、磺胺甲噻二唑（Sulfamethizole）、磺胺甲㗁唑（Sulfamethoxazole）、磺胺亞胺基（Sulfanilimide）、柳氮磺胺吡啶（Sulfasalazine）、磺胺異㗁唑（Sulfisoxazole）、甲氧苄啶-磺胺甲㗁唑（Trimethoprim-Sulfamethoxazole）（複方磺胺甲㗁唑（Co-trimoxazole））及磺醯胺基柯衣汀（Sulfonamidochrysoidine）。據信，磺醯胺藉由競爭性抑制二氫蝶酸合成酶來抑制葉酸合成，由此抑制核酸合成。Sulfonamides include but are not limited to Mafenide, Sulfacetamide, Sulfadiazine, Silver Sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethizole Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (Compound Sulfamethoxazole (Co-trimoxazole)) and Sulfonamidochrysoidine. It is believed that sulfonamides inhibit folic acid synthesis by competitively inhibiting dihydropteroate synthase, thereby inhibiting nucleic acid synthesis.

四環素類包括但不限於地美環素（Demeclocycline）、強力黴素（Doxycycline）、米諾環素（Minocycline）、土黴素（Oxytetracycline）及四環素。四環素可有效抵抗例如革蘭氏陰性細菌。據信，四環素結合至細菌30S核糖體亞基，由此抑制細菌蛋白合成。Tetracyclines include, but are not limited to, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, and Tetracycline. Tetracyclines are effective against, for example, Gram-negative bacteria. Tetracycline is believed to bind to the bacterial 30S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

抗分枝桿菌化合物包括但不限於氯法齊明（Clofazimine）、胺苯碸（Dapsone）、卷麯黴素（Capreomycin）、環絲胺酸（Cycloserine）、乙胺丁醇（Ethambutol）、乙硫異菸醯胺（Ethionamide）、異菸酸肼（Isoniazid）、吡𠯤醯胺（Pyrazinamide）、利福平（Rifampicin）、利福布汀（Rifabutin）、利福噴丁（Rifapentine）及鏈黴素（Streptomycin）。Antimycobacterial compounds include, but are not limited to, Clofazimine, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethione Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Rifapentine, and Streptomycin ( Streptomycin).

合適的抗生素還包含胂凡納明（arsphenamine）、氯黴素（chloramphenicol）、磷黴素（fosfomycin）、夫西地酸（fusidic acid）、甲硝唑（metronidazole）、莫匹羅星（mupirocin）、平板黴素（platensimycin）、奎奴普汀（quinupristin）/達福普汀（dalfopristin）、替吉環素（tigecycline）、替硝唑（tinidazole）、甲氧苄啶-阿莫西林（trimethoprim amoxicillin）/克拉維酸鹽、安比西林/舒巴坦、安福黴素-利托菌素（amphomycin ristocetin）、阿奇黴素、桿菌肽、卜福林（buforin）II、卡波黴素（carbomycin）、殺菌肽（cecropin）Pl、克拉黴素、紅黴素、呋喃唑酮、夫西地酸、夫西地鈉、短桿菌素（gramicidin）、亞胺培南、吲哚菌素（indolicidin）、交沙黴素（josamycin）、馬蓋納尼（magainan）II、甲硝唑（metronidazole）、硝基咪唑、米卡黴素（mikamycin）、變鏈素（mutacin）B-Ny266、變鏈素B-JHl 140、變鏈素J-T8、乳鏈球菌素（nisin）、乳鏈球菌素A、新生黴素（novobiocin）、竹桃黴素（oleandomycin）、奧斯立星（ostreogrycin）、哌拉西林/三唑巴坦、普那黴素（pristinamycin）、雷莫拉寧（ramoplanin）、牛蛙皮膚抗菌肽（ranalexin）、羅伊氏素（reuterin）、利福昔明（rifaximin）、薔薇黴素（rosamicin）、羅沙米星（rosaramicin）、大觀黴素、螺旋黴素、葡萄黴素（staphylomycin）、鏈黴殺陽素（streptogramin）、鏈黴殺陽素A、協同菌素（synergistin）、牛磺羅定（taurolidine）、替考拉寧、泰利黴素、替凱西林/克拉維酸（clavulanic acid）、三乙醯基竹桃黴素（triacetyloleandomycin）、泰洛星（tylosin）、短桿菌酪肽（tyrocidin）、短桿菌素（tyrothricin）、萬古黴素、維馬黴素（vemamycin）及維吉黴素（virginiamycin）。Suitable antibiotics also include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin , platensimycin, quinupristin/dalfopristin, tigecycline, tinidazole, trimethoprim amoxicillin )/clavulanate, ampicillin/sulbactam, amphomycin ristocetin, azithromycin, bacitracin, buforin II, carbomycin, cecropin ) Pl, clarithromycin, erythromycin, furazolidone, fusidic acid, fusidic sodium, gramicidin, imipenem, indocidin, josamycin , magainan II, metronidazole, nitroimidazole, mikamycin, mutacin B-Ny266, mutacin B-JHl 140, mutacin J-T8, nisin, nisin A, novobiocin, oleandomycin, ostreogrycin, piperacillin/tazobactam, pristinamycin, ramoplanin, ranalexin, reuterin, rifaximin, rosamicin, rosamicin Rosaramicin, spectinomycin, spiramycin, staphylomycin, streptogramin, streptavidin A, synergistin, taurolidine , teicoplanin, telithromycin, tikacillin/clavulanic acid, triacetyloleandomycin, tylosin, tyrocidin, short Tyrothricin, vancomycin, vemamycin, and virginiamycin.

在一些實施方式中，另外的治療劑係免疫抑制劑、DMARD、止痛藥、類固醇、非類固醇抗炎藥（NSAID）或細胞介素拮抗劑，及其組合。代表性藥劑包括但不限於環孢素、類視黃醇、皮質類固醇、丙酸衍生物、乙酸衍生物、烯醇酸衍生物、芬那酸衍生物、Cox-2抑制劑、魯美昔布（lumiracoxib）、伊布洛芬（ibuprophen）、水楊酸膽鹼鎂（cholin magnesium salicylate）、非諾洛芬（fenoprofen）、雙水楊酯（salsalate）、二氟苯水楊酸（difunisal）、托美汀（tolmetin）、酮洛芬（ketoprofen）、氟比洛芬（flurbiprofen）、奧沙普秦（oxaprozin）、吲哚美辛（indomethacin）、舒林酸（sulindac）、依託度酸（etodolac）、酮咯酸（ketorolac）、萘丁美酮（nabumetone）、萘普生（naproxen）、伐地考昔（valdecoxib）、依託考昔（etoricoxib）、MK0966；羅非昔布（rofecoxib）、對乙醯胺基酚（acetominophen）、塞來昔布（Celecoxib）、雙氯芬酸（Diclofenac）、曲馬多（tramadol）、吡羅昔康（piroxicam）、美洛昔康（meloxicam）、替諾昔康（tenoxicam）、屈昔康（droxicam）、氯諾昔康（lornoxicam）、伊索昔康（isoxicam）、甲芬那酸（mefanamic acid）、甲氯芬那酸（meclofenamic acid）、氟芬那酸（flufenamic acid）、托芬那酸（tolfenamic）、伐地考昔（valdecoxib）、帕瑞昔布（parecoxib）、依託度酸（etodolac）、吲哚美辛（indomethacin）、阿司匹林（aspirin）、伊布洛芬（ibuprophen）、非羅考昔（firocoxib）、胺甲喋呤（methotrexate（MTX））、抗瘧疾藥物（例如，羥基氯喹（hydroxychloroquine）及氯喹（chloroquine））、柳氮磺胺吡啶（sulfasalazine）、來氟米特（Leflunomide）、硫唑嘌呤（azathioprine）、環孢素（cyclosporin）、金鹽（gold salt）、米諾環素（minocycline）、環磷醯胺（cyclophosphamide）、D-青黴胺（D-penicillamine）、米諾環素（minocycline）、金諾芬（auranofin）、他克莫司（tacrolimus）、硫代苯酸金鈉（myocrisin）、苯丁酸氮芥（chlorambucil）、TNF α拮抗劑（例如，TNF α拮抗劑或TNF α受體拮抗劑），例如，阿達木單抗（Humira®）、依那西普（Enbrel®）、英夫利昔單抗（Remicade®；TA-650）、聚乙二醇賽妥珠單抗（Cimzia®；CDP870）、戈利木單抗（Simpom®；CNTO 148）、阿那白滯素（Kineret®）、利妥昔單抗（Rituxan®；MabThera®）、阿巴西普（Orencia®）、托珠單抗（RoActemra /Actemra®）、整合素拮抗劑（TYSABRI®（那他珠單抗））、IL-1拮抗劑（ACZ885（Ilaris））、阿那白滯素（Kineret®））、CD4拮抗劑、IL-23拮抗劑、IL-20拮抗劑、IL-6拮抗劑、BLyS拮抗劑（例如，阿塞西普、Benlysta®/ LymphoStat-B®（貝利木單抗））、p38抑制劑、CD20拮抗劑（奧瑞珠單抗（Ocrelizumab）、奧法木單抗（Arzerra®））、干擾素γ拮抗劑（芳妥珠單抗（Fontolizumab））、潑尼松龍（prednisolone）、強的松（Prednisone）、地塞米松（dexamethasone）、皮質醇（Cortisol）、可的松（cortisone）、氫化可的松（hydrocortisone）、甲基潑尼松龍（methylprednisolone）、倍他米松（betamethasone）、曲安奈德（triamcinolone）、倍氯米松（beclometasome）、氟氫可的松（fludrocortisone）、去氧皮質酮（deoxycorticosterone）、醛固酮（aldosterone）、強力黴素（Doxycycline）、萬古黴素（vancomycin）、吡格列酮（pioglitazone）、SBI-087、SCIO-469、Cura-100、Oncoxin + Viusid、TwHF、甲氧沙林（Methoxsalen）、維生素D-麥角鈣化醇（Vitamin D - ergocalciferol）、米那普侖（Milnacipran）、紫杉醇（Paclitaxel）、羅西格塔松（rosig tazone）、他克莫司（Tacrolimus）（Prograf®）、RADOOl、拉帕蒙（rapamune）、雷帕黴素（rapamycin）、福斯馬替尼（fostamatinib）、芬太尼（Fentanyl）、XOMA 052、福斯馬替尼二鈉（Fostamatinib disodium）、羅格列酮（rosightazone）、薑黃素（Curcumin）（Longvida™）、瑞舒伐他汀（Rosuvastatin）、馬拉韋羅（Maraviroc）、雷米普利（ramipnl）、米那普侖（Milnacipran）、考前列酮（Cobiprostone）、生長激素（somatropin）、tgAAC94基因治療媒劑、MK0359、GW856553、埃索美拉唑（esomeprazole）、依維莫司（everolimus）、曲妥珠單抗（trastuzumab）、JAKl及JAK2抑制劑、泛JAK抑制劑，例如，四環吡啶酮6（P6）、325、PF-956980、狄諾塞麥（denosumab）、IL-6拮抗劑、CD20拮抗劑、CTLA4拮抗劑、IL-8拮抗劑、IL-21拮抗劑、IL-22拮抗劑、整合素拮抗劑（Tysarbri®（那他珠單抗））、VGEF拮抗劑、CXCL拮抗劑、MMP拮抗劑、防禦素拮抗劑、IL-1拮抗劑（包括IL-1 β拮抗劑），及IL-23拮抗劑（例如，受體誘捕物、拮抗性抗體等）。In some embodiments, the additional therapeutic agent is an immunosuppressant, a DMARD, an analgesic, a steroid, a non-steroidal anti-inflammatory drug (NSAID), or a cytokine antagonist, and combinations thereof. Representative agents include, but are not limited to, cyclosporine, retinoids, corticosteroids, propionic acid derivatives, acetic acid derivatives, enolic acid derivatives, fenamic acid derivatives, Cox-2 inhibitors, lumiracoxib (lumiracoxib), ibuprofen, cholin magnesium salicylate, fenoprofen, salsalate, difunisal, tolmetin, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac ), ketorolac, nabumetone, naproxen, valdecoxib, etoricoxib, MK0966; rofecoxib, acetamide acetominophen, celecoxib, diclofenac, tramadol, piroxicam, meloxicam, tenoxicam, dreroxicam droxicam, lornoxicam, isoxicam, mefanamic acid, meclofenamic acid, flufenamic acid, Tolfenamic, valdecoxib, parecoxib, etodolac, indomethacin, aspirin, ibuprophen, non Firocoxib, methotrexate (MTX), antimalarials (eg, hydroxychloroquine and chloroquine), sulfasalazine, leflunomide ), azathioprine, cyclosporin, gold salt, minocycline, cyclophosphamide, D-penicillamine, rice Nocycline (minoc ycline), auranofin, tacrolimus, myocrisin, chlorambucil, TNF alpha antagonists (eg, TNF alpha antagonist or TNF alpha antagonists), eg, adalimumab (Humira®), etanercept (Enbrel®), infliximab (Remicade®; TA-650), pegylated certolizumab (Cimzia®; CDP870), golimumab (Simpom®; CNTO 148), anakinra (Kineret®), rituximab (Rituxan®; MabThera®), abatacept (Orencia®) , tocilizumab (RoActemra /Actemra®), integrin antagonist (TYSABRI® (natalizumab)), IL-1 antagonist (ACZ885 (Ilaris)), anakinra (Kineret®)) , CD4 antagonists, IL-23 antagonists, IL-20 antagonists, IL-6 antagonists, BLyS antagonists (eg, Acecept, Benlysta®/LymphoStat-B® (belimumab)), p38 inhibitors, CD20 antagonists (Ocrelizumab, Arzerra®), interferon gamma antagonists (Fontolizumab), prednisolone ), prednisone, dexamethasone, cortisol, cortisone, hydrocortisone, methylprednisolone, betamethasone (betamethasone), triamcinolone, beclometasone, fludrocortisone, deoxycorticosterone, aldosterone, doxycycline, vancomycin (vancomycin), pioglitazone, SBI-087, SCIO-469, Cura-100, Oncoxin + Viusid, TwHF, Methoxsalen, Vitamin D-ergocalciferol, rice Nacipran (Milnacipran), paclitaxel (Paclitaxel), rosig tazone (rosig tazone) , Tacrolimus (Prograf®), RADOOl, rapamune, rapamycin, fostamatinib, Fentanyl, XOMA 052, FOSS Fostamatinib disodium, rosiglitazone (rosightazone), curcumin (Longvida™), rosuvastatin, maraviroc, ramipril (ramipnl) , Milnacipran, Cobiprostone, Somatropin, tgAAC94 gene therapy vehicle, MK0359, GW856553, esomeprazole, everolimus, Trastuzumab, JAK1 and JAK2 inhibitors, pan-JAK inhibitors, eg, tetracyclopyridone 6 (P6), 325, PF-956980, denosumab, IL-6 antagonists , CD20 antagonist, CTLA4 antagonist, IL-8 antagonist, IL-21 antagonist, IL-22 antagonist, integrin antagonist (Tysarbri® (natalizumab)), VGEF antagonist, CXCL antagonist , MMP antagonists, defensin antagonists, IL-1 antagonists (including IL-1β antagonists), and IL-23 antagonists (eg, receptor decoys, antagonistic antibodies, etc.).

在一些實施方式中，另外的療法可以包括JAK抑制劑，例如巴瑞替尼、盧梭替尼、托法替尼和/或帕利替尼。In some embodiments, the additional therapy may include a JAK inhibitor, such as baricitinib, ruxolitinib, tofacitinib, and/or palitinib.

在一些實施方式中，另外的治療劑係免疫抑制劑。免疫抑制劑的實例包括但不限於皮質類固醇激素、美沙拉𠯤（mesalazine）、美沙拉明（mesalamine）、柳氮磺胺吡啶（sulfasalazine）、柳氮磺胺吡啶衍生物、免疫抑制藥物、環孢素A、巰基嘌呤、硫唑嘌呤（azathiopurine）、強的松、胺甲喋呤、抗組胺藥、糖皮質激素、腎上腺素、茶鹼、色甘酸鈉、抗白三烯、用於鼻炎的抗膽鹼能藥物、TLR拮抗劑、發炎體抑制劑、抗膽鹼能解充血劑、肥大細胞穩定劑、單株抗IgE抗體、疫苗（例如，用於其中使過敏原的量逐漸增加的接種疫苗的疫苗）、細胞介素抑制劑（如抗IL-6抗體）、TNF抑制劑（如英夫利昔單抗、阿達木單抗、聚乙二醇賽妥珠單抗、戈利木單抗或依那西普及其組合）。In some embodiments, the additional therapeutic agent is an immunosuppressant. Examples of immunosuppressants include, but are not limited to, corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives, immunosuppressive drugs, cyclosporine A , mercaptopurine, azathiopurine, prednisone, methotrexate, antihistamines, corticosteroids, epinephrine, theophylline, cromolyn sodium, antileukotrienes, anticholesterol for rhinitis Alkalinergics, TLR antagonists, inflammasome inhibitors, anticholinergic decongestants, mast cell stabilizers, monoclonal anti-IgE antibodies, vaccines (eg, for vaccinations in which the amount of allergen is gradually increased vaccine), interleukin inhibitors (such as anti-IL-6 antibody), TNF inhibitors (such as infliximab, adalimumab, pegylated certolizumab, golimumab or Nacept and its combinations).

在一些實施方式中，另外的治療劑係RNA分子，例如雙股RNA。In some embodiments, the additional therapeutic agent is an RNA molecule, such as double-stranded RNA.

在一些實施方式中，另外的治療劑係反義寡核苷酸。 施用 In some embodiments, the additional therapeutic agent is an antisense oligonucleotide. apply

在某些方面中，本文提供向受試者遞送本文描述的固體劑型之方法。在本文提供之方法的一些實施方式中，包含細菌和/或mEV的固體劑型與另外的治療劑的施用一起施用。在一些實施方式中，固體劑型包含與另外的治療劑共同配製的藥劑。在一些實施方式中，固體劑型與另外的治療劑共同施用。在一些實施方式中，在施用固體劑型之前（例如之前約1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50或55分鐘，之前約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23小時，或之前約1、2、3、4、5、6、7、8、9、10、11、12、13或14天），向受試者施用另外的治療劑。在一些實施方式中，在施用固體劑型之後（例如之後約1、2、3、4、5、6、7、8、9、10、15、20、25、30、35、40、45、50或55分鐘，之後約1、2、3、4、5、6、7、8、9、10、11、12、13、14、15、16、17、18、19、20、21、22或23小時，或之後約1、2、3、4、5、6、7、8、9、10、11、12、13或14天），向受試者施用另外的治療劑。在一些實施方式中，使用相同遞送模式來遞送固體劑型及另外的治療劑。在一些實施方式中，使用不同遞送模式來施用固體劑型及另外的治療劑。例如，在一些實施方式中，經口施用固體劑型，而經由注射（例如靜脈內、肌內和/或腫瘤內注射）施用另外的治療劑。In certain aspects, provided herein are methods of delivering a solid dosage form described herein to a subject. In some embodiments of the methods provided herein, a solid dosage form comprising bacteria and/or mEV is administered with the administration of an additional therapeutic agent. In some embodiments, solid dosage forms comprise pharmaceutical agents co-formulated with additional therapeutic agents. In some embodiments, solid dosage forms are co-administered with additional therapeutic agents. In some embodiments, the solid dosage form is administered prior to (eg, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes prior to approximately 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days prior), the additional therapeutic agent is administered to the subject. In some embodiments, after (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes, then about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22 or 23 hours, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days thereafter), the additional therapeutic agent is administered to the subject. In some embodiments, the solid dosage form and the additional therapeutic agent are delivered using the same mode of delivery. In some embodiments, the solid dosage form and the additional therapeutic agent are administered using different modes of delivery. For example, in some embodiments, the solid dosage form is administered orally, while the additional therapeutic agent is administered via injection (eg, intravenous, intramuscular, and/or intratumoral injection).

在某些實施方式中，本文所述之固體劑型可與任一其他常規抗癌治療（例如諸如放射療法及腫瘤手術切除術）聯合施用。該等治療可在需要和/或指示時應用且可發生於施用本文所述之固體劑型之前、同時或之後。In certain embodiments, the solid dosage forms described herein may be administered in conjunction with any other conventional anti-cancer treatments such as, for example, radiation therapy and surgical tumor resection. Such treatments may be applied as needed and/or indicated and may occur prior to, concurrently with, or after administration of the solid dosage forms described herein.

劑量方案可為各種方法及量中的任一者，且可由熟悉該項技術者根據已知臨床因素來確定。如醫學領域中已知，任一患者的劑量可取決於許多因素，包括受試者物種、大小、體表面積、年齡、性別、免疫能力及總體健康狀況、有待施用的特定微生物、持續時間及施用途徑、疾病種類及階段（例如腫瘤大小）及其他化合物（例如同時或近乎同時施用的藥物）。除上述因素外，該等水平可受微生物感染性及微生物性質影響，如可由熟悉該項技術者所確定。在本發明之方法中，微生物的適當最小劑量水平可為足夠使微生物存活、生長及複製的水平。可根據劑型、施用途徑、靶疾病的程度或階段等來適當地設定或調節本文描述的藥劑（例如呈固體劑型）的劑量。例如，藥劑的一般有效劑量範圍可為0.01 mg/kg體重/天至1000 mg/kg體重/天、0.1 mg/kg體重/天至1000 mg/kg體重/天、0.5 mg/kg體重/天至500 mg/kg體重/天、1 mg/kg體重/天至100 mg/kg體重/天或5 mg/kg體重/天至50 mg/kg體重/天。有效劑量可為0.01、0.05、0.1、0.5、1、2、3、5、10、20、30、40、50、60、70、80、90、100、200、500或1000 mg/kg體重/天或更高，但劑量並不限於此。 Dosage regimens can be any of a variety of methods and amounts, and can be determined by those skilled in the art based on known clinical factors. As is known in the medical arts, the dosage for any one patient may depend on many factors including the subject species, size, body surface area, age, sex, immunocompetence and general health, the particular microorganism to be administered, duration and administration Pathway, disease type and stage (such as tumor size), and other compounds (such as drugs administered at or near the same time). In addition to the above factors, such levels can be influenced by the infectivity and nature of the microorganism, as can be determined by one skilled in the art. In the methods of the invention, an appropriate minimum dosage level of the microorganism may be a level sufficient to allow the microorganism to survive, grow and replicate. Doses of agents described herein (for example, in solid dosage forms) can be appropriately set or adjusted depending on the dosage form, administration route, degree or stage of the target disease, and the like. For example, the general effective dosage range of medicament can be 0.01 mg/kg body weight/day to 1000 mg/kg body weight/day, 0.1 mg/kg body weight/day to 1000 mg/kg body weight/day, 0.5 mg/kg body weight/day to 500 mg/kg body weight/day, 1 mg/kg body weight/day to 100 mg/kg body weight/day, or 5 mg/kg body weight/day to 50 mg/kg body weight/day. Effective doses may be 0.01, 0.05, 0.1, 0.5, 1, 2, 3, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 200, 500 or 1000 mg/kg body weight/ days or higher, but the dosage is not limited thereto.

在一些實施方式中，向受試者施用的劑量足以預防疾病（例如，自體免疫性疾病、炎性疾病、代謝性疾病、生態失調或癌症）、延遲其發作或減緩或停止其進展，或減輕疾病的一個或多個症狀。熟悉該項技術者將認識到，劑量將取決於多種因素，包括所採用特定試劑（例如藥劑）的強度以及受試者的年齡、物種、病症及體重。還根據以下因素來確定劑量大小：施用途徑、時機及頻率以及可伴隨特定藥劑的施用的任何不良副作用的存在、性質及程度及期望的生理學效果。In some embodiments, the dose administered to the subject is sufficient to prevent the disease (e.g., autoimmune disease, inflammatory disease, metabolic disease, dysbiosis, or cancer), delay its onset, or slow or stop its progression, or Relief of one or more symptoms of a disease. Those skilled in the art will recognize that dosage will depend on a variety of factors, including the strength of the particular agent (eg, agent) employed and the age, species, condition and weight of the subject. The size of the dose will also be determined by the route, timing, and frequency of administration, as well as the existence, nature, and extent of any adverse side effects that may accompany the administration of the particular agent and the desired physiological effect.

可藉由熟悉該項技術者已知的常規範圍探測技術來確定合適的劑量及劑量方案。通常，以不超過化合物最佳劑量的較小劑量開始治療。然後，以小增量增加劑量直至達到該狀況下的最佳效果為止。有效劑量及治療方案可藉由常規及常規方式來確定，例如，其中在實驗室動物中以低劑量開始且然後增加劑量，同時監測效果，且還系統地改變劑量方案。通常使用動物研究來測定每公斤重量的生物活性藥劑的最大可耐受劑量（「MTD」）。本領域技術人類員通常在其他物種（包含人類）中外推劑量以達到功效，同時避免毒性。Appropriate dosages and dosage regimens can be determined by conventional range-finding techniques known to those skilled in the art. Generally, treatment is initiated with smaller dosages not exceeding the optimum dose of the compound. Then, the dosage is increased in small increments until the optimum effect under the circumstances is reached. Effective doses and treatment regimens can be determined by conventional and conventional means, for example, by starting with low doses in laboratory animals and then increasing the dose while monitoring the effect, and also changing the dosage regimen systematically. Animal studies are commonly used to determine the maximum tolerable dose ("MTD") per kilogram weight of a biologically active agent. Those skilled in the art will typically extrapolate dosages in other species, including humans, to achieve efficacy while avoiding toxicity.

根據上文，在治療應用中，根據本文所述方法使用的藥劑的劑量取決於以下因素有所變化：活性劑，接受患者的年齡、體重及臨床狀況及施用療法的臨床醫師或從業人員的經歷及判斷，以及影響所選劑量的其他因素。例如，對於癌症治療，劑量應足以導致減緩腫瘤的生長，較佳的是使腫瘤的生長消退，並且最較佳的是使癌症完全消退，或者轉移的大小或數目減小。作為另一個實例，劑量應足以導致減緩受試者正在治療的疾病的進展，較佳的是改善受試者正在治療的疾病的一個或多個症狀。In light of the above, in therapeutic applications, dosages of agents used in accordance with the methods described herein will vary depending on the active agent, the age, weight, and clinical condition of the receiving patient, and the experience of the clinician or practitioner administering the therapy. and judgment, as well as other factors affecting the selected dose. For example, for cancer treatment, the dosage should be sufficient to result in slowing of tumor growth, preferably regression of tumor growth, and most preferably complete regression of the cancer, or a reduction in the size or number of metastases. As another example, the dosage should be sufficient to result in slowing of the progression of, and preferably amelioration of, one or more symptoms of the disease being treated in the subject.

分開施用可包括任何數量的兩次或更多次施用，包括二、三、四、五或六次施用。熟悉該項技術者可容易地根據本領域中已知的用於監測治療方法之方法及本文提供的其他監測方法確定有待進行的施用次數或進行一次或多次另外的施用的需求性。因此，本文提供之方法包括向受試者提供固體劑型的一次或多次施用之方法，其中可藉由監測受試者且基於監測結果測定是否提供一次或多次另外的施用來確定施用次數。可基於各種監測結果決定是否提供一次或多次另外的施用。Split administration can include any number of two or more administrations, including two, three, four, five or six administrations. One skilled in the art can readily determine the number of administrations to be performed or the desirability of one or more additional administrations according to methods known in the art for monitoring methods of treatment and other monitoring methods provided herein. Accordingly, the methods provided herein include methods of providing one or more administrations of a solid dosage form to a subject, wherein the number of administrations can be determined by monitoring the subject and determining whether one or more additional administrations are provided based on the monitoring results. Whether to provide one or more additional administrations can be decided based on various monitoring results.

施用間的時間段可為各個時間段中的任一者。施用間的時間段可隨各種因素中的任一者而變化，包括監測步驟（如關於施用次數所描述的）、受試者建立免疫應答的時間段。在一個實例中，時間段可隨受試者建立免疫應答的時間段而變化；例如，時間段可大於受試者建立免疫應答的時間段，如大於約一週、大於約十天、大於約兩週或大於約一個月；在另一個實例中，時間段可不超過受試者建立免疫應答的時間段，如不超過約一週、不超過約十天、不超過約兩週或不超過約一個月。The time period between administrations can be any of the various time periods. The period of time between administrations can vary with any of a variety of factors, including monitoring steps (as described for the number of administrations), the period of time over which the subject has established an immune response. In one example, the time period can vary with the time period over which the subject has established an immune response; for example, the time period can be greater than the time period over which the subject has established an immune response, such as greater than about one week, greater than about ten days, greater than about two weeks or greater than about one month; in another example, the period of time can be no more than the time period during which the subject establishes an immune response, such as no more than about one week, no more than about ten days, no more than about two weeks, or no more than about one month .

在一些實施方式中，另外的治療劑與本文描述的固體劑型的組合的遞送減少另外的治療劑的不利影響和/或改善另外的治療劑的功效。In some embodiments, delivery of an additional therapeutic agent in combination with a solid dosage form described herein reduces the adverse effects of the additional therapeutic agent and/or improves the efficacy of the additional therapeutic agent.

本文所述之另外的治療劑的有效劑量係針對特定受試者、組成物及施用模式有效達成所需治療劑反應且對受試者的毒性最小的另外的治療劑的量。可使用本文所述之方法來鑒別有效劑量水平且將取決於多種藥物動力學因素，包含所施用特定組成物或藥劑的活性、施用途徑、施用時間、所採用特定化合物的排泄速率、治療持續時間、與所採用特定組成物組合使用的其他藥物、化合物和/或材料、所治療受試者的年齡、性別、體重、病症、總體健康狀況及先前醫學史以及醫學技術中熟知的類似因素。一般而言，另外的治療劑的有效劑量將是該另外的治療劑的量，其為有效產生治療效應的最低劑量。通常這樣的有效劑量將取決於上文所述之該等因素。An effective dosage of an additional therapeutic agent described herein is the amount of the additional therapeutic agent effective to achieve the desired therapeutic agent response for a particular subject, composition, and mode of administration with minimal toxicity to the subject. Effective dosage levels can be identified using the methods described herein and will depend on a variety of pharmacokinetic factors, including the activity of the particular composition or agent administered, the route of administration, the time of administration, the rate of excretion of the particular compound employed, the duration of treatment , other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, weight, condition, general health and prior medical history of the subject being treated and similar factors well known in the medical art. In general, an effective dose of an additional therapeutic agent will be that amount of the additional therapeutic agent which is the lowest dose effective to produce a therapeutic effect. Generally such an effective dosage will depend upon the factors mentioned above.

另外的治療劑的毒性係受試者在治療期間及治療之後經受的不利效應的程度。與另外的治療毒性相關的不良事件可以包括但不限於腹痛、酸消化不良、酸回流、過敏反應、禿髮、全身性過敏性反應、貧血、焦慮、食欲不振、關節痛、無力、運動失調、氮質血症、失去平衡、骨痛、出血、血凝塊、低血壓、血壓升高、呼吸困難、支氣管炎、淤血、白血球計數降低、紅血球計數降低、血小板計數降低、心臟毒性、膀胱炎、出血性膀胱炎、心律不整、心瓣膜疾病、心肌病、冠狀動脈疾病、白內障、中樞神經毒性、認知障礙、意識模糊、結膜炎、便秘、咳嗽、痙攣、膀胱炎、深層靜脈栓塞、脫水、抑鬱、腹瀉、眩暈（dizziness）、口乾、皮膚乾燥、消化不良、呼吸困難（dyspnea）、水腫、電解質不平衡、食道炎、疲乏、生育力喪失、發燒、腸胃氣脹、面紅、胃逆流、胃食道逆流病、生殖器疼痛、粒細胞減少症、男子女性型乳房、青光眼、脫髮、手足綜合症（hand-foot syndrome）、頭痛、聽覺損失、心臟衰竭、心悸、胃灼熱、血腫、出血性膀胱炎、肝毒性、高澱粉酶血症、高鈣血症、高氯血症、高糖血症、高鉀血症、高脂血症、高鎂血症、高鈉血症、高磷血症、色素沈著、高甘三油酯血症、高尿酸血症、低白蛋白血症、低鈣血症、低氯血症、低血糖症、低鉀血症、低鎂血症、低鈉血症、低磷血症、陽萎、感染、注射部位反應、失眠、缺鐵、瘙癢、關節痛、腎衰竭、白血球減少症、肝功能障礙、失憶、閉經、口瘡、黏膜炎、肌肉痛、肌痛、骨髓抑制、心肌炎、嗜中性白血球減少性發熱、噁心、腎毒性、嗜中性白血球減少症、流鼻血、麻木、耳毒性、疼痛、手足綜合症（palmar-plantar erythrodysesthesia）、各類血細胞減少症、心包炎、周邊神經病變、咽炎、畏光、光敏感、肺炎（pneumonia）、肺炎（pneumonitis）、蛋白尿、肺栓塞、肺性纖維化、肺毒性、皮疹、心跳加快、直腸出血、坐立不安、鼻炎、癲癇、呼吸短促、鼻竇炎、血小板減少症、耳鳴、泌尿道感染、陰道出血、陰道乾燥、眩暈（vertigo）、水瀦留（water retention）、虛弱、體重減輕、體重增加及口腔乾燥（xerostomia）。一般而言，如果經由療法所達到的受試者益處勝過受試者因療法所經歷的不良事件，則毒性係可接受的。 免疫障礙 Toxicity of an additional therapeutic agent is the degree of adverse effects experienced by a subject during and after treatment. Adverse events associated with additional treatment toxicity may include, but are not limited to, abdominal pain, acid dyspepsia, acid reflux, anaphylaxis, alopecia, anaphylaxis, anemia, anxiety, loss of appetite, arthralgia, weakness, ataxia, Azotemia, loss of balance, bone pain, bleeding, blood clots, low blood pressure, increased blood pressure, trouble breathing, bronchitis, congestion, low white blood cell count, low red blood cell count, low platelet count, cardiotoxicity, cystitis, Hemorrhagic cystitis, cardiac arrhythmia, heart valve disease, cardiomyopathy, coronary artery disease, cataract, central nervous system toxicity, cognitive impairment, confusion, conjunctivitis, constipation, cough, cramps, cystitis, deep vein thrombosis, dehydration, depression, Diarrhea, dizziness, dry mouth, dry skin, indigestion, dyspnea, edema, electrolyte imbalance, esophagitis, fatigue, loss of fertility, fever, flatulence, flushing, gastric reflux, gastric Esophageal reflux disease, genital pain, neutropenia, gynecomastia, glaucoma, hair loss, hand-foot syndrome, headache, hearing loss, heart failure, palpitations, heartburn, hematoma, hemorrhagic cystitis , liver toxicity, hyperamylaseemia, hypercalcemia, hyperchloremia, hyperglycemia, hyperkalemia, hyperlipidemia, hypermagnesemia, hypernatremia, hyperphosphatemia, Hyperpigmentation, hypertriglyceridemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypochloremia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia , hypophosphatemia, impotence, infection, injection site reactions, insomnia, iron deficiency, pruritus, arthralgia, renal failure, leukopenia, hepatic dysfunction, amnesia, amenorrhea, aphtha, mucositis, myalgia, myalgia , bone marrow suppression, myocarditis, neutropenic fever, nausea, nephrotoxicity, neutropenia, nosebleeds, numbness, ototoxicity, pain, palmar-plantar erythrodysesthesia, various types of blood cell reduction pericarditis, peripheral neuropathy, pharyngitis, photophobia, light sensitivity, pneumonia, pneumonia, proteinuria, pulmonary embolism, pulmonary fibrosis, pulmonary toxicity, rash, tachycardia, rectal bleeding, restlessness , rhinitis, epilepsy, shortness of breath, sinusitis, thrombocytopenia, tinnitus, urinary tract infection, vaginal bleeding, vaginal dryness, vertigo, water retention, weakness, weight loss, weight gain, and dry mouth ( xerostomia). In general, toxicity is acceptable if the subject's benefit from the therapy outweighs the subject's adverse events experienced as a result of the therapy. immune disorder

在一些實施方式中，本文描述之方法及固體劑型涉及治療或預防與病理學免疫應答相關的疾病或障礙（如自體免疫性疾病、過敏反應和/或炎性疾病）。在一些實施方式中，疾病或障礙係炎性腸病（例如，克羅恩氏病或潰瘍性結腸炎）。在一些實施方式中，疾病或障礙係牛皮癬。在一些實施方式中，疾病或障礙係特應性皮炎。In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of diseases or disorders associated with pathological immune responses (eg, autoimmune diseases, allergic reactions, and/or inflammatory diseases). In some embodiments, the disease or disorder is an inflammatory bowel disease (eg, Crohn's disease or ulcerative colitis). In some embodiments, the disease or disorder is psoriasis. In some embodiments, the disease or disorder is atopic dermatitis.

本文描述之方法和固體劑型可用以治療有需要的任何受試者。如本文所用，「有需要的受試者」包括患有與病理學免疫應答相關的疾病或病症（例如，炎性腸病）的任何受試者，及獲得此疾病或病症的可能性更大的任何受試者。The methods and solid dosage forms described herein can be used to treat any subject in need thereof. As used herein, a "subject in need thereof" includes any subject suffering from a disease or condition (e.g., inflammatory bowel disease) associated with a pathological immune response, and having a greater likelihood of acquiring such a disease or condition any subject.

本文描述的固體劑型可例如用作預防或治療（部分或完全減少以下疾病的不利影響）自體免疫性疾病，如慢性炎性腸病、全身性紅斑狼瘡、牛皮癬、穆-韋二氏綜合症、類風濕性關節炎、多發性硬化或橋本病（Hashimoto's disease）；過敏性疾病，如食物過敏、花粉熱或氣喘；傳染性疾病，如艱難梭菌感染；炎性疾病，如TNF介導的炎性疾病（例如，胃腸道炎性疾病，如結腸袋炎（pouchitis）；心血管炎性病症，如動脈粥樣硬化；或炎性肺病，如慢性阻塞性肺疾病）的藥物組成物；用作用於抑制器官移植中的排斥或其中可能發生組織排斥的其他情況的藥物組成物；用作用於改善免疫功能的補充劑、食物或飲料；或用作用於抑制免疫細胞的增殖或功能的試劑。The solid dosage forms described herein can be used, for example, for the prophylaxis or treatment (partially or completely reducing the adverse effects of) autoimmune diseases such as chronic inflammatory bowel disease, systemic lupus erythematosus, psoriasis, Muwell syndrome , rheumatoid arthritis, multiple sclerosis, or Hashimoto's disease; allergic diseases, such as food allergies, hay fever, or asthma; infectious diseases, such as Clostridium difficile infection; inflammatory diseases, such as TNF-mediated Pharmaceutical compositions for inflammatory diseases (e.g., gastrointestinal inflammatory diseases, such as pouchitis; cardiovascular inflammatory disorders, such as atherosclerosis; or inflammatory lung diseases, such as chronic obstructive pulmonary disease); A pharmaceutical composition for inhibiting rejection in organ transplantation or other conditions in which tissue rejection may occur; for use as a supplement, food or drink for improving immune function; or as an agent for inhibiting the proliferation or function of immune cells.

在一些實施方式中，本文提供之方法和固體劑型適用於治療炎症。在某些實施方式中，身體的任何組織及器官的炎症，包括肌肉骨骼炎症、血管炎症、神經炎症、消化系統炎症、眼部炎症、生殖系統炎症及其他炎症，如下文討論。In some embodiments, the methods and solid dosage forms provided herein are useful for treating inflammation. In certain embodiments, inflammation of any tissue and organ of the body, including musculoskeletal inflammation, vascular inflammation, neuroinflammation, digestive system inflammation, ocular inflammation, reproductive system inflammation, and other inflammation, as discussed below.

肌肉骨骼系統的免疫障礙包括但不限於那些影響骨骼關節（包括手、手腕、肘部、肩部、下巴、脊柱、頸部、臀部、膝蓋、踝部及足部的關節）的病症，及影響將肌肉連接至骨頭的組織（如肌腱）的病症。可用本文所述之方法及組成物治療的此類免疫障礙的實例包括但不限於關節炎（包括，例如，骨關節炎、類風濕性關節炎、牛皮癬關節炎、強直性脊柱炎、急性及慢性感染性關節炎、與痛風和假痛風相關的關節炎及幼年特發性關節炎）、肌腱炎、滑膜炎、腱鞘炎、滑囊炎、纖維組織炎（纖維肌痛）、上髁炎、肌炎及骨炎（包括，例如，佩吉特病（Paget's disease）、恥骨炎及囊性纖維性骨炎）。Immune disorders of the musculoskeletal system include, but are not limited to, those affecting the skeletal joints (including those of the hands, wrists, elbows, shoulders, jaw, spine, neck, hips, knees, ankles, and feet), and those affecting A disorder of the tissues that connect muscles to bones, such as tendons. Examples of such immune disorders that can be treated with the methods and compositions described herein include, but are not limited to, arthritis (including, for example, osteoarthritis, rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, acute and chronic Infectious arthritis, arthritis associated with gout and pseudogout, and juvenile idiopathic arthritis), tendonitis, synovitis, tenosynovitis, bursitis, fibrous tissue inflammation (fibromyalgia), epicondylitis, muscular Osteitis and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis cystic fibrosis).

眼部免疫障礙係指影響眼睛的任何結構（包括眼瞼）的免疫障礙。可用本文描述之方法及組成物治療的眼部免疫障礙的實例包括但不限於瞼緣炎、眼瞼皮膚松垂症、結膜炎、淚腺炎、角膜炎、乾燥性角膜結膜炎（乾眼症）、鞏膜炎、倒睫及眼色素層炎。Ocular immune disorders are immune disorders affecting any structure of the eye, including the eyelids. Examples of ocular immune disorders that may be treated with the methods and compositions described herein include, but are not limited to, blepharitis, blepharoptosis, conjunctivitis, dacryodenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis , Trichiasis and uveitis.

可用本文描述之方法及固體劑型治療的神經系統免疫障礙的實例包括但不限於腦炎、格林-巴厘綜合症（Guillain-Barre syndrome）、腦膜炎、神經性肌強直、發作性睡病、多發性硬化、脊髓炎及精神分裂症。可用本文所述之方法及組成物治療的脈管系統或淋巴系統炎症的實例包括但不限於關節硬化、關節炎、靜脈炎、血管炎及淋巴管炎。Examples of neuroimmune disorders that may be treated with the methods and solid dosage forms described herein include, but are not limited to, encephalitis, Guillain-Barre syndrome, meningitis, neuromyotonia, narcolepsy, multiple sclerosis, myelitis and schizophrenia. Examples of inflammation of the vasculature or lymphatic system that may be treated with the methods and compositions described herein include, but are not limited to, arthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.

可用本文描述之方法及固體劑型治療的消化系統免疫障礙的實例包括但不限於膽管炎、膽囊炎、腸炎、小腸結腸炎、胃炎、腸胃炎、炎性腸病、回腸炎及直腸炎。炎性腸病包括（例如）一組相關病症的某些本領域公認的形式。已知炎性腸病的幾種主要形式，該等障礙中最常見的為克羅恩氏病（區域性腸病，例如，非活性及活性形式）及潰瘍性結腸炎（例如，非活性及活性形式）。另外，炎性腸病涵蓋腸易激綜合症、顯微鏡下結腸炎、淋巴細胞性-漿細胞性腸炎、乳糜瀉、膠原性結腸炎、淋巴細胞性結腸炎及嗜酸性小腸結腸炎。IBD的其他不常見形式包括未確定型結腸炎、偽膜性結腸炎（壞死性結腸炎）、缺血性炎性腸病、白塞氏病（Behcet's disease）、類肉瘤病、硬皮病、IBD相關性發育不良、發育不良相關性團塊或病變及原發性硬化性膽管炎。Examples of immune disorders of the digestive system that may be treated with the methods and solid dosage forms described herein include, but are not limited to, cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease, ileitis, and proctitis. Inflammatory bowel disease includes, for example, certain art-recognized forms of a group of related disorders. Several major forms of inflammatory bowel disease are known, the most common of these disorders being Crohn's disease (regional bowel disease, e.g., inactive and active forms) and ulcerative colitis (e.g., inactive and active form). In addition, inflammatory bowel disease encompasses irritable bowel syndrome, microscopic colitis, lymphocytic-plasmacytic colitis, celiac disease, collagenous colitis, lymphocytic colitis, and eosinophilic enterocolitis. Other less common forms of IBD include indeterminate colitis, pseudomembranous colitis (necrotizing colitis), ischemic inflammatory bowel disease, Behcet's disease, sarcoidosis, scleroderma, IBD Associated dysplasia, dysplasia-associated mass or lesion, and primary sclerosing cholangitis.

可用本文所述之方法及固體劑型治療的生殖系統免疫障礙的實例包括但不限於宮頸炎、絨毛膜羊膜炎、子宮內膜炎、附睾炎、臍炎、卵巢炎、睾丸炎、輸卵管炎、輸卵管卵巢膿腫、尿道炎、陰道炎、外陰炎及外陰痛。Examples of immune disorders of the reproductive system that may be treated with the methods and solid dosage forms described herein include, but are not limited to, cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, fallopian tube Ovarian abscess, urethritis, vaginitis, vulvitis and vulvar pain.

本文描述之方法及固體劑型可用以治療具有發炎成分的自體免疫性疾病。此病症包括但不限於全身性急性播散性禿頭症、白塞氏病、恰加斯氏病（Chagas' disease）、慢性疲勞綜合症、自主神經失調、腦脊髓炎、強直性脊柱炎、再生障礙性貧血、化膿性汗腺炎、自體免疫性肝炎、自體免疫性卵巢炎、乳糜瀉、克羅恩氏病、1型糖尿病、巨細胞動脈炎、古德帕斯丘綜合症、格雷夫斯病、格林-巴厘綜合症、橋本病、亨諾-許蘭二氏紫斑症（Henoch-Schonlein purpura）、川崎病（Kawasaki's disease）、紅斑狼瘡、顯微鏡下結腸炎、顯微鏡下多動脈炎、混合結締組織病、穆-韋二氏綜合症（Muckle-Wells syndrome）、多發性硬化、重症肌無力、眼陣攣肌陣攣綜合症、視神經炎、奧德氏甲狀腺炎、天皰瘡、結節性多動脈炎、多肌痛、類風濕性關節炎、萊特爾氏綜合症（Reiter's syndrome）、休葛籣氏綜合症（Sjogren's syndrome）、顳動脈炎、韋格納肉芽腫病（Wegener's granulomatosis）、溫熱自體免疫性溶血性貧血、間質性膀胱炎、萊姆病（Lyme disease）、局限性硬皮病、牛皮癬、類肉瘤病、硬皮病、潰瘍性結腸炎及白斑病。The methods and solid dosage forms described herein can be used to treat autoimmune diseases with an inflammatory component. Such conditions include, but are not limited to, generalized acute disseminated alopecia, Behçet's disease, Chagas' disease, chronic fatigue syndrome, autonomic dysregulation, encephalomyelitis, ankylosing spondylitis, regenerative Obstructive anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, type 1 diabetes, giant cell arteritis, Goodpasture syndrome, Graves Guillain-Bali syndrome, Hashimoto's disease, Henoch-Schonlein purpura, Kawasaki's disease, lupus erythematosus, microscopic colitis, microscopic polyarteritis, mixed Connective tissue disease, Muckle-Wells syndrome, multiple sclerosis, myasthenia gravis, oculoclonus-myoclonus syndrome, optic neuritis, Oder's thyroiditis, pemphigus, nodular Polyarteritis, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, warm Fever autoimmune hemolytic anemia, interstitial cystitis, Lyme disease, localized scleroderma, psoriasis, sarcoidosis, scleroderma, ulcerative colitis, and leukoplakia.

本文描述之方法及固體劑型可用以治療具有發炎成分的T細胞介導的超敏性疾病。此類病症包括但不限於接觸性超敏反應、接觸性皮炎（包括由於毒葛引起的接觸性皮炎）、蕁麻疹、皮膚過敏、呼吸道過敏（花粉症、過敏性鼻炎、屋塵蟎過敏）及麩膠敏感性腸病（乳糜瀉）。The methods and solid dosage forms described herein can be used to treat T cell-mediated hypersensitivity diseases that have an inflammatory component. Such conditions include, but are not limited to, contact hypersensitivity, contact dermatitis (including contact dermatitis due to poison ivy), hives, skin allergies, respiratory allergies (hay fever, allergic rhinitis, house dust mite allergy) and Gluten-sensitive enteropathy (celiac disease).

可用本發明之方法及固體劑型治療的其他免疫障礙包括例如闌尾炎、皮炎、皮肌炎、心內膜炎、纖維組織炎、齒齦炎、舌炎、肝炎、化膿性汗腺炎、虹膜炎、喉炎、乳腺炎、心肌炎、腎炎、耳炎、胰臟炎、腮腺炎、心包炎、腹膜炎（peritonoitis）、咽炎、胸膜炎、局限性肺炎、前列腺增生症（prostatistis）、腎盂腎炎及口炎（stomatisi）、移植排斥（涉及如腎、肝、心臟、肺、胰臟（例如，胰島細胞）、骨髓、角膜、小腸的器官，同種異體皮膚移植、皮膚同種移植物及心臟瓣膜異種移植、血清病及移植物抗宿主病）、急性胰臟炎、慢性胰臟炎、急性呼吸窘迫症候群、西紮利氏綜合症（Sexary's syndrome）、先天性腎上腺增生、非化膿性甲狀腺炎、高鈣血症相關癌症、天皰瘡、大皰性皰疹樣皮炎、重度多形紅斑、剝脫性皮炎、脂溢性皮炎、季節性或常年性過敏性鼻炎、支氣管氣喘、接觸性皮炎、特應性皮炎、藥物超敏反應、過敏性結膜炎、角膜炎、眼帶狀皰疹、虹膜炎及虹膜睫狀體炎、脈絡膜視網膜炎、視神經炎、症狀性類肉瘤病、暴發性或散播性肺結核化學療法、成人特發性血小板減少性紫癜、成人繼發性血小板減少症、獲得性（自體免疫性）溶血性貧血症、成人白血病及淋巴瘤、兒童急性白血病、局限性腸炎、自體免疫性血管炎、多發性硬化、慢性阻塞性肺疾病、實體器官移植排斥反應、敗血症。較佳的治療包括以下的治療：移植排斥、類風濕性關節炎、牛皮癬關節炎、多發性硬化、1型糖尿病、氣喘、炎性腸病、全身性紅斑狼瘡、牛皮癬、慢性阻塞性肺疾病及伴隨感染病症的炎症（例如，敗血症）。 代謝失調 Other immune disorders treatable with the methods and solid dosage forms of the invention include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis , mastitis, myocarditis, nephritis, otitis, pancreatitis, mumps, pericarditis, peritonitis (peritonoitis), pharyngitis, pleurisy, localized pneumonia, prostatic hyperplasia (prostatistis), pyelonephritis and stomatitis (stomatisi), Transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (eg, islet cells), bone marrow, cornea, small intestine, skin allograft, skin allograft and heart valve xenograft, serum sickness, and graft anti-host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sexary's syndrome, congenital adrenal hyperplasia, non-suppurative thyroiditis, hypercalcemia-related cancers, Herpes, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensitivity reaction, allergic conjunctivitis, keratitis, herpes zoster ocular, iritis and iridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminant or disseminated tuberculosis chemotherapy, adult idiopathic Thrombocytopenic purpura, secondary thrombocytopenia in adults, acquired (autoimmune) hemolytic anemia, leukemia and lymphoma in adults, acute leukemia in children, Crohn's disease, autoimmune vasculitis, multiple sclerosis , chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis. Preferred treatments include the following: transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, chronic obstructive pulmonary disease, and Inflammation that accompanies infectious conditions (eg, sepsis). metabolic disorder

在一些實施方式中，本文描述之方法和固體劑型涉及治療或預防代謝性疾病或障礙，例如II型糖尿病、糖耐量受損、胰島素抵抗、肥胖、高血糖、高胰島素血症、脂肪肝、非酒精性脂肪性肝炎、高膽固醇血症、高血壓、高脂蛋白血症、高脂血症、高甘油三酯血症、酮酸中毒、低血糖、血栓性疾病、血脂異常、非酒精性脂肪性肝病（NAFLD）、非酒精性脂肪性肝炎（NASH）或相關疾病。在一些實施方式中，相關疾病係心血管疾病、動脈粥樣硬化、腎臟疾病、腎病、糖尿病性神經病、糖尿病性視網膜病變、性功能障礙、皮膚病、消化不良或水腫。在一些實施方式中，本文所述之方法和藥物組成物涉及非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）之治療。In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of metabolic diseases or disorders, such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, non- Alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, ketoacidosis, hypoglycemia, thrombotic disease, dyslipidemia, nonalcoholic fat NAFLD, nonalcoholic steatohepatitis (NASH), or related conditions. In some embodiments, the associated disease is cardiovascular disease, atherosclerosis, renal disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, or edema. In some embodiments, the methods and pharmaceutical compositions described herein relate to the treatment of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).

本文描述之方法和固體劑型可用以治療有需要的任何受試者。如本文所使用的，「有需要的受試者」包括具有代謝性疾病或障礙的任何受試者，以及具有獲得這種疾病或障礙的增加的可能性的任何受試者。The methods and solid dosage forms described herein can be used to treat any subject in need thereof. As used herein, a "subject in need thereof" includes any subject with a metabolic disease or disorder, as well as any subject with an increased likelihood of acquiring such a disease or disorder.

本文描述的固體劑型可用於例如預防或治療代謝性疾病（部分或完全地減少代謝性疾病的不利影響），該代謝性疾病係例如II型糖尿病、糖耐量受損、胰島素抵抗、肥胖、高血糖、高胰島素血症、脂肪肝、非酒精性脂肪性肝炎、高膽固醇血症、高血壓、高脂蛋白血症、高脂血症、高甘油三酯血症、酮酸中毒、低血糖、血栓性疾病、血脂異常、非酒精性脂肪性肝病（NAFLD）、非酒精性脂肪性肝炎（NASH）或相關疾病。在一些實施方式中，相關疾病係心血管疾病、動脈粥樣硬化、腎臟疾病、腎病、糖尿病性神經病、糖尿病性視網膜病變、性功能障礙、皮膚病、消化不良或水腫。 癌症 The solid dosage forms described herein are useful, for example, in the prevention or treatment of (partially or completely reducing the adverse effects of) metabolic diseases such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia , hyperinsulinemia, fatty liver, nonalcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglyceridemia, ketoacidosis, hypoglycemia, thrombosis disease, dyslipidemia, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), or related diseases. In some embodiments, the associated disease is cardiovascular disease, atherosclerosis, renal disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, skin disease, dyspepsia, or edema. cancer

在一些實施方式中，本文描述之方法及固體劑型涉及癌症治療。在一些實施方式中，任何癌症可使用本文所述之方法治療。可藉由本文所述之方法及固體劑型治療的癌症的實例包括但不限於來自以下的癌細胞：膀胱、血液、骨頭、骨髓、腦、乳房、結腸、食道、胃腸、牙齦、頭、腎、肝、肺、鼻咽、頸、卵巢、前列腺、皮膚、胃、睪丸、舌頭或子宮。另外，癌症可特定地是下列組織學類型，但其不限於這類類型：贅瘤，惡性；癌；癌，未分化；巨大及梭細胞癌；小細胞癌；乳頭狀癌；鱗狀細胞癌；淋巴上皮癌；基底細胞癌（basal cell carcinoma）；毛髮基質（pilomatrix）癌；移行細胞癌；乳頭狀移行細胞癌；腺癌；胃泌素瘤，惡性；膽管癌；肝細胞癌；肝細胞癌合併膽管癌；小梁腺癌；腺樣囊性癌；腺瘤息肉的腺癌；腺癌，家族性結腸息肉；實體癌；類癌瘤，惡性；細支氣管肺泡（branchiolo-alveolar）腺癌；乳頭狀腺癌；嫌色細胞癌；嗜酸性細胞癌；嗜酸性腺癌；嗜鹼性粒細胞癌；透明細胞腺癌；顆粒細胞癌；濾泡性腺癌；乳頭狀及濾泡性腺癌；非包膜性硬化性癌；腎上腺皮質癌；子宮內膜樣癌；皮膚附器癌；頂漿（apocrine）腺癌；皮脂腺癌；耵聹（ceruminous）腺癌；黏液表皮樣癌；囊腺癌；乳頭狀囊腺癌；乳頭狀漿液性囊腺癌；黏液性囊腺癌；黏液性腺癌；戒環細胞癌；浸潤性導管癌；髓樣癌；小葉癌；炎性癌；佩吉特病，乳房；腺泡細胞癌；腺鱗癌；腺癌與鱗狀轉移瘤（adenocarcinoma w/squamous metaplasia）；胸腺瘤，惡性；卵巢間質瘤，惡性；卵泡膜細胞瘤（thecoma），惡性；粒層細胞瘤，惡性；及成釉細胞瘤，惡性；賽特利氏（sertoli）細胞癌；睾丸間質細胞（leydig cell）瘤，惡性；脂質細胞瘤，惡性；副神經節瘤，惡性；乳房外副神經節瘤，惡性；嗜鉻細胞瘤；血管球肉瘤（glomangiosarcoma）；惡性黑色素瘤；無色素性黑色素瘤；淺表擴散性黑色素瘤；巨大色素痣中的惡性黑色素瘤；上皮樣細胞黑色素瘤；藍痣，惡性；肉瘤；纖維肉瘤；纖維組織細胞瘤，惡性；黏液肉瘤；脂肉瘤（liposarcoma）；平滑肌肉瘤；橫紋肌肉瘤；胚胎性橫紋肌肉瘤；肺泡橫紋肌肉瘤；基質肉瘤；混合瘤，惡性；苗勒氏混合瘤（mullerian mixed tumor）；腎母細胞瘤；肝母細胞瘤；癌肉瘤；間質瘤，惡性；布倫納瘤（brenner tumor），惡性；葉狀瘤，惡性；滑膜肉瘤；間皮瘤，惡性；無性細胞瘤；胚胎性癌；畸胎瘤，惡性；卵巢甲狀腺瘤，惡性；絨毛膜癌；中腎瘤，惡性；血管肉瘤；血管內皮瘤，惡性；卡波西氏肉瘤；血管外皮細胞瘤，惡性；淋巴管肉瘤；骨肉瘤；近皮質骨肉瘤；軟骨肉瘤；軟骨胚細胞瘤，惡性；間葉細胞軟骨肉瘤；骨巨細胞瘤；尤因肉瘤；齒源性腫瘤，惡性；釉質母細胞齒源性瘤；釉質母細胞瘤，惡性；釉質母細胞纖維肉瘤；松果體瘤，惡性；脊索瘤；神經膠質瘤，惡性；室管膜瘤；星形細胞瘤；原漿性星形細胞瘤；纖維性星形細胞瘤；星形母細胞瘤；膠質母細胞瘤；少突神經膠質瘤；少突膠質母細胞瘤；原始神經外胚葉腫瘤；小腦肉瘤；節細胞母細胞瘤；神經母細胞瘤；視網膜母細胞瘤；嗅神經源性腫瘤；腦膜瘤，惡性；神經纖維肉瘤；神經鞘瘤，惡性；顆粒細胞瘤，惡性；惡性淋巴瘤；霍奇金病；何杰金氏淋巴瘤；副肉芽腫；小淋巴細胞性惡性淋巴瘤；彌漫性大細胞惡性淋巴瘤；濾泡型惡性淋巴瘤；蕈樣真菌病；其他特定的非何杰金氏淋巴瘤；惡性組織細胞增生症；多發性骨髓瘤；肥大細胞肉瘤；免疫增殖性小腸病；白血病；淋巴樣白血病；漿細胞白血病；紅白血病；淋巴肉瘤細胞白血病；髓樣白血病；嗜鹼性白血病；嗜酸性球白血病；單核細胞白血病；肥大細胞白血病；巨核細胞性白血病；髓樣肉瘤；及毛細胞白血病。In some embodiments, the methods and solid dosage forms described herein relate to the treatment of cancer. In some embodiments, any cancer can be treated using the methods described herein. Examples of cancers that may be treated by the methods and solid dosage forms described herein include, but are not limited to, cancer cells from the following: bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestinal, gingival, head, kidney, Liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, testes, tongue or uterus. In addition, the cancer may be specifically, but not limited to, the following histological types: neoplastic, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma ; Lymphoepithelial Carcinoma; Basal Cell Carcinoma; Pilomatrix Carcinoma; Transitional Cell Carcinoma; Papillary Transitional Cell Carcinoma; Adenocarcinoma; Carcinoma with cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma of adenomatous polyp; adenocarcinoma, familial polyposis of the colon; solid carcinoma; carcinoid, malignant; ; Papillary adenocarcinoma; Chromophobe cell carcinoma; Eosinophilic cell carcinoma; Eosinophilic adenocarcinoma; Nonencapsulated sclerosing carcinoma; adrenocortical carcinoma; endometrioid carcinoma; skin adnexa carcinoma; apocrine adenocarcinoma; sebaceous gland carcinoma; ceruminous adenocarcinoma; mucoepidermoid carcinoma; cystadenocarcinoma ; Papillary cystadenocarcinoma; Papillary serous cystadenocarcinoma; Mucinous cystadenocarcinoma; Mucinous adenocarcinoma; Ring cell carcinoma; Invasive ductal carcinoma; Medullary carcinoma; Lobular carcinoma; Inflammatory carcinoma; Paget's disease , breast; acinar cell carcinoma; adenosquamous carcinoma; adenocarcinoma w/squamous metaplasia; thymoma, malignant; ovarian stromal tumor, malignant; thecoma, malignant; granular Lamellar cell tumor, malignant; and ameloblastoma, malignant; sertoli cell carcinoma; leydig cell tumor, malignant; lipocytoma, malignant; paraganglioma, malignant; breast External Paraganglioma, Malignant; Pheochromocytoma; Glomangiosarcoma; Malignant Melanoma; Amelanotic Melanoma; Superficially Spreading Melanoma; Malignant Melanoma in Giant Pigmented Nevus; Epithelioid Melanoma ; blue nevi, malignant; sarcoma; fibrosarcoma; fibrous histiocytoma, malignant; myxosarcoma; liposarcoma; leiomyosarcoma; rhabdomyosarcoma; embryonal rhabdomyosarcoma; alveolar rhabdomyosarcoma; stromal sarcoma; mixed tumor, malignant; Mullerian mixed tumor; Wilms tumor; hepatoblastoma; carcinosarcoma; stromal tumor, malignant; brenner tumor, malignant; phyllodes tumor, malignant; synovial sarcoma ; Mesothelioma, malignant; Dysgerminoma; Embryonal carcinoma; Teratoma, malignant; Thyroid tumor of the ovary, malignant; Choriocarcinoma; Hemangiopericytoma, malignant; lymphangiosarcoma; osteosarcoma; juxcortical osteosarcoma; chondrosarcoma; chondroblastoma, malignant; mesenchymal chondrosarcoma; giant cell tumor of bone Ewing sarcoma; odontogenic neoplasm, malignant; ameloblastoma, malignant; ameloblastoma, malignant; ameloblastoma, malignant; ameloblastoma, malignant; chordoma; glioma, malignant; ventricular duct Thymoma; Astrocytoma; Protoplasmic astrocytoma; Fibrous astrocytoma; Astrocytoma; Glioblastoma; Oligodendroglioma; Oligodendroglioma; Germ tumor; cerebellar sarcoma; ganglioblastoma; neuroblastoma; retinoblastoma; olfactory neurogenic tumor; meningioma, malignant; neurofibrosarcoma; schwannoma, malignant; granulosa cell tumor, malignant; malignant Lymphoma; Hodgkin's disease; Hodgkin's lymphoma; paragranuloma; small lymphocytic malignant lymphoma; diffuse large cell malignant lymphoma; follicular malignant lymphoma; mycosis fungoides; other specified Non-Hodgkin's lymphoma; malignant histiocytosis; multiple myeloma; mast cell sarcoma; immunoproliferative enteropathy; leukemia; lymphoid leukemia; plasma cell leukemia; erythroleukemia; lymphosarcoma cell leukemia; myeloid leukemia ; basophilic leukemia; eosinophilic leukemia; monocytic leukemia; mast cell leukemia; megakaryocytic leukemia; myeloid sarcoma; and hairy cell leukemia.

在一些實施方式中，癌症包含乳癌（例如三陰性乳癌）。In some embodiments, the cancer comprises breast cancer (eg, triple negative breast cancer).

在一些實施方式中，癌症包含結直腸癌（例如，微衛星穩定（MSS）結直腸癌）。In some embodiments, the cancer comprises colorectal cancer (eg, microsatellite stable (MSS) colorectal cancer).

在一些實施方式中，癌症包含腎細胞癌。In some embodiments, the cancer comprises renal cell carcinoma.

在一些實施方式中，癌症包含肺癌（例如，非小細胞肺癌）。In some embodiments, the cancer comprises lung cancer (eg, non-small cell lung cancer).

在一些實施方式中，癌症包含膀胱癌。In some embodiments, the cancer comprises bladder cancer.

在一些實施方式中，癌症包含胃食管癌。In some embodiments, the cancer comprises gastroesophageal cancer.

在一些實施方式中，本文提供之方法及固體劑型涉及白血病的治療。術語「白血病」在廣義上包括造血器官/系統的進展性、惡性疾病且其特徵通常在於白血球及其先質在血液及骨髓中的異常增殖及發育。白血病疾病的非限制性實例包括急性非淋巴細胞性白血病、慢性淋巴細胞性白血病、急性粒細胞性白血病、慢性粒細胞性白血病、急性前骨髓細胞性白血病、成人T細胞白血病、非白血性白血病、白血球增多性白血病、嗜鹼粒細胞白血病、胚細胞白血病、牛白血病、慢性骨髓細胞性白血病、皮膚白血病、胚細胞性白血病、嗜酸性粒細胞性白血病、格羅斯氏白血病（Gross' leukemia）、裡德爾細胞白血病（Rieder cell leukemia）、希林氏白血病（Schilling's leukemia）、幹細胞白血病、亞白血病性白血病、未分化細胞白血病、毛細胞白血病、成血細胞性白血病（hemoblastic leukemia）、成血胚細胞性白血病（hemocytoblastic leukemia）、組織細胞性白血病、幹細胞白血病、急性單核細胞性白血病、白血球減少性白血病、淋巴性白血病、淋巴母細胞性白血病、淋巴細胞性白血病、淋巴源性白血病、淋巴樣白血病、淋巴肉瘤細胞白血病、肥大細胞白血病、巨核細胞性白血病、小骨髓母細胞性白血病、單核細胞性白血病、骨髓母細胞性白血病、骨髓細胞性白血病、骨髓性粒細胞性白血病、骨髓單核細胞性白血病、內格利白血病（Naegeli leukemia）、漿細胞白血病、漿細胞性白血病及前骨髓細胞性白血病。In some embodiments, the methods and solid dosage forms provided herein relate to the treatment of leukemia. The term "leukemia" broadly includes progressive, malignant diseases of the hematopoietic organs/system and is usually characterized by abnormal proliferation and development of leukocytes and their precursors in the blood and bone marrow. Non-limiting examples of leukemia diseases include acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, acute promyelocytic leukemia, adult T cell leukemia, nonleukemic leukemia, Leukocytosis leukemia, basophilic leukemia, blastocytic leukemia, bovine leukemia, chronic myelogenous leukemia, cutaneous leukemia, blastocytic leukemia, eosinophilic leukemia, Gross' leukemia, li Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia, hairy cell leukemia, hemoblastic leukemia, hemoblastic leukemia ( hemocytoblastic leukemia), histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphocytic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphoid leukemia, lymphoid leukemia, lymphosarcoma leukemia, mast cell leukemia, megakaryoblastic leukemia, small myeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloblastic leukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasma cell leukemia, and promyelocytic leukemia.

在一些實施方式中，本文提供之方法及固體劑型涉及癌治療。術語「癌」係指上皮細胞的惡性生長，該等上皮細胞往往浸潤環繞組織和/或抑制生理學及非生理學細胞死亡信號並產生轉移。癌的非限制性示例性類型包含腺泡癌、腺泡樣癌、腺囊樣癌、腺樣囊性癌、腺癌（carcinoma adenomatosum）、腎上腺皮質癌、肺泡癌、肺泡細胞癌、基底細胞癌（basal cell carcinoma）、基底細胞癌（carcinoma basocellulare）、基底細胞樣癌、基底鱗狀細胞癌、支氣管肺泡癌、細支氣管癌、支氣管癌、腦狀癌、膽管細胞癌、絨毛膜癌、膠狀癌、粉刺癌、子宮體癌、篩狀癌、鎧甲狀癌、皮膚癌、柱狀癌、柱狀細胞癌、導管癌、硬癌（carcinoma durum）、胚胎性癌、腦狀癌（encephaloid carcinoma）、表皮樣癌、腺樣上皮細胞癌、外植癌、潰瘍性癌、纖維癌、膠狀癌（gelatiniform carcinoma）、膠樣癌（gelatinous carcinoma）、巨細胞癌（giant cell carcinoma）、印戒細胞癌（signet-ring cell carcinoma）、單純癌、小細胞癌、馬鈴薯狀癌、球狀細胞癌、梭形細胞癌、髓狀癌、鱗狀癌、鱗狀細胞癌、繩捆癌（string carcinoma）、毛細管擴張癌（carcinoma telangiectaticum）、毛細管擴張性癌（carcinoma telangiectodes）、移行細胞癌、塊狀癌、結節性皮癌、疣狀癌、絨毛狀癌、巨細胞癌（carcinoma gigantocellulare）、腺體癌（glandular carcinoma）、粒層細胞癌、毛基質細胞癌（hair-matrix carcinoma）、血樣癌、肝細胞癌、許特耳細胞癌（Hurthle cell carcinoma）、玻質狀癌、腎上腺樣癌、幼稚型胚胎性癌、原位癌、表皮內癌、上皮內癌、克羅姆佩柯赫爾氏腫瘤（Krompecher's carcinoma）、庫爾契茨基氏細胞癌（Kulchitzky-cell carcinoma）、大細胞癌、豆狀癌（lenticular carcinoma）、豆樣癌（carcinoma lenticulare）、脂瘤樣癌、淋巴上皮癌、髓樣癌、髓質癌、黑色素癌、軟癌、黏液性癌（mucinous carcinoma）、黏液癌（carcinoma muciparum）、黏液細胞癌（carcinoma mucocellulare）、黏液表皮樣癌、黏膜癌（carcinoma mucosum）、黏膜性癌（mucous carcinoma）、黏液瘤樣癌、鼻咽癌、燕麥狀細胞癌、骨化性癌、骨質癌（osteoid carcinoma）、乳頭狀癌、門靜脈周癌、浸潤前癌、棘細胞癌、糜爛性癌、腎臟的腎細胞癌、儲備細胞癌、肉瘤樣癌、施奈德氏癌（schneiderian carcinoma）、硬性癌（scirrhous carcinoma）及陰囊癌（carcinoma scroti）。In some embodiments, the methods and solid dosage forms provided herein relate to cancer treatment. The term "carcinoma" refers to a malignant growth of epithelial cells that tend to infiltrate surrounding tissues and/or suppress physiological and non-physiological cell death signals and generate metastasis. Non-limiting exemplary types of carcinoma include acinar carcinoma, acinar-like carcinoma, adenoid cystoid carcinoma, adenoid cystic carcinoma, carcinoma adenomatosum, adrenocortical carcinoma, alveolar carcinoma, alveolar cell carcinoma, basal cell carcinoma (basal cell carcinoma), basal cell carcinoma (carcinoma basocellulare), basal cell carcinoma, basal squamous cell carcinoma, bronchoalveolar carcinoma, bronchiolar carcinoma, bronchial carcinoma, encephaloid carcinoma, cholangiocarcinoma, choriocarcinoma, colloid Carcinoma, acne cancer, uterine body cancer, cribriform carcinoma, armor-shaped carcinoma, skin cancer, columnar carcinoma, columnar cell carcinoma, ductal carcinoma, sclerosing carcinoma (carcinoma durum), embryonal carcinoma, encephaloid carcinoma (encephaloid carcinoma) , epidermoid carcinoma, adenoid carcinoma, explanted carcinoma, ulcerative carcinoma, fibrocarcinoma, gelatiniform carcinoma, gelatinous carcinoma, giant cell carcinoma, signet ring cell Carcinoma (signet-ring cell carcinoma), simple carcinoma, small cell carcinoma, potato-shaped carcinoma, spherical cell carcinoma, spindle cell carcinoma, medullary carcinoma, squamous carcinoma, squamous cell carcinoma, string carcinoma (string carcinoma) , carcinoma telangiectaticum, carcinoma telangiectodes, transitional cell carcinoma, massive carcinoma, nodular skin carcinoma, verrucous carcinoma, villous carcinoma, giant cell carcinoma (carcinoma gigantocellulare), glandular carcinoma (glandular carcinoma), granulosa cell carcinoma, hair-matrix carcinoma (hair-matrix carcinoma), blood sample carcinoma, hepatocellular carcinoma, Hurthle cell carcinoma (Hurthle cell carcinoma), vitreous carcinoma, adrenal carcinoma, naive type Embryonal carcinoma, carcinoma in situ, intraepidermal carcinoma, intraepithelial carcinoma, Krompecher's carcinoma, Kulchitzky-cell carcinoma, large cell carcinoma, lentiform Lenticular carcinoma, carcinoma lenticulare, lipomatoid carcinoma, lymphoepithelial carcinoma, medullary carcinoma, medullary carcinoma, melanoma, soft carcinoma, mucinous carcinoma, mucinous carcinoma (carcinoma muciparum) ), mucinous cell carcinoma (carcinoma mucocellulare), mucoepidermoid carcinoma, mucosal carcinoma (carcinoma mucosum), mucous carcinoma, myxomatoid carcinoma, nasopharyngeal carcinoma, oat cell carcinoma, ossifying carcinoma, osteoid carcinoma, papillary carcinoma, periportal carcinoma, preinvasive carcinoma, spinous carcinoma Cell carcinoma, erosive carcinoma, renal cell carcinoma of the kidney, reserve cell carcinoma, sarcomatoid carcinoma, schneiderian carcinoma, scirrhous carcinoma, and carcinoma scroti.

在一些實施方式中，本文提供之方法及固體劑型涉及肉瘤的治療。術語「肉瘤」通常是指如胚胎結締組織等物質組成的腫瘤且通常由包埋於原纖維、異質或均質物質中的緊密堆積細胞構成。肉瘤包括但不限於軟骨肉瘤、纖維肉瘤、淋巴肉瘤、黑色素肉瘤、黏液肉瘤、骨肉瘤、子宮內膜肉瘤、基質肉瘤、尤文氏肉瘤（Ewing' s sarcoma）、筋膜肉瘤、成纖維細胞性肉瘤、巨細胞肉瘤、艾伯內西氏肉瘤（Abemethy's sarcoma）、脂肪肉瘤、脂肉瘤、軟組織腺泡狀肉瘤、釉質母細胞肉瘤、葡萄形肉瘤、綠色肉瘤、絨毛膜癌、胚胎性肉瘤、維爾姆斯氏腫瘤肉瘤（Wilms' tumor sarcoma）、粒細胞肉瘤、何傑金氏肉瘤（Hodgkin's sarcoma）、特發性多發性色素沈著出血性肉瘤、B細胞免疫母細胞肉瘤、淋巴瘤、T細胞免疫母細胞肉瘤、晏森氏肉瘤（Jensen's sarcoma）、卡波西氏肉瘤（Kaposi's sarcoma）、庫普弗細胞肉瘤（Kupffer cell sarcoma）、血管肉瘤、白血病性肉瘤、惡性間葉瘤肉瘤、骨周肉瘤、網狀細胞肉瘤、勞斯肉瘤（Rous sarcoma）、漿液囊性肉瘤、滑膜肉瘤及毛細血管擴張性肉瘤。In some embodiments, the methods and solid dosage forms provided herein relate to the treatment of sarcoma. The term "sarcoma" generally refers to tumors composed of a substance such as embryonic connective tissue and usually composed of tightly packed cells embedded in a fibrillar, heterogeneous or homogeneous substance. Sarcomas include but are not limited to chondrosarcoma, fibrosarcoma, lymphosarcoma, melanosarcoma, myxosarcoma, osteosarcoma, endometrial sarcoma, stromal sarcoma, Ewing's sarcoma, fascial sarcoma, fibroblastic sarcoma , giant cell sarcoma, Abemethy's sarcoma, liposarcoma, liposarcoma, alveolar sarcoma of soft tissue, ameloblastoma, bophyllous sarcoma, chlorosarcoma, choriocarcinoma, embryonal sarcoma, Wilm Wilms' tumor sarcoma, granulocytic sarcoma, Hodgkin's sarcoma, idiopathic multipigmented hemorrhagic sarcoma, B-cell immunoblastic sarcoma, lymphoma, T-cell immunoblastic Cell sarcoma, Jensen's sarcoma, Kaposi's sarcoma, Kupffer cell sarcoma, angiosarcoma, leukemic sarcoma, malignant mesenchymal sarcoma, periosteal sarcoma, Reticulocyte sarcoma, Rous sarcoma, serous cystic sarcoma, synovial sarcoma, and telangiectatic sarcoma.

可使用本文描述之方法及固體劑型治療的另外的示例性腫瘤包括霍奇金病（Hodgkin’s Disease）、非何杰金氏淋巴瘤、多發性骨髓瘤、神經母細胞瘤、乳癌、卵巢癌、肺癌、橫紋肌肉瘤、原發性血小板增多症、原發性巨球蛋白血症、小細胞肺腫瘤、原發性腦腫瘤、胃癌、大腸癌、惡性胰臟胰島素瘤、惡性類癌、癌前皮膚病變、睪丸癌、淋巴瘤、甲狀腺癌、神經母細胞瘤、食道癌、泌尿生殖道癌、惡性高鈣血症、宮頸癌、子宮內膜癌、漿細胞瘤、結直腸癌、直腸癌及腎上腺皮質癌。Additional exemplary tumors that may be treated using the methods and solid dosage forms described herein include Hodgkin's Disease, Non-Hodgkin's Lymphoma, Multiple Myeloma, Neuroblastoma, Breast Cancer, Ovarian Cancer, Lung Cancer , rhabdomyosarcoma, essential thrombocythemia, essential macroglobulinemia, small cell lung tumors, primary brain tumors, gastric cancer, colorectal cancer, malignant pancreatic insulinoma, malignant carcinoid, precancerous skin lesions , testicular cancer, lymphoma, thyroid cancer, neuroblastoma, esophageal cancer, genitourinary tract cancer, malignant hypercalcemia, cervical cancer, endometrial cancer, plasmacytoma, colorectal cancer, rectal cancer and adrenal cortex cancer.

在一些實施方式中，所治療的癌症係黑色素瘤。術語「黑色素瘤」意指源自皮膚及其他器官的黑色素細胞系統的腫瘤。黑色素瘤的非限制性實例係哈-巴二氏黑色素瘤（Harding-Passey melanoma）、幼年型黑色素瘤、惡性小痣性痣黑色素瘤、惡性黑色素瘤、肢端小痣性黑色素瘤、無黑色素性黑色素瘤、良性幼年型黑色素瘤、克勞德曼氏黑色素瘤（Cloudman's melanoma）、S91黑色素瘤、結節性黑色素瘤甲下黑色素瘤及淺表擴展性黑色素瘤。In some embodiments, the cancer treated is melanoma. The term "melanoma" means a tumor arising from the melanocyte system of the skin and other organs. Non-limiting examples of melanoma are Harding-Passey melanoma, juvenile melanoma, malignant small nevus melanoma, malignant melanoma, acral small nevus melanoma, amelanotic Melanoma, benign juvenile melanoma, Cloudman's melanoma, S91 melanoma, nodular melanoma, subungual melanoma, and superficial extending melanoma.

可使用本文描述之方法及固體劑型治療的腫瘤的特定類別包括淋巴組織增生性疾病、乳癌、卵巢癌、前列腺癌、宮頸癌、子宮內膜癌、骨癌、肝癌、胃癌、大腸癌、胰臟癌、甲狀腺癌、頭頸癌、中樞神經系統的癌症、外周神經系統的癌症、皮膚癌、腎癌、及所有上述的轉移。特定類型的腫瘤包含肝細胞癌、肝細胞瘤、肝母細胞瘤、橫紋肌肉瘤、食管癌、甲狀腺癌、惡性神經節瘤、纖維肉瘤、黏液肉瘤、脂肉瘤、軟骨肉瘤、成骨性肉瘤、脊索瘤、血管肉瘤、內皮肉瘤、尤文氏腫瘤、平滑肌肉瘤、橫紋肌內皮肉瘤、侵襲性導管癌、乳頭狀腺癌、黑色素瘤、肺鱗狀細胞癌、基底細胞癌、腺癌（充分分化、中等分化、分化不良或未分化）、支氣管肺泡癌、腎細胞癌、腎上腺樣瘤、腎上腺樣腺癌、膽管癌、絨毛膜癌、精原細胞瘤、胚胎性癌、維爾姆斯氏腫瘤、睾丸腫瘤、肺癌（包含小細胞肺癌、非小細胞肺癌及大細胞肺癌）、膀胱癌、神經膠質瘤、星形細胞瘤、髓母細胞瘤、顱咽管瘤、室管膜瘤、松果體瘤、視網膜母細胞瘤、神經母細胞瘤、大腸癌、直腸癌、血液系統惡性腫瘤（包含所有類型的白血病及淋巴瘤，包含：急性髓性白血病、急性髓細胞性白血病、急性淋巴細胞性白血病、慢性髓性白血病、慢性淋巴球性白血病、肥大細胞白血病、多發性骨髓瘤、髓樣淋巴瘤、何傑金氏淋巴瘤、非何傑金氏淋巴瘤、漿細胞瘤、結直腸癌及直腸癌。Specific types of tumors that may be treated using the methods and solid dosage forms described herein include lymphoproliferative disorders, breast cancer, ovarian cancer, prostate cancer, cervical cancer, endometrial cancer, bone cancer, liver cancer, gastric cancer, colorectal cancer, pancreatic cancer cancer, thyroid cancer, head and neck cancer, cancer of the central nervous system, cancer of the peripheral nervous system, skin cancer, kidney cancer, and metastases of all of the above. Specific types of tumors include hepatocellular carcinoma, hepatoma, hepatoblastoma, rhabdomyosarcoma, esophageal carcinoma, thyroid carcinoma, malignant ganglioma, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, notochord Tumor, angiosarcoma, endothelial sarcoma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, invasive ductal carcinoma, papillary adenocarcinoma, melanoma, lung squamous cell carcinoma, basal cell carcinoma, adenocarcinoma (well differentiated, moderately differentiated , poorly differentiated or undifferentiated), bronchoalveolar carcinoma, renal cell carcinoma, adrenal adenoid tumor, adrenal adenoid adenocarcinoma, cholangiocarcinoma, choriocarcinoma, seminoma, embryonal carcinoma, Wilms' tumor, testicular tumor, Lung cancer (including small cell lung cancer, non-small cell lung cancer and large cell lung cancer), bladder cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, retina Blastoma, neuroblastoma, colorectal cancer, rectal cancer, hematological malignancies (including all types of leukemia and lymphoma, including: acute myeloid leukemia, acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia leukemia, chronic lymphocytic leukemia, mast cell leukemia, multiple myeloma, myeloid lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, plasmacytoma, colorectal cancer and rectal cancer.

某些實施方式中所治療的癌症還包括癌前病灶，例如光化性角化病（日光性角化病）、莫耳痣（發育異常痣）、光化性唇炎（農夫唇）、皮角、巴瑞特氏食管症（Barrett's esophagus）、萎縮性胃炎、先天性角化不良、缺鐵性咽下困難、扁平苔蘚、口腔黏膜下纖維化、光化性（日光性）彈性組織變性及宮頸發育不良。Cancers treated in certain embodiments also include precancerous lesions such as actinic keratoses (solar keratosis), moles (dysplastic moles), actinic cheilitis (farmer's lips), dermatitis Horns, Barrett's esophagus, atrophic gastritis, dyskeratosis congenita, iron deficiency dysphagia, lichen planus, oral submucosal fibrosis, actinic (solar) elastosis, and Cervical dysplasia.

一些實施方式中所治療的癌症包含非癌性或良性腫瘤，例如內胚層、外胚層或間質起源的腫瘤，包括但不限於膽管瘤、結腸息肉、腺瘤、乳頭瘤、囊腺瘤、肝細胞腺瘤、葡萄胎、腎小管腺瘤、鱗狀細胞乳頭瘤、胃息肉、血管瘤、骨瘤、軟骨瘤、脂肪瘤、纖維瘤、淋巴管瘤、平滑肌瘤、橫紋肌瘤、星形細胞瘤、痣、腦膜瘤及神經節瘤。 其他疾病及障礙 In some embodiments, the cancer treated comprises non-cancerous or benign tumors, such as tumors of endodermal, ectodermal, or mesenchymal origin, including but not limited to cholangiomas, colonic polyps, adenomas, papillomas, cystadenomas, liver Cell adenoma, hydatidiform mole, tubular adenoma, squamous cell papilloma, gastric polyp, hemangioma, osteoma, chondroma, lipoma, fibroma, lymphangioma, leiomyoma, rhabdoid myoma, astrocytoma Tumors, moles, meningiomas, and gangliomas. Other Diseases and Disorders

在一些實施方式中，本文描述之方法及固體劑型涉及肝疾病的治療。此疾病包括（但不限於）阿拉吉爾綜合症（Alagille Syndrome）、酒精相關肝病、α-1抗胰蛋白酶缺乏症、自體免疫性肝炎、良性肝腫瘤、膽管閉鎖、肝硬化、半乳糖血症、吉伯特綜合症、血色素沈著病、A型肝炎、B型肝炎、C型肝炎、肝性腦病、妊娠期肝內膽汁淤積症（ICP）、溶酶體酸脂肪酶缺乏症（LAL-D）、肝囊腫、肝癌、新生兒黃疸、原發性膽汁性膽管炎（PBC）、原發性硬化性膽管炎（PSC）、雷氏綜合症（Reye Syndrome）、I型糖原貯積病及威爾森病（Wilson Disease）。In some embodiments, the methods and solid dosage forms described herein relate to the treatment of liver disease. Such disorders include (but are not limited to) Alagille Syndrome, alcohol-related liver disease, alpha-1 antitrypsin deficiency, autoimmune hepatitis, benign liver tumors, biliary atresia, cirrhosis, galactosemia , Gilbert's syndrome, hemochromatosis, hepatitis A, hepatitis B, hepatitis C, hepatic encephalopathy, intrahepatic cholestasis of pregnancy (ICP), lysosomal acid lipase deficiency (LAL-D ), liver cyst, liver cancer, neonatal jaundice, primary biliary cholangitis (PBC), primary sclerosing cholangitis (PSC), Reye Syndrome, type I glycogen storage disease and Wilson Disease.

本文描述之方法及固體劑型可用以治療神經退化性及神經性疾病。在某些實施方式中，神經退化性和/或神經性疾病係巴金森氏病、阿爾茲海默症、普里昂疾病、亨廷頓病、運動神經元疾病（MND）、脊髓小腦共濟失調、脊髓性肌萎縮症、肌張力障礙、特發性顱內高壓、癲癇、神經系統疾病、中樞神經系統疾病、運動障礙、多發性硬化、腦病、周圍神經病變或術後認知功能障礙。 生態失調 The methods and solid dosage forms described herein can be used to treat neurodegenerative and neurological diseases. In certain embodiments, the neurodegenerative and/or neurological disease is Parkinson's disease, Alzheimer's disease, Prion's disease, Huntington's disease, motor neuron disease (MND), spinocerebellar ataxia, spinal cord muscular dystrophy, dystonia, idiopathic intracranial hypertension, epilepsy, neurological disease, central nervous system disease, movement disorders, multiple sclerosis, encephalopathy, peripheral neuropathy, or postoperative cognitive impairment. dysbiosis

近年來，越來越清楚的是，腸道微生物組（也稱為「腸道微生物群」）可藉由微生物對宿主的免疫細胞和其他細胞的活性以及影響（局部和/或遠端）對個體健康產生顯著影響（Walker, W.A., Dysbiosis[生態失調].The Microbiota in Gastrointestinal Pathophysiology[胃腸道病理生理學中的微生物].第25章.2017；Weiss和Thierry, Mechanisms and consequences of intestinal dysbiosis [腸道生態失調的機制和後果]. Cellular and Molecular Life Sciences[細胞與分子生命科學].(2017) 74(16):2959-2977.Zurich Open Repository and Archive [蘇黎世開放存儲庫和歸檔], doi.org/10.1007/s00018-017-2509-x））。 In recent years, it has become increasingly clear that the gut microbiome (also referred to as the "gut microbiota") is influenced by the activity and influence (local and/or distal) of microbes on the host's immune and other cells. individual health (Walker, WA, Dysbiosis [ecological imbalance]. The Microbiota in Gastrointestinal Pathophysiology [microbes in gastrointestinal pathophysiology]. Chapter 25. 2017; Weiss and Thierry, Mechanisms and consequences of intestinal dysbiosis [intestinal dysbiosis]. Mechanisms and consequences of Tao dysbiosis]. Cellular and Molecular Life Sciences [Cell and Molecular Life Science]. (2017) 74(16):2959-2977. Zurich Open Repository and Archive [Zurich Open Repository and Archive], doi. org/10.1007/s00018-017-2509-x)).

健康的宿主腸道微生物組穩態有時被稱為「生態平衡」或「正常生態」，而宿主微生物組的組成和/或其多樣性的有害變化可能導致微生物組的不健康失衡，或「生態失調」（Hooks和O'Malley.Dysbiosis and its discontents [生態失調及其缺憾].American Society for Microbiology [美國微生物學會].2017年10月.第8卷.第5期. mBio 8: e01492-17. doi.org/10.1128/mBio.01492-17）。當微生物組穩態喪失或減弱時，可能會發生生態失調以及相關的局部或遠端宿主炎性或免疫效應，從而導致：對病原體的敏感性增加；宿主細菌代謝活性改變；誘導宿主促炎活性和/或降低宿主抗炎活性。此類效應部分地由宿主免疫細胞（例如，T細胞、樹突細胞、肥大細胞、NK細胞、腸上皮淋巴細胞（IEC）、巨噬細胞和吞噬細胞）和細胞介素，以及由此類細胞和其他宿主細胞釋放的其他物質之間的相互作用介導。Healthy host gut microbiome homeostasis is sometimes referred to as "ecological balance" or "normal ecology," whereas deleterious changes in the composition and/or diversity of the host microbiome can lead to unhealthy imbalances in the microbiome, or "ecological balance." Dysbiosis and its discontents" (Hooks and O'Malley. Dysbiosis and its discontents). American Society for Microbiology. October 2017. Vol. 8. No. 5. mBio 8: e01492-17 . doi.org/10.1128/mBio.01492-17). Dysbiosis and associated local or distant host inflammatory or immune effects can occur when microbiome homeostasis is lost or diminished, leading to: increased susceptibility to pathogens; altered host bacterial metabolic activity; induction of host pro-inflammatory activity and/or reduce host anti-inflammatory activity. Such effects are in part mediated by host immune cells (e.g., T cells, dendritic cells, mast cells, NK cells, intestinal epithelial lymphocytes (IEC), macrophages, and phagocytes) and cytokines, as well as by such cells Interactions with other substances released by other host cells are mediated.

生態失調可能發生在胃腸道內（「胃腸道生態失調」或「腸道生態失調」），或者可能發生在胃腸道管腔外（「遠端生態失調」）。胃腸生態失調通常與腸上皮屏障完整性降低、緊密連接完整性降低和腸通透性增加有關。Citi, S. Intestinal Barriers protect against disease [腸屏障可預防疾病], Science[科學] 359:1098-99 (2018)；Srinivasan等人, TEER measurement techniques for in vitro barrier model systems [用於體外屏障模型系統的TEER測量技術]. J. Lab.Autom [ 實驗室自動化雜誌 ].20:107-126 (2015)。胃腸生態失調可以在胃腸道內外產生生理和免疫作用。 Dysbiosis may occur within the GI tract ("GI dysbiosis" or "gut dysbiosis") or may occur outside the lumen of the GI tract ("distal dysbiosis"). Gastrointestinal dysbiosis is often associated with decreased intestinal epithelial barrier integrity, decreased tight junction integrity, and increased intestinal permeability. Citi, S. Intestinal Barriers protect against disease, Science 359:1098-99 (2018); Srinivasan et al, TEER measurement techniques for in vitro barrier model systems TEER Measurement Technique]. J. Lab.Autom [ Journal of Laboratory Automation ]. 20:107-126 (2015). Gastrointestinal dysbiosis can have physiological and immunological effects both in and out of the GI tract.

生態失調的存在已與多種疾病和病症相關，包括：感染，癌症，自體免疫性疾病（例如全身性紅斑狼瘡(SLE)）或炎性疾病（例如功能性胃腸疾病如炎症性腸病(IBD)，潰瘍性結腸炎和克羅恩氏病），神經炎性疾病（例如多發性硬化症），移植性疾病（例如移植物抗宿主病），脂肪性肝病，I型糖尿病，類風濕性關節炎，乾燥綜合症，乳糜瀉，囊性纖維化，慢性阻塞性肺疾病(COPD)和其他與免疫功能障礙相關的疾病和病症。Lynch等人, The Human Microbiome in Health and Disease [健康與疾病中的人類微生物組], N. Engl. J. Med [ 新英格蘭醫學雜誌 ].375:2369-79 (2016)，Carding等人, Dysbiosis of the gut microbiota in disease [疾病中腸道微生物群的生態失調]. Microb.Ecol.Health Dis[ 微生物生態與健康疾病 ].(2015); 26: 10: 3402/mehd.v26.2619；Levy等人, Dysbiosis and the Immune System [生態失調和免疫系統], Nature Reviews Immunology [自然評論免疫學] 17:219 (2017年4月)。 The presence of dysbiosis has been associated with a variety of diseases and conditions including: infection, cancer, autoimmune diseases such as systemic lupus erythematosus (SLE) or inflammatory diseases such as functional gastrointestinal disorders such as inflammatory bowel disease (IBD ), ulcerative colitis and Crohn's disease), neuroinflammatory diseases (such as multiple sclerosis), transplant diseases (such as graft-versus-host disease), fatty liver disease, type I diabetes, rheumatoid arthritis Inflammation, Sjogren's syndrome, celiac disease, cystic fibrosis, chronic obstructive pulmonary disease (COPD) and other diseases and conditions associated with immune dysfunction. Lynch et al, The Human Microbiome in Health and Disease, N. Engl. J. Med [ New England Journal of Medicine ]. 375:2369-79 (2016), Carding et al, Dysbiosis of the gut microbiota in disease [dysbiosis of gut microbiota in disease]. Microb.Ecol.Health Dis[ microbial ecology and health disease ]. (2015); 26: 10: 3402/mehd.v26.2619; Levy et al People, Dysbiosis and the Immune System, Nature Reviews Immunology 17:219 (April 2017).

本文所揭露的示例性藥物組成物和/或固體劑型可以藉由修飾存在於生態失調部位的免疫活性來治療生態失調及其影響。如本文所述，此類組成物可經由對宿主免疫細胞的作用（導致例如抗炎細胞介素的分泌增加和/或促炎細胞介素的分泌減少，從而減輕受試接受者的炎症）或經由代謝物生產的變化來修飾生態失調。Exemplary pharmaceutical compositions and/or solid dosage forms disclosed herein can treat dysbiosis and its effects by modifying immune activity present at the site of dysbiosis. As described herein, such compositions may reduce inflammation in the subject via an effect on the immune cells of the host (resulting in, for example, increased secretion of anti-inflammatory cytokines and/or decreased secretion of pro-inflammatory cytokines) or Modification of dysbiosis via changes in metabolite production.

本文揭露的可用於治療與生態失調相關的障礙的示例性藥物組成物和/或固體劑型包含一種或多種類型的免疫調節細菌（例如抗炎細菌）和/或由此類細菌產生的mEV（微生物胞外囊泡）。此類組成物能夠影響接受者宿主在胃腸道中的免疫功能，和/或在受試者胃腸道外的遠端部位產生系統性作用。Exemplary pharmaceutical compositions and/or solid dosage forms disclosed herein that are useful for treating disorders associated with dysbiosis comprise one or more types of immunomodulatory bacteria (eg, anti-inflammatory bacteria) and/or mEVs (microbial extracellular vesicles). Such compositions can affect the immune function of the recipient host in the gastrointestinal tract, and/or produce systemic effects at remote sites outside the gastrointestinal tract of the subject.

本文揭露的可用於治療與生態失調相關的障礙的示例性藥物組成物和/或固體劑型包含單一細菌物種（例如，單一菌株）的免疫調節細菌（例如，抗炎細菌）的群體和/或由此類細菌產生的mEV。此類組成物能夠影響接受者宿主在胃腸道中的免疫功能，和/或在受試者胃腸道外的遠端部位產生系統性作用。Exemplary pharmaceutical compositions and/or solid dosage forms disclosed herein that are useful for treating disorders associated with dysbiosis comprise populations of immunomodulatory bacteria (eg, anti-inflammatory bacteria) of a single bacterial species (eg, single strain) and/or are composed of mEVs produced by such bacteria. Such compositions can affect the immune function of the recipient host in the gastrointestinal tract, and/or produce systemic effects at remote sites outside the gastrointestinal tract of the subject.

在一個實施方式中，將包含經分離的免疫調節細菌（例如抗炎細菌細胞）群體或由此類細菌產生的mEV的藥物組成物和/或固體劑型以有效治療哺乳動物接受者的生態失調和其一種或多種影響的量施用（例如口服）給該接受者。該生態失調可以是胃腸道生態失調或遠端生態失調。In one embodiment, a pharmaceutical composition and/or solid dosage form comprising an isolated population of immunomodulatory bacteria (e.g., anti-inflammatory bacterial cells) or mEVs produced by such bacteria is effective for treating dysbiosis and One or more affecting amounts thereof are administered (eg, orally) to the recipient. The dysbiosis may be gastrointestinal dysbiosis or distal dysbiosis.

在另一個實施方式中，本文所述之藥物組成物和/或固體劑型可以治療胃腸道生態失調及其對宿主免疫細胞的一種或多種影響，導致抗炎細胞介素的分泌增加和/或促炎細胞介素的分泌減少，從而減輕受試接受者的炎症。In another embodiment, the pharmaceutical composition and/or solid dosage form described herein can treat gastrointestinal dysbiosis and one or more effects on host immune cells, resulting in increased secretion of anti-inflammatory cytokines and/or pro-inflammatory cytokines The secretion of inflammatory cytokines was reduced, thereby reducing inflammation in the test recipients.

在另一個實施方式中，藥物組成物和/或固體劑型可以藉由以下來治療胃腸道生態失調及其一種或多種影響：經由細胞和細胞介素調節來調節接受者的免疫應答，以藉由增加腸上皮屏障的完整性來降低腸道通透性。In another embodiment, the pharmaceutical composition and/or solid dosage form may treat gastrointestinal dysbiosis and one or more of its effects by modulating the recipient's immune response through cellular and cytokine modulation, by Increases the integrity of the intestinal epithelial barrier to reduce intestinal permeability.

在另一個實施方式中，藥物組成物和/或固體劑型可以藉由以下來治療遠端生態失調及其一種或多種影響：經由調節宿主免疫細胞來調節接受者生態失調部位的免疫應答。In another embodiment, the pharmaceutical composition and/or solid dosage form can treat distal dysbiosis and one or more effects thereof by modulating the recipient's immune response at the site of dysbiosis through modulation of host immune cells.

其他示例性藥物組成物和/或固體劑型可用於治療與生態失調有關的失調症，該等組成物包含一種或多種類型的細菌或mEV，該等細菌和/或mEV能夠改變接受者中的宿主免疫細胞亞群（例如T細胞、免疫淋巴樣細胞、樹突細胞、NK細胞和其他免疫細胞的亞群）相對比例或其功能。Other exemplary pharmaceutical compositions and/or solid dosage forms useful in the treatment of dysbiosis-related disorders comprise one or more types of bacteria or mEVs capable of altering the host in a recipient The relative proportions of immune cell subsets (such as T cells, immune lymphoid cells, dendritic cells, NK cells, and other immune cell subsets) or their function.

其他示例性藥物組成物和/或固體劑型可用於治療與生態失調有關的障礙，組成物包含單一細菌物種（例如，單一菌株）的免疫調節細菌和/或mEV的群體，其能夠改變接受者中免疫細胞亞群（例如T細胞亞群、免疫淋巴樣細胞、NK細胞和其他免疫細胞）的相對比例或其功能。Other exemplary pharmaceutical compositions and/or solid dosage forms can be used to treat disorders associated with dysbiosis, the compositions comprising a single bacterial species (e.g., a single strain) of immunomodulatory bacteria and/or populations of mEVs capable of altering The relative proportions of immune cell subsets (such as T cell subsets, immune lymphoid cells, NK cells, and other immune cells) or their functions.

在一個實施方式中，本文提供了藉由以下來治療胃腸生態失調及其一種或多種影響之方法：向有需要的受試者口服施用藥物組成物和/或固體劑型，該等藥物組成物和/或固體劑型改變存在於生態失調部位的微生物組群體。藥物組成物和/或固體劑型可以包含一種或多種類型的免疫調節細菌或mEV或單一細菌物種（例如，單一菌株）的免疫調節細菌和/或mEV的群體。In one embodiment, provided herein is a method of treating gastrointestinal dysbiosis and one or more effects thereof by orally administering to a subject in need thereof a pharmaceutical composition and/or a solid dosage form, the pharmaceutical composition and and/or the solid dosage form alters the microbiome population present at the site of dysbiosis. The pharmaceutical composition and/or solid dosage form may comprise one or more types of immunomodulatory bacteria or mEVs or a population of immunomodulatory bacteria and/or mEVs of a single bacterial species (eg, a single strain).

在一個實施方式中，本文提供了藉由以下來治療遠端生態失調及其一種或多種影響之方法：向有需要的受試者口服施用藥物組成物和/或固體劑型，該等藥物組成物和/或固體劑型改變受試者的胃腸道外的免疫應答。藥物組成物和/或固體劑型可以包含一種或多種類型的免疫調節細菌或mEV或單一細菌物種（例如，單一菌株）的免疫調節細菌和/或mEV的群體。In one embodiment, provided herein is a method of treating distal dysbiosis and one or more effects thereof by orally administering to a subject in need thereof a pharmaceutical composition and/or a solid dosage form, the pharmaceutical composition And/or the solid dosage form alters the subject's parenteral immune response. The pharmaceutical composition and/or solid dosage form may comprise one or more types of immunomodulatory bacteria or mEVs or a population of immunomodulatory bacteria and/or mEVs of a single bacterial species (eg, a single strain).

在示例性實施方式中，可用於治療與生態失調有關的障礙的藥物組成物和/或固體劑型刺激宿主免疫細胞分泌一種或多種抗炎細胞介素。抗炎細胞介素包括但不限於IL-10、IL-13、IL-9、IL-4、IL-5、TGFβ及其組合。在其他示例性實施方式中，可用於治療與生態失調有關的障礙的藥物組成物和/或固體劑型減少（例如抑制）宿主免疫細胞分泌一種或多種促炎細胞介素。促炎細胞介素包括但不限於IFNγ、IL-12p70、IL-1α、IL-6、IL-8、MCP1、MIP1α、MIP1β、TNFα及其組合。其他示例性細胞介素係本領域已知的並且在本文中描述。In an exemplary embodiment, the pharmaceutical composition and/or solid dosage form useful for treating a disorder associated with dysbiosis stimulates host immune cells to secrete one or more anti-inflammatory cytokines. Anti-inflammatory cytokines include, but are not limited to, IL-10, IL-13, IL-9, IL-4, IL-5, TGFβ, and combinations thereof. In other exemplary embodiments, the pharmaceutical composition and/or solid dosage form useful for treating a disorder associated with dysbiosis reduces (eg, inhibits) secretion of one or more pro-inflammatory cytokines by host immune cells. Pro-inflammatory cytokines include, but are not limited to, IFNγ, IL-12p70, IL-1α, IL-6, IL-8, MCP1, MIP1α, MIP1β, TNFα, and combinations thereof. Other exemplary cytokine lines are known in the art and described herein.

在另一方面，本文提供了在有需要的受試者中治療或預防與生態失調有關的障礙之方法，該方法包括向受試者施用（例如口服施用）益生菌食品或醫療食品形式的治療組成物，該治療組成物包含的細菌和/或mEV的量足以改變生態失調部位的微生物組，從而治療與生態失調相關的障礙。In another aspect, provided herein is a method of treating or preventing a disorder associated with dysbiosis in a subject in need thereof, the method comprising administering (e.g., orally administering) to the subject the treatment in the form of a probiotic food or medical food Compositions comprising bacteria and/or mEVs in an amount sufficient to alter the microbiome at a site of dysbiosis, thereby treating a disorder associated with dysbiosis.

在另一個實施方式中，本文提供的以益生菌食品或醫療食品形式的治療性組成物可用於預防或延遲處於發展為生態失調風險的受試者中生態失調的發作。 製造增強的細菌之方法 In another embodiment, a therapeutic composition provided herein in the form of a probiotic food or medical food can be used to prevent or delay the onset of dysbiosis in a subject at risk of developing dysbiosis. Method for making enhanced bacteria

在某些方面中，本文提供製造用於產生本文描述的細菌和/或mEV（例如smEV和/或pmEV）的工程改造的細菌之方法。在一些實施方式中，該等工程改造的細菌經修飾以增強某些所需性質。例如，在一些實施方式中，對工程改造的細菌進行修飾以增強細菌和/或mEV（例如smEV和/或pmEV）的免疫調節作用和/或治療效果（例如，單獨或與另一種治療劑組合），以降低毒性和/或改善細菌和/或mEV（例如smEV和/或pmEV）製造（例如更高的耐氧性、更高的抗凍融性、更短的產生時間）。工程改造的細菌可使用本領域中已知的任何技術產生，包括（但不限於）定點誘變、轉座子誘變、敲除、敲入、聚合酶鏈反應誘變、化學誘變、紫外線誘變、轉形（化學或藉由電穿孔）、噬菌體轉導、定向演化、CRISPR/Cas9或其任何組合。In certain aspects, provided herein are methods of making engineered bacteria for producing the bacteria described herein and/or mEV (eg, smEV and/or pmEV). In some embodiments, the engineered bacteria are modified to enhance certain desired properties. For example, in some embodiments, engineered bacteria are modified to enhance the immunomodulatory and/or therapeutic effects of bacteria and/or mEVs (e.g., smEV and/or pmEV) (e.g., alone or in combination with another therapeutic agent). ), to reduce virulence and/or improve bacterial and/or mEV (e.g. smEV and/or pmEV) production (e.g. higher oxygen tolerance, higher freeze-thaw resistance, shorter production time). Engineered bacteria can be generated using any technique known in the art, including but not limited to site-directed mutagenesis, transposon mutagenesis, knockout, knockin, polymerase chain reaction mutagenesis, chemical mutagenesis, ultraviolet light Mutagenesis, transformation (chemical or by electroporation), phage transduction, directed evolution, CRISPR/Cas9 or any combination thereof.

在本文提供之方法的一些實施方式中，細菌藉由定向演化進行修飾。在一些實施方式中，該定向演化包含將細菌暴露於環境條件並選擇在環境條件下具有經改善的存活和/或生長的細菌。在一些實施方式中，該方法包括使用識別增強的細菌的分析篩選誘變細菌。在一些實施方式中，該方法還包括誘變細菌（例如，藉由暴露於化學誘變劑和/或UV輻射），或將它們暴露於治療劑（例如抗生素），接著進行分析以檢測具有所需表型的細菌（例如，體內分析、離體分析或體外分析）。 感染 In some embodiments of the methods provided herein, the bacterium is modified by directed evolution. In some embodiments, the directed evolution comprises exposing bacteria to environmental conditions and selecting for bacteria with improved survival and/or growth under the environmental conditions. In some embodiments, the method comprises screening for mutagenized bacteria using an assay that recognizes enhanced bacteria. In some embodiments, the method further includes mutagenizing the bacteria (e.g., by exposure to chemical mutagens and/or UV radiation), or exposing them to therapeutic agents (e.g., antibiotics), followed by analysis to detect Bacteria to be phenotyped (for example, in vivo, ex vivo, or in vitro assays). Infect

炎症可以是對有害刺激（例如入侵病原體、受損細胞、有毒化合物或癌細胞）的保護性應答。但是，對這種刺激的過度炎性應答會導致嚴重的不利影響，包括組織損傷甚至死亡。例如，產生促炎性細胞介素（例如白細胞介素8（IL-8）、白細胞介素6（IL-6）、白細胞介素1β（IL-1β）和腫瘤壞死因子α（TNFα））以應答許多病毒感染係與感染相關的不良症狀（在某些情況下包括死亡）的主要原因之一。例如，炎性細胞介素的釋放與多種病毒感染（包括冠狀病毒（例如，SARS-CoV-2、導致冠狀病毒病2019（COVID-19）的病毒、流感病毒和呼吸道合胞病毒）感染）引起的疾病嚴重程度有關。例如，患有嚴重COVID-19的患者經常在肺部表現出升高水平的炎性細胞介素，其促成COVID-19患者經歷的肺損傷。Inflammation can be a protective response to harmful stimuli such as invading pathogens, damaged cells, toxic compounds, or cancer cells. However, an excessive inflammatory response to such stimuli can lead to serious adverse effects, including tissue damage and even death. For example, the production of pro-inflammatory cytokines such as interleukin 8 (IL-8), interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor alpha (TNFα) to Response to many viral infections is one of the major causes of adverse symptoms associated with infection, including death in some cases. For example, the release of inflammatory cytokines is associated with a variety of viral infections, including coronaviruses (eg, SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), influenza virus, and respiratory syncytial virus) related to disease severity. For example, patients with severe COVID-19 often exhibit elevated levels of inflammatory interleukins in the lungs that contribute to the lung injury experienced by COVID-19 patients.

在一些實施方式中，本文描述之方法和固體劑型涉及細菌性敗血症性休克、細胞介素風暴和/或病毒感染的治療或預防。在一些實施方式中，固體劑型包含棲組織普雷沃菌細菌（例如，普雷沃菌屬菌株B 50329（NRRL保藏號B 50329））。在一些實施方式中，固體劑型包含普雷沃菌屬菌株C（ATCC保藏號PTA-126140）。In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of bacterial septic shock, cytokine storm, and/or viral infection. In some embodiments, the solid dosage form comprises Prevotella histotropes bacteria (eg, Prevotella strain B 50329 (NRRL Deposit No. B 50329)). In some embodiments, the solid dosage form comprises Prevotella strain C (ATCC Deposit No. PTA-126140).

在一些實施方式中，本文描述之方法和固體劑型涉及治療或預防病毒感染，例如呼吸道病毒感染，例如冠狀病毒感染（例如，MERS（中東呼吸綜合症），嚴重急性呼吸綜合症（SARS）感染，例如SARS-CoV-2感染），流感感染和/或呼吸道合胞病毒感染。在一些實施方式中，本文提供的本文描述之方法和固體劑型用於治療冠狀病毒感染（例如，MERS感染，嚴重急性呼吸綜合症（SARS）感染，例如SARS-CoV-2感染）。在一些實施方式中，本文提供了用於治療COVID-19之方法和固體劑型。In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of viral infections, such as respiratory viral infections, such as coronavirus infections (e.g., MERS (Middle East Respiratory Syndrome), Severe Acute Respiratory Syndrome (SARS) infection, such as SARS-CoV-2 infection), influenza infection and/or respiratory syncytial virus infection. In some embodiments, the methods and solid dosage forms described herein provided herein are used to treat coronavirus infections (eg, MERS infection, severe acute respiratory syndrome (SARS) infection, eg, SARS-CoV-2 infection). In some embodiments, provided herein are methods and solid dosage forms for treating COVID-19.

在一些實施方式中，本文描述之方法和固體劑型涉及病毒感染的治療或預防。在一些實施方式中，感染係冠狀病毒感染、流感感染和/或呼吸道合胞病毒感染。在一些實施方式中，病毒感染係SARS-CoV-2感染。In some embodiments, the methods and solid dosage forms described herein relate to the treatment or prevention of viral infections. In some embodiments, the infection is a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection. In some embodiments, the viral infection is a SARS-CoV-2 infection.

在一些實施方式中，向受試者施用另外的療法。在一些實施方式中，另外的療法包含抗病毒藥物。在一些實施方式中，另外的療法包含抗病毒藥物，例如利巴韋林、神經胺酸酶抑制劑、蛋白酶抑制劑、重組干擾素、抗體、奧司他韋、紮那米韋、帕拉米韋或巴羅薩韋瑪波酯。在一些實施方式中，另外的療法包含羥氯喹和/或氯喹。在一些實施方式中，另外的療法包含瑞德西韋。在一些實施方式中，另外的療法包含從感染受試者的相同病毒的感染中恢復的受試者的血漿（例如，從SARS-CoV-2感染中恢復的受試者的血漿）。在一些實施方式中，另外的療法包括抗炎劑，例如NSAID或抗炎類固醇。在一些實施方式中，另外的療法包括地塞米松。In some embodiments, an additional therapy is administered to the subject. In some embodiments, the additional therapy comprises antiviral drugs. In some embodiments, the additional therapy comprises antiviral drugs such as ribavirin, neuraminidase inhibitors, protease inhibitors, recombinant interferons, antibodies, oseltamivir, zanamivir, paramil Viagra or barosavir maplelate. In some embodiments, the additional therapy comprises hydroxychloroquine and/or chloroquine. In some embodiments, the additional therapy comprises remdesivir. In some embodiments, the additional therapy comprises plasma from a subject who has recovered from an infection with the same virus that infected the subject (eg, plasma from a subject who has recovered from a SARS-CoV-2 infection). In some embodiments, additional therapy includes anti-inflammatory agents, such as NSAIDs or anti-inflammatory steroids. In some embodiments, the additional therapy includes dexamethasone.

在一些實施方式中，另外的療法包含對IL-6和/或IL-6受體具有特異性的抗體。在一些實施方式中，另外的療法包含托珠單抗（Actemra®）。在一些實施方式中，另外的療法包含薩瑞魯單抗（Kevzara®）。In some embodiments, the additional therapy comprises antibodies specific for IL-6 and/or the IL-6 receptor. In some embodiments, the additional therapy comprises tocilizumab (Actemra®). In some embodiments, the additional therapy comprises sarelumab (Kevzara®).

在一些實施方式中，另外的療法可以包含抗病毒療法。例如，抗病毒療法可包含核苷酸類似物，例如瑞德西韋、伽利德韋或克拉夫定；病毒RNA聚合酶抑制劑，例如法匹雷韋或伽利德韋；蛋白酶抑制劑，如利托那韋、達盧那韋或丹諾普韋；病毒膜融合抑制劑，如烏芬諾韋；和/或抗SARS-CoV-2血漿。In some embodiments, additional therapy may comprise antiviral therapy. For example, antiviral therapy may include nucleotide analogs such as remdesivir, galidesvir or clavudine; viral RNA polymerase inhibitors such as fapiravir or galidesvir; protease inhibitors, Such as ritonavir, darunavir, or danoprevir; viral membrane fusion inhibitors such as uvenovir; and/or anti-SARS-CoV-2 plasma.

在一些實施方式中，另外的療法可以包括抗炎療法。例如，該抗炎療法可以包括皮質類固醇；西羅莫司；阿那白滯素；filamod；或抗體。在一些實施方式中，抗體可以包括GMSF抑制劑，例如侖茲魯單抗或瑾司魯單抗；抗IL1 β抑制劑，例如卡那單抗；IL-6抑制劑，例如托珠單抗或司妥昔單抗；IL-6R抑制劑，例如薩瑞魯單抗；和/或CCR5拮抗劑，例如來羅單抗（leronlimab）。In some embodiments, additional therapy may include anti-inflammatory therapy. For example, the anti-inflammatory therapy can include corticosteroids; sirolimus; anakinra; filamod; In some embodiments, antibodies may include GMSF inhibitors, such as lenzcalumab or gensirumab; anti-IL1β inhibitors, such as canakinumab; IL-6 inhibitors, such as tocilizumab or Siltuximab; IL-6R inhibitors, such as sarrelumab; and/or CCR5 antagonists, such as leronlimab.

在一些實施方式中，另外的療法可以包括JAK抑制劑，例如巴瑞替尼、盧梭替尼、托法替尼和/或帕利替尼。In some embodiments, the additional therapy may include a JAK inhibitor, such as baricitinib, ruxolitinib, tofacitinib, and/or palitinib.

在一些實施方式中，另外的療法可以包含TLR7促効劑，例如咪喹莫特或reisquimod。In some embodiments, the additional therapy may comprise a TLR7 agonist, such as imiquimod or reisquimod.

在一些實施方式中，另外的療法可以包含基於細胞的療法。例如，基於細胞的療法可以包含Remestemcel-L；骨髓幹細胞療法，例如MultiStem或Bm-Allo-MSC；間充質基質細胞；和/或脂肪衍生的間充質幹細胞，例如AstroStem。In some embodiments, additional therapy may comprise cell-based therapy. For example, a cell-based therapy may comprise Remestemcel-L; bone marrow stem cell therapy, such as MultiStem or Bm-Allo-MSC; mesenchymal stromal cells; and/or adipose-derived mesenchymal stem cells, such as AstroStem.

在一些實施方式中，另外的療法可以包含ACE受體抑制劑。In some embodiments, the additional therapy may comprise an ACE receptor inhibitor.

在一些實施方式中，另外的療法可以包含σ1和/或σ2受體的調節劑。 γ 照射：樣本方案： In some embodiments, the additional therapy may comprise modulators of σ1 and/or σ2 receptors. Gamma Irradiation: Sample Protocol:

可以在環境溫度下以17.5 kGy輻射單位對粉末進行γ輻照。可以在乾冰存在下以25 kGy輻射單位對冷凍生物質進行γ輻照。 冷凍生物質製備：樣本方案 The powder can be gamma irradiated at ambient temperature with a radiation unit of 17.5 kGy. Frozen biomass can be gamma irradiated at 25 kGy radiation units in the presence of dry ice. Frozen Biomass Preparation: Sample Protocol

在達到所需水平的細菌培養物生長後，離心培養物，棄去上清液，使沈澱盡可能乾燥。渦旋沈澱以使生物質疏鬆。將沈澱重懸於所需的冷凍保護劑溶液中，轉移至低溫管中，並在液氮中速凍。儲存在-80攝氏度的冰箱中。 粉末製備：樣本方案 After the desired level of bacterial culture growth has been achieved, the culture is centrifuged, the supernatant discarded and the pellet dried as much as possible. Vortex the pellet to loosen the biomass. Resuspend the pellet in the desired cryoprotectant solution, transfer to a cryogenic tube, and snap freeze in liquid nitrogen. Store in a -80 °C freezer. Powder Preparation: Sample Protocol

在達到所需水平的細菌培養物生長後，將培養物離心，棄去上清液，使沈澱盡可能乾燥。將沈澱重懸於所需的冷凍保護劑溶液中，製成配製的細胞糊。冷凍保護劑可包括例如麥芽糊精、抗壞血酸鈉、麩胺酸鈉和/或氯化鈣。將配製的細胞糊裝載到不銹鋼託盤上，然後裝載到冷凍乾燥機中，例如以定義的循環參數在自動模式下運行。將冷凍乾燥的產品送入銑床中，並收集所得的粉末。After the desired level of bacterial culture growth has been achieved, the culture is centrifuged, the supernatant is discarded, and the pellet is kept as dry as possible. Resuspend the pellet in the desired cryoprotectant solution to make a formulated cell paste. Cryoprotectants may include, for example, maltodextrin, sodium ascorbate, sodium glutamate, and/or calcium chloride. The formulated cell paste is loaded onto stainless steel trays and loaded into a freeze dryer, e.g. run in automatic mode with defined cycle parameters. The freeze-dried product is fed into a milling machine and the resulting powder is collected.

將粉末在2-8攝氏度（例如在4攝氏度）下，儲存於例如乾燥器中（例如真空密封袋中）。 實例實例1：作為EV來源的代表性菌株 The powder is stored eg in a desiccator (eg in a vacuum sealed bag) at 2-8°C (eg at 4°C). Examples Example 1: Representative strains as EV sources

從表J中列出的菌株中分離出分泌型微生物胞外囊泡（smEV）。表J中還提供了每種菌株的革蘭氏染色、細胞壁結構和分類學分類的資訊。Secreted microbial extracellular vesicles (smEVs) were isolated from the strains listed in Table J. Information on the Gram stain, cell wall structure and taxonomic classification of each strain is also provided in Table J.

表J中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌可以用於本文描述的固體劑型中。Bacteria of the taxonomic groups (eg, class, order, family, genus, species, or strain) listed in Table J can be used in the solid dosage forms described herein.

表J中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌的mEV可以用於本文描述的固體劑型中。 [ 表 J] ：胞外囊泡（ EV ）由其分離出的菌株 菌株 革蘭氏染色 細胞被膜結構 門 綱 目 科 狄氏副擬桿菌DRLU022118 A ILEUM-6 革蘭氏染色陰性 雙層 擬桿菌門 擬桿菌綱 擬桿菌目 卟啉單胞菌科 古氏副擬桿菌S4 革蘭氏染色陰性 雙層 擬桿菌門 擬桿菌綱 擬桿菌目 卟啉單胞菌科 棲組織普雷沃菌 革蘭氏染色陰性 雙層 擬桿菌門 擬桿菌綱 擬桿菌目 普雷沃菌科 棲組織普雷沃菌 革蘭氏染色陰性 雙層 擬桿菌門 擬桿菌綱 擬桿菌目 普雷沃菌科 Fournierella massiliensisS10 GIMucosa-297 革蘭氏染色陰性 單層 厚壁菌門 梭菌綱 真細菌目 顫螺旋菌科（以前為瘤胃菌科） Harryflintia acetisporaS4-M5 革蘭氏染色陰性 單層 厚壁菌門 梭菌綱 真細菌目 顫螺旋菌科 馬賽布勞特氏菌S1046-4A5 革蘭氏染色陰性 單層 厚壁菌門 梭菌綱 真細菌目 毛螺菌科 地中海桿菌/活潑 [ 瘤胃球菌 ]S10 GIMucosa-412 革蘭氏染色陰性 單層 厚壁菌門 梭菌綱 真細菌目 毛螺菌科 艱難梭菌S10 GImucosa-525 革蘭氏染色陽性 單層 厚壁菌門 梭菌綱 真細菌目 消化鏈球菌科 Aminipila屬物種S16-M4 革蘭氏染色陽性 單層 厚壁菌門 梭菌綱 真細菌目 梭菌目XIII科/地位未定41/[真細菌目，無科] 巨型球菌屬物種S29-N3 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 巨型球菌屬物種S1007 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 菲利克斯月形單胞菌S34N-300R 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 月形單胞菌目 月形單胞菌科 小韋榮氏球菌S14Ileum-201 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 Propionispora屬物種DSM100705-1A 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 月形單胞菌目 Sporomusaceae Rarimicrobium hominisS24RS2-T2-5 革蘭氏染色陰性 雙層 互養菌門 互養菌綱 互養菌目 互養菌科 埃夫裡氯酸桿菌S29-M8 革蘭氏染色陰性 雙層 互養菌門 互養菌綱 互養菌目 互養菌科 小韋榮氏球菌S14-205 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 韋榮氏球菌屬物種/殊異ECD01-DP-201 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 小韋榮氏球菌/殊異ECD01-DP-223 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 小韋榮氏球菌S16 GIMucosa-95 革蘭氏染色陰性 雙層 厚壁菌門 Negativicutes 韋榮球氏菌屬目 韋榮氏球菌科 實例2：製備包含小韋榮氏球菌的固體劑型 mEVs of bacteria from taxonomic groups (eg, class, order, family, genus, species, or strain) listed in Table J can be used in the solid dosage forms described herein. [ Table J ] : Strains from which extracellular vesicles ( EV ) were isolated strain a cell membrane structure Door outlining head division Parabacteroides distrobacter DRLU022118 A ILEUM-6 Gram negative double layer Bacteroidetes Bacteroides Bacteroidales Porphyromonas Parabacteroides guerzii S4 Gram negative double layer Bacteroidetes Bacteroides Bacteroidales Porphyromonas Prevotella histotropica Gram negative double layer Bacteroidetes Bacteroides Bacteroidales Prevotaceae Prevotella histotropica Gram negative double layer Bacteroidetes Bacteroides Bacteroidales Prevotaceae Fournierella massiliensis S10 GIMucosa-297 Gram negative single layer Firmicutes Clostridia Eubacteriales Fibrospiraceae (formerly Ruminobacteriaceae) Harryflintia acetispora S4-M5 Gram negative single layer Firmicutes Clostridia Eubacteriales Fibrospiraceae Broutia marseille S1046-4A5 Gram negative single layer Firmicutes Clostridia Eubacteriales Lachnospiraceae Mederenebacterium / Viva [ Ruminococcus ] S10 GIMucosa-412 Gram negative single layer Firmicutes Clostridia Eubacteriales Lachnospiraceae Clostridium difficile S10 GImucosa-525 Gram positive single layer Firmicutes Clostridia Eubacteriales Peptostreptococcus Aminipila species S16-M4 Gram positive single layer Firmicutes Clostridia Eubacteriales Clostridiaceae Family XIII/Status indeterminate 41/[Eubacteriales, no families] Megasphaera sp. S29-N3 Gram negative double layer Firmicutes Negativicutes Veillonellales Veillonellaceae Megasphaera sp. S1007 Gram negative double layer Firmicutes Negativicutes Veillonellales Veillonellaceae Luenomonas Felix S34N-300R Gram negative double layer Firmicutes Negativicutes Luneomonales Lunatomonadaceae Veillonella parvum S14Ileum-201 Gram negative double layer Firmicutes Negativicutes Veillonellales Veillonellaceae Propionispora genus DSM100705-1A Gram negative double layer Firmicutes Negativicutes Luneomonales Sporomusaceae Rarimicrobium hominis S24RS2-T2-5 Gram negative double layer Syntrophy Syntrophs Syntrophyles Syntrophyceae Chlorobacter efrifolia S29-M8 Gram negative double layer Syntrophy Syntrophs Syntrophyles Syntrophyceae Veillonella parvum S14-205 Gram negative double layer Firmicutes Negativicutes Veillonellales Veillonellaceae Veillonella sp./Different ECD01-DP-201 Gram negative double layer Firmicutes Negativicutes Veillonellales Veillonellaceae Veillonella parvum/Different ECD01-DP-223 Gram negative double layer Firmicutes Negativicutes Veillonellales Veillonellaceae Veillonella parvum S16 GIMucosa-95 Gram negative double layer Firmicutes Negativicutes Veillonellales Veillonellaceae Example 2: Preparation of solid dosage forms comprising Veillonella parvum

製備表K中配方的片劑： [ 表 K] ：兩種活性片劑的組成（ 400 mg ） 材料 高劑量 低劑量 % w/w mg/ 片 % w/w mg/ 片 小韋榮氏球菌（DS（原料藥）/粉末） 33.0 132 6.6 26.4 矽化微晶纖維素（PROSOLV ® SMCC HD90） 50.0 200 76.4 305.6 交聚維酮 15.0 60 15.0 60 硬脂酸鎂 1.0 4 1.0 4 膠態二氧化矽 1.0 4 1.0 4 Preparation of tablets of the formulation in Table K: [ Table K ] : Composition of the two active tablets ( 400 mg ) Material high dose low dose %w/w mg/ tablet %w/w mg/ tablet Veillonella parvum (DS (drug substance)/powder) 33.0 132 6.6 26.4 Silicified Microcrystalline Cellulose (PROSOLV ® SMCC HD90) 50.0 200 76.4 305.6 Crospovidone 15.0 60 15.0 60 Magnesium stearate 1.0 4 1.0 4 colloidal silica 1.0 4 1.0 4

表K中的小韋榮氏球菌菌株係小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）。在摻入藥物物質之前對細菌進行γ射線照射。 實例3：包衣配製物 The Veillonella parvum strain in Table K is Veillonella parvum strain A (ATCC Accession No. PTA-125691). Bacteria were gamma-irradiated prior to incorporation of drug substances. Example 3: Coating Formulation

包衣溶液組成及製程參數見表L和表M： [ 表 L] ：小韋榮氏球菌單片劑崩散結果 批 \r\n 參考 儲存條件 時間點 （月） 結果（ hh:mm:ss ） 0.1 M HCl 6.8 PH 緩衝液 小韋榮氏球菌高劑量 2°C-8°C 初始 DND* 00:19:08 小韋榮氏球菌低劑量 2°C-8°C 初始    DND* 00:09:05 * DND-未崩散 [ 表 M] ：包衣懸浮液的配製物組成 材料 粉衣層 頂包衣層（ Top-coat ，腸溶的） 組成成分 % (w/w) 組成成分 % (w/w) Kollicoat MAE 100P - 15.00 TEC - 2.25 滑石粉 - 3.00 補充水 - 79.75 歐巴代 II白色 15.0 - WFI 85.0 - 總計 100.0 100.0 The coating solution composition and process parameters are shown in Table L and Table M: [ Table L ] : Disintegration results of Veillonella parvum single tablet Batch \r\ nReference Storage conditions time point (month) result ( hh:mm:ss ) 0.1 M HCl 6.8 pH buffer Veillonella parvum high dose 2°C-8°C initial DND* 00:19:08 Veillonella parvum low dose 2°C-8°C initial DND* 00:09:05 *DND - Not Disintegrated [ Table M ] : Formulation Composition of Coating Suspension Material Powder coat Top coating layer ( Top-coat , enteric-coated) Composition % (w/w) Composition % (w/w) Kollicoat MAE 100P - 15.00 TEC - 2.25 talcum powder - 3.00 add water - 79.75 Opadry II White 15.0 - WFI 85.0 - total 100.0 100.0

包衣懸浮液製造程序： 1.  將水分成兩部分，然後將第一部分注射用水分配到去皮不銹鋼容器中。 2.  稱重並分配檸檬酸三乙酯到合適的去皮容器中。 3.  將已分配的檸檬酸三乙酯添加到水中，同時用頂置式攪拌器混合。 4.  稱重滑石並將其分配到合適的去皮容器中。 5.  將已分配的滑石緩慢添加到水/檸檬酸三乙酯溶液中，同時用頂置式攪拌器混合。 6.  滑石完全水合後，將容器轉移到Silverson。均質化至少10分鐘，確保所有滑石已完全分散/均質化，沒有任何結塊並且沒有材料黏附在混合器頭部上。 7.  將第二部分注射用水分配到去皮不銹鋼容器中 8.  稱重並將Kollicoat分配到合適的去皮容器中 9.  將已分配的Kollicoat緩慢添加到步驟7的水中，同時用頂置式攪拌器混合。 10.      繼續混合直到所有的Kollicoat添加完成並完全水合且分散，沒有任何結塊並且沒有材料黏附在槳上。 11.      將水/檸檬酸三乙酯/滑石懸浮液轉移至頂置式攪拌器中並開始混合。 12.      在繼續混合的同時，將Kollicoat懸浮液轉移到容器中。以適當的速度混合至少45分鐘以形成渦流，不進行任何充氣。 13.      使包衣懸浮液通過500 µm的篩進入不銹鋼容器。確保所有固體均通過篩網。 實例4：製備包含棲組織普雷沃菌smEV的固體劑型 Coating Suspension Manufacturing Procedure: 1. Divide the water into two parts and dispense the first part of the water for injection into the peeled stainless steel container. 2. Weigh and dispense triethyl citrate into suitable tare containers. 3. Add the dispensed triethyl citrate to the water while mixing with an overhead stirrer. 4. Weigh and dispense the talc into suitable tare containers. 5. Slowly add the dispensed talc to the water/triethyl citrate solution while mixing with an overhead stirrer. 6. After the talc is fully hydrated, transfer the container to Silverson. Homogenize for at least 10 minutes, making sure all talc is fully dispersed/homogenized without any lumps and no material sticking to the mixer head. 7. Dispense the second portion of water for injection into the peeled stainless steel container 8. Weigh and dispense Kollicoat into suitable tare containers 9. Slowly add the dispensed Kollicoat to the water from step 7 while mixing with an overhead mixer. 10. Continue mixing until all the Kollicoat addition is complete and fully hydrated and dispersed without any lumps and no material sticking to the paddle. 11. Transfer the water/triethyl citrate/talc suspension to the overhead stirrer and start mixing. 12. While continuing to mix, transfer the Kollicoat suspension to a container. Mix at moderate speed to create a vortex for at least 45 minutes without any aeration. 13. Pass the coating suspension through a 500 µm sieve into a stainless steel container. Make sure all solids pass through the screen. Example 4: Preparation of Solid Dosage Forms Comprising Prevotella histopathogens smEV

製備表N中配方的片劑： [ 表 N] ：活性片劑的組成（ 400 mg ） 片劑 低強度 中等強度 高強度 棲組織普雷沃菌smEV（原料藥/粉末） 10%（LS DS） 10%（HS DS） 62.5%（HS DS） SMCC HD90 72.5% 72.5% 20.0% 交聚維酮 15.0% 15.0% 15.0% SiO 2 1.0% 1.0% 1.0% 硬脂酸鎂 1.5% 1.5% 1.5% 片劑重量（mg） 400 400 400 Preparation of tablets of the formulation in Table N: [ Table N ] : Composition of the active tablet ( 400 mg ) tablet low intensity medium intensity high strength Prevotella histohabitats smEV (API/powder) 10% (LSDS) 10% (HSDS) 62.5% (HSDS) SMCC HD90 72.5% 72.5% 20.0% Crospovidone 15.0% 15.0% 15.0% SiO 2 1.0% 1.0% 1.0% Magnesium stearate 1.5% 1.5% 1.5% Tablet weight (mg) 400 400 400

表N中的棲組織普雷沃菌smEV來自菌株棲組織普雷沃菌菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes smEV in Table N was from the strain Prevotella histotropes strain B 50329 (NRRL Deposit No. B 50329).

HS DS：高強度原料藥。HS DS: High Strength API.

LS DS：低強度原料藥。LS DS: Low Strength API.

LS DS藉由在凍乾前稀釋HS DS 10x（使用凍乾賦形劑）來製備。LS DS was prepared by diluting HS DS 10x (using lyophilization excipient) before lyophilization.

為了製備藥物組成物片劑，對含有smEV的原料藥（藥劑）進行濕法製粒。原料藥 (i) 與水混合；(ii) 在流化床乾燥器上乾燥；(iii) 研磨；(iv) 然後與表N中提供的藥品賦形劑共混。To prepare pharmaceutical composition tablets, wet granulation is performed on the drug substance (drug) containing smEV. The drug substance is (i) mixed with water; (ii) dried on a fluid bed drier; (iii) ground; (iv) then blended with the drug product excipients provided in Table N.

片劑為5.5 mm x 15.8 mm。Tablets are 5.5 mm x 15.8 mm.

10%（LS DS）片劑在6.8 pH下的平均核心崩散時間為00:25（mm:ss）。The average core disintegration time of 10% (LS DS) tablets at pH 6.8 was 00:25 (mm:ss).

然後用下表O中所示的兩種包衣配製物中的一種包衣10%低強度藥物物質（LS DS）片劑。包衣片劑在6.8 pH下的崩散時間見表O。 [ 表 O] ：經包衣的 10% 低強度（ LS DS ）活性片劑的崩散時間 10% LS DS棲組織普雷沃菌smEV片劑上的包衣 酸然後6.8 pH崩散時間（mm:ss） Kollicoat MAE 30DP（10.67%） 15% PG和7.5% SiO 2 06:54 06:58 05:12 05:12 07:34 05:16 Kollicoat MAE 30DP（10.23%） 15% PG和30%滑石粉 07:06 07:36 07:40 實例5：包含8%、23%、40%和50%質量棲組織普雷沃菌細菌活性物質（DS）的650 mg固體劑型的製備 The 10% low strength drug substance (LS DS) tablets were then coated with one of the two coating formulations shown in Table O below. See Table O for the disintegration times at pH 6.8 for the coated tablets. [ Table O ] : Disintegration times of coated 10% low strength ( LS DS ) active tablets Coating on 10% LS DS Prevotella histotropes smEV Tablets Acid then 6.8 pH disintegration time (mm:ss) Kollicoat MAE 30DP (10.67%) 15% PG and 7.5% SiO 2 06:54 06:58 05:12 05:12 07:34 05:16 Kollicoat MAE 30DP (10.23%) 15% PG and 30% talc 07:06 07:36 07:40 Example 5: Preparation of 650 mg solid dosage forms comprising 8%, 23%, 40% and 50% by mass of Prevotella histolivans bacterial active substance (DS)

製備表P中配方的片劑： [ 表 P] ：活性片劑的組成（ 650 mg ） 8% 活性 23% 活性 組分 質量百分比（ % ） 質量（ g ） 質量百分比（ % ） 質量（ g ） 棲組織普雷沃菌細菌DS 8 8 23 23 SMCC HD90 42 42 27 27 LH-B1 27 27 27 27 AcDiSol 6 6 6 6 科利當CL-F 15 15 15 15 二氧化矽 1 1 1 1 硬脂酸鎂 1 1 1 1 總和 100 100 100 100 40% 活性 50% 活性 組分 質量百分比（ % ） 質量（ g ） 質量百分比（ % ） 質量（ g ） 棲組織普雷沃菌細菌DS 40 64 50 85 SMCC HD90 10 16 5 8.5 LH-B1 27 43.2 22 37.4 AcDiSol 6 9.6 6 10.2 科利當CL-F 15 24 15 25.5 二氧化矽 1 1.6 1 1.7 硬脂酸鎂 1 1.6 1 1.7 總和 100 160 100 170 Preparation of tablets of the formulation in Table P: [ Table P ] : Composition of the active tablet ( 650 mg ) 8% active 23% activity components Mass percentage ( % ) mass ( g ) Mass percentage ( % ) mass ( g ) Prevotella histoclita bacteria DS 8 8 twenty three twenty three SMCC HD90 42 42 27 27 LH-B1 27 27 27 27 AcDiSol 6 6 6 6 Corydown CL-F 15 15 15 15 silicon dioxide 1 1 1 1 Magnesium stearate 1 1 1 1 sum 100 100 100 100 40% activity 50% activity components Mass percentage ( % ) mass ( g ) Mass percentage ( % ) mass ( g ) Prevotella histoclita bacteria DS 40 64 50 85 SMCC HD90 10 16 5 8.5 LH-B1 27 43.2 twenty two 37.4 AcDiSol 6 9.6 6 10.2 Corydown CL-F 15 twenty four 15 25.5 silicon dioxide 1 1.6 1 1.7 Magnesium stearate 1 1.6 1 1.7 sum 100 160 100 170

表P中的棲組織普雷沃菌細菌來自菌株棲組織普雷沃菌菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes bacterium in Table P is from the strain Prevotella histotropes strain B 50329 (NRRL Deposit No. B 50329).

對於8%、23%、40%和50%活性配製物中的每一種，將除硬脂酸鎂之外的表P的組分在一起混合15分鐘。然後添加硬脂酸鎂，並且將混合物再混合3分鐘。然後將混合粉末壓製成650 mg片劑。將8%和23%活性粉末以約10 kN（壓實力）壓製。將40%活性粉末以約8、10、12或15 kN壓製。將50%活性粉末以約10、12或15 kN壓製。片劑為7.1 mm x 17.4 mm。For each of the 8%, 23%, 40% and 50% active formulations, the components of Table P except magnesium stearate were mixed together for 15 minutes. Magnesium stearate was then added and the mixture blended for an additional 3 minutes. The blended powders are then compressed into 650 mg tablets. The 8% and 23% active powders were compacted at about 10 kN (compaction force). The 40% active powder was compressed at about 8, 10, 12 or 15 kN. The 50% active powder was compressed at about 10, 12 or 15 kN. Tablets are 7.1 mm x 17.4 mm.

崩散時間隨活性和壓實力的百分比而變化，如下表Q所示： [ 表 Q] ：活性片劑（ 650 mg ）的在 6.8 pH 下的崩散時間相比於壓實力 崩散時間（ mm:ss ）相比於壓實力 8 kN 10 kN 12 kN 15 kN 8%活性    1:00       23%活性    2:27       40%活性 7:06 8:56 6:52 5:01 50%活性 14:12 11:45 11:35 實例6：包含10%、20%和40%質量棲組織普雷沃菌細菌活性物質（DS）的400 mg和500 mg固體劑型的製備 Disintegration time as a function of percentage of active and compaction force is shown in Table Q below: [ Table Q ] : Disintegration time at 6.8 pH for active tablet ( 650 mg ) compared to compaction force Breakup time ( mm:ss ) compared to compaction force 8 kN 10 kN 12kN 15 kN 8% activity 1:00 23% active 2:27 40% active 7:06 8:56 6:52 5:01 50% activity 14:12 11:45 11:35 Example 6: Preparation of 400 mg and 500 mg solid dosage forms comprising 10%, 20% and 40% by mass of Prevotella histolivans bacterial active substance (DS)

製備表R中配方的片劑： [ 表 R] ：活性片劑的組成（ 400/500 mg ） 組分 質量百分比（ % ） 棲組織普雷沃菌細菌DS 10 20 40 SMCC HD90 40 30 10 LH-B1 27 27 27 AcDiSol 6 6 6 科利當CL-F 15 15 15 二氧化矽 1 1 1 硬脂酸鎂 1 1 1 總和 100 100 100 Preparation of tablets of the formulation in Table R: [ Table R ] : Composition of active tablet ( 400/500 mg ) components Mass percentage ( % ) Prevotella histoclita bacteria DS 10 20 40 SMCC HD90 40 30 10 LH-B1 27 27 27 AcDiSol 6 6 6 Corydown CL-F 15 15 15 silicon dioxide 1 1 1 Magnesium stearate 1 1 1 sum 100 100 100

表R中的棲組織普雷沃菌細菌來自菌株棲組織普雷沃菌菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes bacterium in Table R is from the strain Prevotella histotropes strain B 50329 (NRRL Deposit No. B 50329).

表R中配方的片劑如實例5中上表P形成為具有不同質量百分比的棲組織普雷沃菌細菌DS和SMCC HD90的400 mg和500 mg片劑。 實例7：包含棲組織普雷沃菌細菌的具有低崩散時間的固體劑型的製備 Tablets of the formulations in Table R were formed as 400 mg and 500 mg tablets with different mass percentages of Prevotella histotropes bacteria DS and SMCC HD90 as in Table P above in Example 5. Example 7: Preparation of solid dosage forms with low disintegration time comprising Prevotella histophilum bacteria

製備表S中配方的片劑： [ 表 S] ：在 6.8 pH 下崩散時間短的活性片劑的組成（ 400 mg ）    27% LH-B1 配製物 32% LH-B1 配製物 組分 質量百分比 質量（g） 質量百分比 質量（g） 棲組織普雷沃菌細菌DS 40.00% 20 40.00% 20 SMCC HD90 10.00% 5 5.00% 2.5 LH-B1 27.00% 13.5 32.00% 16 AcDiSol SD-711NF 6.00% 3 6.00% 3 SiO₂ 1.00% 0.5 1.00% 0.5 科利當CL-F 15.00% 7.5 15.00% 7.5 硬脂酸鎂 1.00% 0.5 1.00% 0.5 總和 100.00% 50 100.00% 50 Preparation of tablets of the formulation in Table S: [ Table S ] : Composition of active tablet with short disintegration time at 6.8 pH ( 400 mg ) 27% LH-B1 formulation 32% LH-B1 formulation components mass percentage mass (g) mass percentage mass (g) Prevotella histotropica bacterium DS 40.00% 20 40.00% 20 SMCC HD90 10.00% 5 5.00% 2.5 LH-B1 27.00% 13.5 32.00% 16 AcDiSol SD-711NF 6.00% 3 6.00% 3 SiO₂ 1.00% 0.5 1.00% 0.5 Corydown CL-F 15.00% 7.5 15.00% 7.5 Magnesium stearate 1.00% 0.5 1.00% 0.5 sum 100.00% 50 100.00% 50

表S中的棲組織普雷沃菌細菌來自菌株棲組織普雷沃菌菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes bacterium in Table S is from the strain Prevotella histotropes strain B 50329 (NRRL Deposit No. B 50329).

表S中配方的片劑如實例5中上表P形成為400 mg片劑（9.55 mm直徑）。發現該等片劑在6.8 pH下的崩散時間少於10分鐘。27% LH-B1配製物在6.8 pH下的崩散時間為9:17分鐘。37% LH-B1配製物在6.8 pH下的崩散時間為8:07分鐘。 實例8：包含通過#200篩網的棲組織普雷沃菌細菌DS的固體劑型的製備 Tablets of the formulation in Table S were formed as 400 mg tablets (9.55 mm diameter) as Table P above in Example 5. The disintegration time of the tablets was found to be less than 10 minutes at 6.8 pH. The disintegration time of the 27% LH-B1 formulation at 6.8 pH was 9:17 minutes. The disintegration time of the 37% LH-B1 formulation at 6.8 pH was 8:07 minutes. Example 8: Preparation of Solid Dosage Forms Comprising Prevotella histolivans Bacteria DS Passing #200 Mesh Mesh

製備表T中配方的片劑： [ 表 T] ：具有通過 #200 篩網的 DS 的活性片劑的組成（ 400 mg ） 20% DS #200 篩網 40% DS #200 篩網 組分 質量百分比 質量（ g ） 質量百分比 質量（ g ） 棲組織普雷沃菌細菌DS（通過#200篩網） 20.00% 10 40.00% 20 SMCC HD90 30.00% 15 10.00% 5 LH-B1 27.00% 13.5 27.00% 13.5 AcDiSol SD-711 NF 6.00% 3 6.00% 3 科利當CL-F 15.00% 7.5 15.00% 7.5 二氧化矽 1.00% 0.5 1.00% 0.5 硬脂酸鎂 1.00% 0.5 1.00% 0.5 總和 100.00% 50 100.00% 50 Preparation of tablets of the formulation in Table T: [ Table T ] : Composition of active tablet with DS passing #200 sieve ( 400 mg ) 20% DS #200 mesh 40% DS #200 screen components mass percentage mass ( g ) mass percentage mass ( g ) Prevotella histotropes bacteria DS (through #200 sieve) 20.00% 10 40.00% 20 SMCC HD90 30.00% 15 10.00% 5 LH-B1 27.00% 13.5 27.00% 13.5 AcDiSol SD-711 NF 6.00% 3 6.00% 3 Corydown CL-F 15.00% 7.5 15.00% 7.5 silicon dioxide 1.00% 0.5 1.00% 0.5 Magnesium stearate 1.00% 0.5 1.00% 0.5 sum 100.00% 50 100.00% 50

表T中的棲組織普雷沃菌細菌來自菌株棲組織普雷沃菌菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes bacterium in Table T is from the strain Prevotella histotropes strain B 50329 (NRRL Deposit No. B 50329).

棲組織普雷沃菌細菌DS通過75微米篩（#200篩網）進行篩選。然後將其與二氧化矽混合10分鐘。然後添加除硬脂酸鎂外的所有其他組分並混合15分鐘。然後將硬脂酸鎂添加到混合物中並混合3分鐘。然後將粉末混合物壓製成400 mg片劑。將20% DS片劑以4.6-4.9 kN壓製並且產生400 mg片劑，平均厚度為約5.58 mm，平均硬度為約54.6N，在6.8 pH條件下平均崩散時間為2:22分鐘。將40% DS片劑以約6.2 kN壓製並且產生400 mg片劑，平均厚度為約5.84 mm，平均硬度為約58 N，在6.8 pH條件下平均崩散時間為約8分鐘。 實例9：包含通過500微米篩的棲組織普雷沃菌細菌DS的固體劑型的製備 Prevotella histotropes bacteria DS were screened through a 75 micron sieve (#200 sieve). Then mix it with the silica for 10 minutes. All other ingredients except the magnesium stearate were then added and mixed for 15 minutes. Magnesium stearate was then added to the mixture and mixed for 3 minutes. The powder blend is then compressed into 400 mg tablets. The 20% DS tablets were compressed at 4.6-4.9 kN and yielded 400 mg tablets with an average thickness of about 5.58 mm, an average hardness of about 54.6N, and an average disintegration time of 2:22 minutes at 6.8 pH. The 40% DS tablets were compressed at about 6.2 kN and produced 400 mg tablets with an average thickness of about 5.84 mm, an average hardness of about 58 N, and an average disintegration time of about 8 minutes at 6.8 pH. Example 9: Preparation of a Solid Dosage Form Comprising Prevotella histolivans Bacteria DS Passing a 500 Micron Sieve

製備表U中配方的片劑： [ 表 U] ：具有通過 500 微米篩的 DS 的活性片劑的組成 400 mg/9.5 mm （ 0.375" ） 組分 質量百分比 質量（ g ） 棲組織普雷沃菌細菌DS 40.00% 20 SMCC HD90 43.00% 21.5 SiO 2 1.00% 0.5 科利當CL-F 15.00% 7.5 硬脂酸鎂 1.00% 0.5 總和 100.00% 50 300 mg/8 mm （ 0.3125" ） 組分 質量百分比 質量（ g ） 棲組織普雷沃菌細菌DS 50.00% 25 SMCC HD90 33.00% 16.5 SiO 2 1.00% 0.5 科利當CL-F 15.00% 7.5 硬脂酸鎂 1.00% 0.5 總和 100.00% 50 Tablets of the formulation in Table U were prepared: [ Table U ] : Composition of active tablet with DS passing through a 500 micron sieve 400mg/9.5mm ( 0.375" ) components mass percentage mass ( g ) Prevotella histotropica bacterium DS 40.00% 20 SMCC HD90 43.00% 21.5 SiO 2 1.00% 0.5 Corydown CL-F 15.00% 7.5 Magnesium stearate 1.00% 0.5 sum 100.00% 50 300mg/8mm ( 0.3125" ) components mass percentage mass ( g ) Prevotella histotropica bacterium DS 50.00% 25 SMCC HD90 33.00% 16.5 SiO 2 1.00% 0.5 Corydown CL-F 15.00% 7.5 Magnesium stearate 1.00% 0.5 sum 100.00% 50

表U中的棲組織普雷沃菌細菌來自菌株棲組織普雷沃菌菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes bacterium in Table U is from the strain Prevotella histotropes strain B 50329 (NRRL Deposit No. B 50329).

棲組織普雷沃菌細菌DS通過500微米篩進行篩選。將除硬脂酸鎂外的表U的所有組分混合15分鐘。然後將硬脂酸鎂添加到混合物中並混合3分鐘。然後將混合物壓製成片劑，如下表V所示。 [ 表 V] ：表 T 片劑的特性 平均片劑特性 400 mg/9.5 mm （ 0.375" ） 300 mg/8 mm （ 0.3125" ） 壓實力（KN） 9 5.2 片劑重量（mg） 403.52 288.98 片劑厚度（mm） 5.85 6.07 片劑硬度（N） 163.5 101.3 崩散時間（mm:ss） 18:23 30:47 Prevotella histotropes bacteria DS were screened through a 500 micron sieve. All ingredients of Table U except magnesium stearate were mixed for 15 minutes. Magnesium stearate was then added to the mixture and mixed for 3 minutes. The blend was then compressed into tablets as shown in Table V below. [ Table V ] : Table T Tablet Characteristics Average Tablet Properties 400mg/9.5mm ( 0.375" ) 300mg/8mm ( 0.3125" ) Compression force (KN) 9 5.2 Tablet weight (mg) 403.52 288.98 Tablet thickness (mm) 5.85 6.07 Tablet hardness (N) 163.5 101.3 Collapse time (mm:ss) 18:23 30:47

表V中的崩散時間係在6.8 pH下測量的。 實例10：包含棲組織普雷沃菌細菌的泡騰固體劑型的製備 The disintegration times in Table V were measured at 6.8 pH. Example 10: Preparation of Effervescent Solid Dosage Forms Comprising Prevotella Histophilia Bacteria

製備表W中配方的泡騰片劑。 [ 表 W] ：活性泡騰片劑的組成 片劑配製物 配方 1 配方 2 組分 質量百分比 質量百分比 棲組織普雷沃菌細菌DS 40.00% 40.00% SiO 2 1.00% 1.00% 滑石粉 1.00% 1.00% 檸檬酸 5.00% 5.00% 碳酸氫鈉 6.50% 6.50% PVP-64    3.50% SMCC HD90 25.50% 22.00% 羧基乙酸澱粉鈉 2.00% - 交聚維酮-CL-F 18.00% 20.00% 硬脂醯富馬酸鈉 1.00% 1.00% 總和 100.00% 100.00% Effervescent tablets of the formulation in Table W were prepared. [ Table W ] : Composition of Active Effervescent Tablets tablet formulation Recipe 1 Recipe 2 components mass percentage mass percentage Prevotella histotropica bacterium DS 40.00% 40.00% SiO 2 1.00% 1.00% talcum powder 1.00% 1.00% citric acid 5.00% 5.00% sodium bicarbonate 6.50% 6.50% PVP-64 3.50% SMCC HD90 25.50% 22.00% Sodium starch glycolate 2.00% - Crospovidone-CL-F 18.00% 20.00% Sodium stearyl fumarate 1.00% 1.00% sum 100.00% 100.00%

表W中的棲組織普雷沃菌細菌來自菌株棲組織普雷沃菌菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes bacterium in Table W is from the strain Prevotella histotropes strain B 50329 (NRRL Deposit No. B 50329).

將除硬脂醯富馬酸鈉外的上表W中列出的所有組分均通過#40篩網。然後將該等組分混合、過篩並共混20分鐘。然後添加硬脂醯富馬酸鈉並將混合物混合3分鐘。然後將配方1的混合物以18 kN壓製以形成片劑。配方1片劑的硬度為130 N。配方2的混合物也被以8.4和14.2 kN壓實力壓製以形成片劑。All ingredients listed in Table W above except sodium stearyl fumarate were passed through a #40 screen. The components were then mixed, sieved and blended for 20 minutes. Sodium stearyl fumarate was then added and the mixture mixed for 3 minutes. The blend of Formulation 1 was then compressed at 18 kN to form tablets. The formulation 1 tablet has a hardness of 130 N. The blend of Formulation 2 was also compressed at 8.4 and 14.2 kN compaction forces to form tablets.

形成的片劑可以進一步用下表X-Z中的以下包衣配製物中的任何一種或多種包衣： [ 表 X] ：包衣溶液配製物 包衣溶液配製物 項# 材料 w/w% 數量（g） 1 Kollicoat MAE 30DP 50.00% 750 2 丙二醇 2.25% 33.75 3 純淨水 44.75% 671.25 4 滑石粉 3.00% 45 總計 100.00% 1500 [ 表 Y] ：彩色包衣溶液配製物 歐巴代黃色包衣配製物 組分 質量百分比 歐巴代黃色 15 DI水 85 總和 100 [ 表 Z] ：包衣溶液配製物 腸溶衣溶液配製物 組分 質量百分比 Eudragit L30 D55 39.23 檸檬酸三乙酯 2.35 滑石粉 5.89 DI水 52.53 總和 100 The formed tablets may be further coated with any one or more of the following coating formulations in Table XZ below: [ Table X ] : Coating Solution Formulations Coating Solution Formulation item# Material w/w% Quantity (g) 1 Kollicoat MAE 30DP 50.00% 750 2 Propylene Glycol 2.25% 33.75 3 pure water 44.75% 671.25 4 talcum powder 3.00% 45 total 100.00% 1500 [ Table Y ] : Color coating solution formulation Opadry yellow coating formulation components mass percentage Opadry yellow 15 DI water 85 sum 100 [ Table Z ] : Coating solution formulation Enteric coating solution formulation components mass percentage Eudragit L30 D55 39.23 triethyl citrate 2.35 talcum powder 5.89 DI water 52.53 sum 100

在包衣的每個階段測量雙包衣配方1片劑（歐巴代黃色，然後是腸溶衣）在6.8 pH下的崩散時間，並在下表AA中顯示，連同顯示了未包衣配方2片劑的崩散時間。 [ 表 AA] ：在 6.8 pH 下的平均崩散時間（ mm:ss ）    未包衣的片劑 經歐巴代黃色包衣 經歐巴代和腸溶包衣 配方1片劑 3:02 4:04 14:07 配方2片劑14.2 kN壓實力 4:49 - - 配方2片劑8.4 kN壓實力 2:17 - - 實例11：包含棲組織普雷沃菌細菌的具有不同SMCC、維格姆HD或PVP 64的固體劑型的製備 The disintegration time at 6.8 pH for the double-coated formulation 1 tablets (Opadry yellow followed by enteric coating) was measured at each stage of coating and is shown in Table AA below, along with the uncoated formulation Disintegration time of 2 tablets. [ Table AA ] : Average disintegration time at 6.8 pH ( mm:ss ) uncoated tablet Coated with Opadry Yellow Opadry and enteric coated Formula 1 Tablet 3:02 4:04 14:07 Formulation 2 Tablets 14.2 kN Compaction Force 4:49 - - Formulation 2 Tablets 8.4 kN Compaction Force 2:17 - - Example 11: Preparation of solid dosage forms with different SMCC, Vigum HD or PVP 64 comprising Prevotella histophilum bacteria

表AB中的配方係用不同量的維格姆 HD或PVP 64代替等質量百分比的SMCC製備的，如表AC所示。例如，在表AB中的配方中添加5%維格姆HD意味著SMCC減少5%：從52%到47%。 [ 表 AB] ：活性片劑的組成 組分 質量百分比 質量（ g ） 棲組織普雷沃菌細菌DS 25.00% 12.5 SiO 2 1.00% 0.5 滑石粉 1.00% 0.5 SMCC HD90 52.00% 26 交聚維酮-CL-F 20.00% 10 硬脂醯富馬酸鈉 1.00% 0.5 總和 100.00% 50 The formulations in Table AB were prepared by substituting different amounts of Vigum HD or PVP 64 for equal mass percentages of SMCC, as shown in Table AC. For example, adding 5% Vigham HD to the formulations in Table AB means a 5% reduction in SMCC: from 52% to 47%. [ Table AB ] : Composition of Active Tablets components mass percentage mass ( g ) Prevotella histoclita bacteria DS 25.00% 12.5 SiO 2 1.00% 0.5 talcum powder 1.00% 0.5 SMCC HD90 52.00% 26 Crospovidone-CL-F 20.00% 10 Sodium stearyl fumarate 1.00% 0.5 sum 100.00% 50

表AB中的棲組織普雷沃菌細菌來自菌株棲組織普雷沃菌菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes bacterium in Tables AB is from the strain Prevotella histotropes strain B 50329 (NRRL Deposit No. B 50329).

將表AB中的成分混合並壓製以形成片劑。 [ 表 AC] ：活性片劑的組成 以下壓實力時的硬度： 5 kN 10 kN 15 kN 表AB 47.8 132.9 197.5 5% PVP 64 58.0 153.1 218.8 10% PVP 64 16.8 53.7 100.1 5%維格姆 18.6 53.0 98.1 10%維格姆 15.3 45.0 83.1 The ingredients in Table AB are mixed and compressed to form tablets. [ Table AC ] : Composition of the active tablet Hardness at the following compaction times: 5 kN 10 kN 15 kN Table AB 47.8 132.9 197.5 5% PVP 64 58.0 153.1 218.8 10% PVP 64 16.8 53.7 100.1 5% Vigham 18.6 53.0 98.1 10% Wigham 15.3 45.0 83.1

表AC顯示了由以下配方製成的各種片劑的壓實力和硬度：(1) 表AB和 (2) 用PVP 64和維格姆HD替代表AB配方中等質量百分比的SMCC HD90。 [ 表 AD] ：活性片劑的特性 以下之後的脆性重量損失（ % ）： 壓實力（ kN ） 硬度（ N ） 最短崩散時間（ s ） 平均崩散時間（ s ） 100 轉 200 轉 表AB 4.9-5.3 47.83 44 59.33 0.000 0.000 5% PVP 64 4.7-5.1 58.00 82 107.17 0.025 0.348 10% PVP 64 9.7-10.1 53.07 158 762.83 0.383 0.717 5%維格姆 9.5-9.8 53.00 64 488.83 0.025 0.290 10%維格姆 12.7-13.0 67.9 254 1214.67 0.000 0.089 Tables AC show the compaction strength and hardness of various tablets made from (1) Table AB and (2) PVP 64 and Vigum HD replacing SMCC HD90 in the middle mass percentage of Table AB formulations. [ Table AD ] : Characteristics of the active tablet Brittle weight loss ( % ) after : Compaction force ( kN ) Hardness ( N ) The shortest disintegration time ( s ) Average disintegration time ( s ) 100 rpm 200 rpm Table AB 4.9-5.3 47.83 44 59.33 0.000 0.000 5% PVP 64 4.7-5.1 58.00 82 107.17 0.025 0.348 10% PVP 64 9.7-10.1 53.07 158 762.83 0.383 0.717 5% Vigham 9.5-9.8 53.00 64 488.83 0.025 0.290 10% Wigham 12.7-13.0 67.9 254 1214.67 0.000 0.089

表AD顯示了由表AB形成的以及維格姆HD或PVP 64配方替代SMCC百分比量後片劑的其他特性。 實例12：製備包含棲組織普雷沃菌細菌的固體劑型 Tables AD show other properties of the tablets formed from Tables AB and following replacement of the percentage amount of SMCC by Vigum HD or PVP 64 formulations. Example 12: Preparation of a solid dosage form comprising Prevotella histophilia bacteria

製備表AE中的藥物物質並將其摻入表AF的片劑組成物中： [ 表 AE] ： DS 組成 DS 組成 重量（ g ） 棲組織普雷沃菌細菌製備 120 HP-β-CD 30 The drug substance in Table AE is prepared and incorporated into the tablet composition of Table AF: [ Table AE ] : DS Composition DS composition weight ( g ) Preparation of Prevotella histoclita bacteria 120 HP-β-CD 30

表AE中的棲組織普雷沃菌細菌來自菌株棲組織普雷沃菌菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes bacterium in Tables AE is from the strain Prevotella histotropes strain B 50329 (NRRL Deposit No. B 50329).

將表AE中的組分混合然後添加到下表AF中的組分中。 [ 表 AF] ：片劑配製物 片劑組成 % % DS 50.0 60.0 SMCC HD90 37.0 27.0 PVP CL-F 7.0 7.0 AcDiSol SD 711 4.0 4.0 硬脂酸鎂 1.0 1.0 SiO 2 1.0 1.0 總和 100.0 100.0 The ingredients in Tables AE were mixed and then added to the ingredients in Tables AF below. [ Table AF ] : Tablet formulation tablet composition % % DS 50.0 60.0 SMCC HD90 37.0 27.0 PVP CL-F 7.0 7.0 AcDiSol SD 711 4.0 4.0 Magnesium stearate 1.0 1.0 SiO 2 1.0 1.0 sum 100.0 100.0

將表AF中的成分混合並壓製以形成片劑。 實例13：包含棲組織普雷沃菌細菌的濕法製粒固體劑型I的製備 The ingredients in Tables AF are mixed and compressed to form tablets. Example 13: Preparation of Wet Granulation Solid Dosage Form I Comprising Prevotella histolivans Bacteria

表AG顯示了用於藉由濕法製粒製程形成400 mg片劑的片劑配製物。 [ 表 AG] ：濕法製粒活性片的組成 片劑配製物 片劑組成 % % % DS顆粒 60.0 60.0 60.0 SMCC HD90 27.0 21.0 15.0 PVP CL-F 7.0 13.0 10.0 AcDiSol SD 711 4.0 4.0 4.0 LH-B1       9.0 硬脂酸鎂 1.0 1.0 1.0 SiO 2 1.0 1.0 1.0 總和 100.0 100.0 100.0 Table AG shows the tablet formulations used to form 400 mg tablets by wet granulation process. [ Table AG ] : Composition of wet granulated active tablets tablet formulation tablet composition % % % DS particles 60.0 60.0 60.0 SMCC HD90 27.0 21.0 15.0 PVP CL-F 7.0 13.0 10.0 AcDiSol SD 711 4.0 4.0 4.0 LH-B1 9.0 Magnesium stearate 1.0 1.0 1.0 SiO 2 1.0 1.0 1.0 sum 100.0 100.0 100.0

表AG中的棲組織普雷沃菌細菌來自菌株棲組織普雷沃菌菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes bacterium in Tables AG is from the strain Prevotella histotropes strain B 50329 (NRRL Deposit No. B 50329).

濕法製粒製程（製粒、乾燥和研磨）用於形成DS顆粒。然後將DS顆粒與表AG片劑配製物中的其他組分混合，並將混合物壓製以形成片劑。 實例14：包含棲組織普雷沃菌細菌的濕法製粒固體劑型II的製備 The wet granulation process (granulation, drying and grinding) is used to form DS granules. The DS granules were then blended with the other ingredients in Table AG Tablet Formulation and the blend was compressed to form tablets. Example 14: Preparation of Wet Granulation Solid Dosage Form II Comprising Prevotella histolivans Bacteria

表AH顯示了用於藉由濕法製粒製程形成400 mg片劑的片劑配製物。 [ 表 AH] ：濕法製粒活性片的組成 片劑配製物 片劑組成 % % % DS顆粒 60 60 60 SMCC HD90 15 5 0 PVP CL-F 10 15 17 AcDiSol SD 711 4 4 4 LH-B1 9 14 17 硬脂酸鎂 1 1 1 SiO 2 1 1 1 總和 100.0 100.0 100.0 Table AH shows the tablet formulations used to form 400 mg tablets by wet granulation process. [ Table AH ] : Composition of wet granulated active tablets tablet formulation tablet composition % % % DS particles 60 60 60 SMCC HD90 15 5 0 PVP CL-F 10 15 17 AcDiSol SD 711 4 4 4 LH-B1 9 14 17 Magnesium stearate 1 1 1 SiO 2 1 1 1 sum 100.0 100.0 100.0

表AH中的棲組織普雷沃菌細菌來自菌株棲組織普雷沃菌菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes bacterium in Tables AH is from the strain Prevotella histotropes strain B 50329 (NRRL Deposit No. B 50329).

將藥物物質（DS）顆粒配製物的組分混合以形成粉末。將DS顆粒配製物和黏合劑溶液用於濕法製粒製程（製粒、乾燥和研磨）以形成DS顆粒。然後將DS顆粒與片劑配製物中的其他組分混合，並將混合物壓製以形成片劑。 實例15：製備包含棲組織普雷沃菌細菌的固體劑型 [ 表 AJ] ：活性片劑的組成（ 400 mg ） 片劑配製物 組分 質量百分比 重量（ g ） 棲組織普雷沃菌DS顆粒 55.00% 27.5 SiO 2 1.00% 0.5 羧基乙酸澱粉鈉 3.00% 1.5 SMCC HD90 25.00% 12.5 交聚維酮-CL-F 15.00% 7.5 硬脂醯富馬酸鈉 1.00% 0.5 總和 100.00% 50 The components of the drug substance (DS) granule formulation are mixed to form a powder. The DS granule formulation and binder solution were used in the wet granulation process (granulation, drying and milling) to form DS granules. The DS granules are then mixed with the other ingredients in the tablet formulation and the mixture compressed to form tablets. Example 15: Preparation of a solid dosage form comprising Prevotella histotropes bacteria [ Table AJ ] : Composition of active tablet ( 400 mg ) tablet formulation components mass percentage weight ( g ) Prevotella histohabitats DS Granules 55.00% 27.5 SiO 2 1.00% 0.5 Sodium starch glycolate 3.00% 1.5 SMCC HD90 25.00% 12.5 Crospovidone-CL-F 15.00% 7.5 Sodium stearyl fumarate 1.00% 0.5 sum 100.00% 50

表AJ中的棲組織普雷沃菌細菌係普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes bacterial line in Table AJ is Prevotella strain B 50329 (NRRL Deposit No. B 50329).

為了製備藥物組成物片劑，進行濕法製粒以形成藥物物質顆粒。將該等組分(i) 混合；(ii) 在流化床乾燥器上乾燥；(iii) 研磨；(iv) 然後與表AJ中提供的藥品賦形劑共混。For the preparation of pharmaceutical composition tablets, wet granulation is performed to form granules of the drug substance. The components were (i) mixed; (ii) dried on a fluid bed drier; (iii) ground; (iv) then blended with the pharmaceutical excipients provided in Table AJ.

將除硬脂醯富馬酸鈉外的表AJ中的組分混合20分鐘。然後添加硬脂醯富馬酸鈉並將粉末混合物再混合3分鐘。然後將混合粉末壓製成400mg片劑。The ingredients in Tables AJ except sodium stearyl fumarate were mixed for 20 minutes. Sodium stearyl fumarate was then added and the powder mixture mixed for an additional 3 minutes. The blended powders were then compressed into 400mg tablets.

藥物組成物400 mg片劑可以進一步用下表AK中所示配方的包衣進行包衣： [ 表 AK] ：片劑包衣組成 項# 材料 w/w% 1 Kollicoat MAE 30DP 50.00% 2 丙二醇 2.25% 3 純淨水 44.75% 4 SiO 2 3.00% 總計 100.00% 實例16：包含棲組織普雷沃菌細菌的具有不同活性DS顆粒百分比的濕法製粒固體劑型的製備 Pharmaceutical composition 400 mg tablets may be further coated with a coating of the formulation shown in Table AK below: [ Table AK ] : Tablet coating composition item# Material w/w% 1 Kollicoat MAE 30DP 50.00% 2 Propylene Glycol 2.25% 3 pure water 44.75% 4 SiO 2 3.00% total 100.00% Example 16: Preparation of Wet Granulated Solid Dosage Forms with Different Active DS Particle Percentages Containing Prevotella histolivans Bacteria

製備表AL中配方的片劑。具有不同活性顆粒百分比的組成物如下表AM所示製備。 [ 表 AL] ： DS 顆粒片劑的組成 組分 質量百分比 質量百分比 質量百分比 棲組織普雷沃菌DS顆粒 50.00% （80%活性顆粒） 40.00% （100%活性顆粒） 70.00% （60%活性顆粒） SiO 2 1.00% 1.00% 1.00% 滑石粉 1.00% 1.00% 1.00% PVP-64 3.00% 3.00% 3.00% SMCC HD90 32.00% 32.00% 17.00% 交聯羧甲基纖維素鈉 2.00% 2.00% 2.00% 交聚維酮 10.00% 20.00% 5.00% 硬脂醯富馬酸鈉 1.00% 1.00% 1.00% 總和 100.00% 100.00% 100.00% Tablets of the formulations in Table AL were prepared. Compositions with different percentages of active particles were prepared as shown in Tables AM below. [ Table AL ] : Composition of DS Granular Tablets components mass percentage mass percentage mass percentage Prevotella histohabitats DS Granules 50.00% (80% active particles) 40.00% (100% active particles) 70.00% (60% active particles) SiO 2 1.00% 1.00% 1.00% talcum powder 1.00% 1.00% 1.00% PVP-64 3.00% 3.00% 3.00% SMCC HD90 32.00% 32.00% 17.00% Croscarmellose Sodium 2.00% 2.00% 2.00% Crospovidone 10.00% 20.00% 5.00% Sodium stearyl fumarate 1.00% 1.00% 1.00% sum 100.00% 100.00% 100.00%

表AL中的棲組織普雷沃菌細菌係普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）。The Prevotella histotropes bacterial line in Table AL is Prevotella strain B 50329 (NRRL Deposit No. B 50329).

下面的表AN顯示了由上面表AL中的配方形成的片劑的片劑特性。 [ 表 AN] ：表 AL 片劑特性 80% 活性顆粒片劑 片劑重量（mg） 厚度（mm） 硬度（N） 崩散 時間（h:mm: ss） 壓實力（kN） 拉伸強度（MP） 391 5.03 147 0:04:48 10.0 1.46 392 5.03 145 0:05:00 292 5.02 148 0:05:06 390 5.43 74 0:01:17 6.0 0.65 393 5.42 75 0:01:48 391 5.42 77 0:02:08 100% 活性顆粒片劑 396 5.46 97 0:20:32 9.9 1.25 397 5.47 99 0:20:14 397 5.47 94 0:19:48 400 5.91 54 0:09:48 6.1 0.58 399 5.9 54 0:10:18 396 5.95 52 0:10:28 390 5.43 74 0:01:17 6.0 0.65 393 5.42 75 0:01:48 391 5.42 77 0:02:08 60% 活性顆粒片劑 433 5.71 120 0:05:52 10.0 0.97 432 5.72 119 0:05:32 436 5.71 126 0:05:36 429 6.31 54 0:01:43 5.5 0.35 429 6.3 53 0:01:26 431 6.31 55 0:01:54 實例17：製備包含棲組織普雷沃菌smEV的固體劑型 Table AN below shows the tablet properties of tablets formed from the formulations in Table AL above. [ Table AN ] : Table AL Tablet Characteristics 80% active granule tablet Tablet weight (mg) Thickness (mm) Hardness (N) Collapse time (h:mm:ss) Compression force (kN) Tensile strength (MP) 391 5.03 147 0:04:48 10.0 1.46 392 5.03 145 0:05:00 292 5.02 148 0:05:06 390 5.43 74 0:01:17 6.0 0.65 393 5.42 75 0:01:48 391 5.42 77 0:02:08 100% active granule tablet 396 5.46 97 0:20:32 9.9 1.25 397 5.47 99 0:20:14 397 5.47 94 0:19:48 400 5.91 54 0:09:48 6.1 0.58 399 5.9 54 0:10:18 396 5.95 52 0:10:28 390 5.43 74 0:01:17 6.0 0.65 393 5.42 75 0:01:48 391 5.42 77 0:02:08 60% active granule tablet 433 5.71 120 0:05:52 10.0 0.97 432 5.72 119 0:05:32 436 5.71 126 0:05:36 429 6.31 54 0:01:43 5.5 0.35 429 6.3 53 0:01:26 431 6.31 55 0:01:54 Example 17: Preparation of a solid dosage form comprising Prevotella histolivans smEV

製備表AO中配方的片劑。 [ 表 AO] ：活性片劑的組成 組分 質量百分比 棲組織普雷沃菌smEV DS 50.00% SMCC HD90 15.50% 交聚維酮 30.00% SiO 2 3.00% 硬脂酸鎂 1.50% 總和 100.00% Tablets of the formulations in Table AO were prepared. [ Table AO ] : Composition of Active Tablets components mass percentage Prevotella smEV DS 50.00% SMCC HD90 15.50% Crospovidone 30.00% SiO 2 3.00% Magnesium stearate 1.50% sum 100.00%

表AO中的棲組織普雷沃菌smEV係普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）的smEV。The Prevotella histotropes smEV in Table AO is the smEV of Prevotella strain B 50329 (NRRL Accession No. B 50329).

將除硬脂酸鎂外的表AO中的組成物混合15分鐘。然後將硬脂酸鎂添加到混合物中並混合3分鐘。然後將混合物壓製以形成具有下表AP所示特性的片劑。 [ 表 AP] ：表 AN 的活性片劑的特性 片劑重量（ mg ） 厚度（ mm ） 硬度（ N ） 崩散時間 （ h:mm:ss ） 403 5.56 70 0:19:19 405 5.55 78 0:19:15 406 5.58 77 0:20:57 405 5.57 75 0:17:37 407 5.57 76 0:17:29 實例18：包含棲組織普雷沃菌smEV的泡騰固體劑型的製備 The compositions in Table AO except the magnesium stearate were mixed for 15 minutes. Magnesium stearate was then added to the mixture and mixed for 3 minutes. The mixture was then compressed to form tablets having the properties shown in Table AP below. [ Table AP ] : Characteristics of the active tablet of Table AN Tablet Weight ( mg ) Thickness ( mm ) Hardness ( N ) Collapse time ( h:mm:ss ) 403 5.56 70 0:19:19 405 5.55 78 0:19:15 406 5.58 77 0:20:57 405 5.57 75 0:17:37 407 5.57 76 0:17:29 Example 18: Preparation of Effervescent Solid Dosage Forms Comprising Prevotella histolivans smEV

製備表AQ中配方的片劑。 [ 表 AQ] ：崩散劑和泡騰活性片劑（ 400 mg ） 30% DS 40% DS 50% DS I 50% DS II 50% DS III 組分 棲組織普雷沃菌smEV DS 30.00% 40.00% 50.00% 50.00% 50.00% SMCC HD90 22.00% 16.00% 12.00% 17.00% 15.00% 檸檬酸 20.00% 18.00% 15.00% 10.00% 12.00% 碳酸氫鈉 20.00% 18.00% 15.00% 10.00% 12.00% 交聚維酮 5.00% 5.00% 5.00% 10.00% - 交聯羧甲基纖維素鈉 - - - - 4.00% 羧基乙酸澱粉鈉 - - - - 4.00% SiO 2 1.50% 1.50% 1.50% 1.50% 1.50% 硬脂酸鎂 1.50% 1.50% 1.50% 1.50% 1.50% 總和 100.00% 100.00% 100.00% 100.00% 100.00% Tablets of the formulations in Tables AQ were prepared. [ Table AQ ] : Disintegrating powder and effervescent active tablet ( 400 mg ) 30%DS 40%DS 50% DS I 50% DS II 50% DS III components Prevotella smEV DS 30.00% 40.00% 50.00% 50.00% 50.00% SMCC HD90 22.00% 16.00% 12.00% 17.00% 15.00% citric acid 20.00% 18.00% 15.00% 10.00% 12.00% sodium bicarbonate 20.00% 18.00% 15.00% 10.00% 12.00% Crospovidone 5.00% 5.00% 5.00% 10.00% - Croscarmellose Sodium - - - - 4.00% Sodium starch glycolate - - - - 4.00% SiO 2 1.50% 1.50% 1.50% 1.50% 1.50% Magnesium stearate 1.50% 1.50% 1.50% 1.50% 1.50% sum 100.00% 100.00% 100.00% 100.00% 100.00%

表AQ中的棲組織普雷沃菌smEV係普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）的smEV。The Prevotella histotropes smEV in Table AQ is the smEV of Prevotella strain B 50329 (NRRL Accession No. B 50329).

將表AQ的組分混合並壓製成400 mg片劑。下表AR顯示了30%和40% DS片劑的某些特性。 [ 表 AR] ：表 AP 片劑的特性    30% DS 40% DS 壓實力（kN） 23.5 29 片劑重量（mg） 394.9 404.68 片劑厚度（mm） 4.5 4.61 片劑硬度（N） 93.63 111.48 崩散時間（秒） 324 527.67 實例19：包含 Fournierella massiliensissmEV的固體劑型I的製備 The components of Tables AQ were mixed and compressed into 400 mg tablets. Table AR below shows some properties of the 30% and 40% DS tablets. [ Table AR ] : Table AP Tablet Characteristics 30%DS 40%DS Compression force (kN) 23.5 29 Tablet weight (mg) 394.9 404.68 Tablet thickness (mm) 4.5 4.61 Tablet hardness (N) 93.63 111.48 Disintegration time (seconds) 324 527.67 Example 19: Preparation of solid dosage form I comprising Fournierella massiliensis smEV

製備了表AS中配方的微型片劑。微型片劑為1.5 mm，每片3.5 mg。 [ 表 AS] ：活性微型片劑的組成 微型片劑配製物 組分 質量百分比 製備的質量（ g ） Fournierella massiliensissmEV顆粒 74.50% 18.625 SMCC HD90 16.00% 4 二氧化矽 1.00% 0.25 交聚維酮 7.00% 1.75 硬脂酸鎂 1.50% 0.375 總和 100.00% 25 Minitablets of the formulations in Table AS were prepared. The microtablets are 1.5 mm and contain 3.5 mg each. [ Table AS ] : Composition of active minitablets Microtablet formulation components mass percentage Prepared mass ( g ) Fournierella massiliensis smEV particles 74.50% 18.625 SMCC HD90 16.00% 4 silicon dioxide 1.00% 0.25 Crospovidone 7.00% 1.75 Magnesium stearate 1.50% 0.375 sum 100.00% 25

表AS中的 Fournierella massiliensissmEV 係 Fournierella massiliensis菌株A（ATCC保藏號PTA-126696）的smEV。 The Fournierella massiliensis smEV in Table AS is the smEV of Fournierella massiliensis strain A (ATCC Accession No. PTA-126696).

將除硬脂酸鎂外的表AS的所有組分混合15分鐘。然後添加硬脂酸錳，並且將混合物進一步混合3分鐘。然後用0.33 kN的平均壓實力壓製混合物以形成微型片劑。 實例20：包含 Fournierella massiliensissmEV的固體劑型II的製備 All ingredients of Table AS except magnesium stearate were mixed for 15 minutes. Manganese stearate was then added and the mixture was further mixed for 3 minutes. The mixture was then compressed with an average compaction force of 0.33 kN to form minitablets. Example 20: Preparation of solid dosage form II comprising Fournierella massiliensis smEV

製備表AT中配方的片劑。 [ 表 AT] ：活性 HS 片劑的組成（ 400 mg ） 組分 % 高強度 Fournierella massiliensissmEV DS顆粒 62.5% SiO 2 1.0% SMCC HD90 20.0% 交聚維酮 15.0% 硬脂酸鎂 1.5% 核心崩散時間（平均） 02:43 Tablets of the formulations in Table AT were prepared. [ Table AT ] : Composition of Active HS Tablets ( 400 mg ) components % High Strength Fournierella massiliensis smEV DS Granules 62.5% SiO 2 1.0% SMCC HD90 20.0% Crospovidone 15.0% Magnesium stearate 1.5% Core collapse time (average) 02:43

表AT中的 Fournierella massiliensissmEV 係 Fournierella massiliensis菌株A（ATCC保藏號PTA-126696）的smEV。 The Fournierella massiliensis smEV in Table AT is the smEV of Fournierella massiliensis strain A (ATCC Accession No. PTA-126696).

將除硬脂酸鎂外的表AT的所有組分混合15分鐘。然後添加硬脂酸錳，並且將混合物進一步混合3分鐘。然後將混合物壓製成400 mg片劑。在6.8 pH下的平均核心崩散時間為02:43（mm:ss）。All ingredients of Table AT except magnesium stearate were mixed for 15 minutes. Manganese stearate was then added and the mixture was further mixed for 3 minutes. The mixture is then compressed into 400 mg tablets. The average core disintegration time at 6.8 pH was 02:43 (mm:ss).

然後將該等高強度 Fournierella massiliensissmEV片劑用下表AU中所示的兩種包衣配製物中的一種進行包衣。 [ 表 AU] ：包衣配製物和崩散時間 表AL片劑上的包衣 酸然後6.8 pH崩散時間（mm:ss） Kollicoat MAE 30DP（10.35%） 15% PG和7.5% SiO 2 10:22 11:42 08:52 11:16 10:40 10:08 Kollicoat MAE 30DP（10.25%） 15% PG和30%滑石粉 10:42 12:07 10:54 These high strength Fournierella massiliensis smEV tablets were then coated with one of the two coating formulations shown in Table AU below. [ Table AU ] : Coating formulation and disintegration time Table AL Coatings on Tablets Acid then 6.8 pH disintegration time (mm:ss) Kollicoat MAE 30DP (10.35%) 15% PG and 7.5% SiO 2 10:22 11:42 08:52 11:16 10:40 10:08 Kollicoat MAE 30DP (10.25%) 15% PG and 30% talc 10:42 12:07 10:54

表AU顯示了用所示包衣之一進行包衣的表AT片劑的崩散時間。片劑首先暴露於酸，然後是6.8 pH的溶液。 實例21：包含 Fournierella massiliensissmEV的固體劑型III的製備 Table AU shows the disintegration time of Table AT tablets coated with one of the coatings indicated. Tablets were first exposed to the acid and then to the 6.8 pH solution. Example 21: Preparation of solid dosage form III comprising Fournierella massiliensis smEV

製備表AV中配方的片劑。 [ 表 AV] ：活性片劑的組成 組分 質量百分比 HS Fournierella massiliensissmEV顆粒DS 10.0% 二氧化矽 1.0% SMCC HD90 72.5% 交聚維酮 15.0% 硬脂酸鎂 1.5% 總和 100.0% 表AV中的 Fournierella massiliensissmEV 係 Fournierella massiliensis菌株A（ATCC保藏號PTA-126696）的smEV。 Tablets of the formulations in Table AV were prepared. [ Table AV ] : Composition of Active Tablets components mass percentage HS Fournierella massiliensis smEV particles DS 10.0% silicon dioxide 1.0% SMCC HD90 72.5% Crospovidone 15.0% Magnesium stearate 1.5% sum 100.0% The Fournierella massiliensis smEV in Table AV is the smEV of Fournierella massiliensis strain A (ATCC Accession No. PTA-126696).

將除硬脂酸鎂外的表AV的所有組分混合15分鐘。然後添加硬脂酸錳，並且將混合物進一步混合3分鐘。然後將混合物壓製成片劑。 實例22：包含小韋榮氏球菌細菌的具有經包衣的DS的固體劑型的製備 All components of Table AV except magnesium stearate were mixed for 15 minutes. Manganese stearate was then added and the mixture was further mixed for 3 minutes. The mixture is then compressed into tablets. Example 22: Preparation of solid dosage forms with coated DS comprising Veillonella parvum bacteria

製備表AW中配方的片劑。 [ 表 AW] ：具有經包衣的 DS 的活性片劑的組成 組分 質量百分比 經包衣的小韋榮氏球菌細菌DS（20%經包衣） 55.00% SiO 2 1.50% 檸檬酸 7.50% 碳酸氫鈉 7.50% SMCC HD90 7.50% 交聚維酮 20.00% 硬脂醯富馬酸鈉 1.00% 總和 100.00% Tablets of the formulations in Tables AW were prepared. [ Table AW ]: Composition of active tablet with coated DS components mass percentage Coated Veillonella parvum bacteria DS (20% coated) 55.00% SiO 2 1.50% citric acid 7.50% sodium bicarbonate 7.50% SMCC HD90 7.50% Crospovidone 20.00% Sodium stearyl fumarate 1.00% sum 100.00%

表AW中的小韋榮氏球菌細菌係小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）。在摻入藥物物質之前對細菌進行γ射線照射。The Veillonella parvum bacterium in Tables AW is Veillonella parvum strain A (ATCC Accession No. PTA-125691). Bacteria were gamma-irradiated prior to incorporation of drug substances.

混合表AW中的組分並將混合物壓製以形成400 mg片劑。The ingredients in Tables AW are mixed and the mixture is compressed to form 400 mg tablets.

下表AX顯示了表AW片劑的某些特性。 [ 表 AX] ：具有經包衣的 DS 的表 AW 片劑的特性 片劑重量（mg） 厚度（mm） 硬度（N） 崩散時間（h:mm:ss） 406 5.25 142 0:04:09 405 5.26 143 0:04:05 406 5.25 146 0:04:22 402 5.25 141 0:04:58 藉由引用併入 Tables AX below show some properties of the tablets in Tables AW. [ Table AX ]: Properties of Table AW Tablets with Coated DS Tablet weight (mg) Thickness (mm) Hardness (N) Collapse time (h:mm:ss) 406 5.25 142 0:04:09 405 5.26 143 0:04:05 406 5.25 146 0:04:22 402 5.25 141 0:04:58 incorporated by reference

在本文中提及的所有出版物、專利申請都藉由引用以其全文特此併入，如同各個單獨的出版物或專利申請被確切地並且單獨地指明為藉由引用併入。如果出現衝突，則以本申請（包含本文的任何定義）為准。 等效形式 All publications, patent applications mentioned herein are hereby incorporated by reference in their entirety as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. In case of conflict, the present application, including any definitions herein, will control. equivalent form

熟悉該項技術者僅使用常規實驗將認識到或能確定本文所述本發明之具體實施方式的許多等效形式。此類等效形式旨在被下列請求項所涵蓋。Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be covered by the following claims.

無none

無none

國外寄存美國；American Type Culture Collection (ATCC)；2018/04/27；PTA-125097 美國；American Type Culture Collection (ATCC)；2018/06/07；PTA-125134 美國；American Type Culture Collection (ATCC)；2018/10/04；PTA-125346 美國；American Type Culture Collection (ATCC)；2018/10/11；PTA-125368 美國；American Type Culture Collection (ATCC)；2019/01/25；PTA-125691 美國；American Type Culture Collection (ATCC)；2019/09/10；PTA-126140 美國；American Type Culture Collection (ATCC)；2020/03/05；PTA-126694 美國；American Type Culture Collection (ATCC)；2020/03/05；PTA-126696 美國；American Type Culture Collection (ATCC)；2020/06/04；PTA-126770 國內寄存食品工業發展研究所；2018年10月16日；BCRC 910854 食品工業發展研究所；2018年11月27日；BCRC 910863 食品工業發展研究所；2019年02月19日；BCRC 910874 食品工業發展研究所；2019年02月19日；BCRC 910873 食品工業發展研究所；2019年05月07日；BCRC 910892 食品工業發展研究所；2021年10月05日；BCRC 911076 食品工業發展研究所；2021年08月31日；BCRC 911074 食品工業發展研究所；2021年08月31日；BCRC 911072 食品工業發展研究所；2021年08月31日；BCRC 911073 American Type Culture Collection (ATCC); 2018/04/27; PTA-125097 United States; American Type Culture Collection (ATCC); 2018/06/07; ;2018/10/04;PTA-125346 United States;American Type Culture Collection (ATCC);2018/10/11;PTA-125368 United States;American Type Culture Collection (ATCC);2019/01/25;PTA-125691 United States; American Type Culture Collection (ATCC); 2019/09/10; PTA-126140 USA; American Type Culture Collection (ATCC); 2020/03/05; PTA-126694 USA; 05; PTA-126696 United States; American Type Culture Collection (ATCC); 04/06/2020; PTA-126770 Domestic Deposit Food Industry Development Institute; October 16, 2018; BCRC 910854 Food Industry Development Institute; February 27; BCRC 910863 Food Industry Development Institute; February 19, 2019; BCRC 910874 Food Industry Development Institute; February 19, 2019; BCRC 910873 Food Industry Development Institute; May 07, 2019; BCRC 910892 Food Industry Development Research Institute; October 5, 2021; BCRC 911076 Food Industry Development Research Institute; August 31, 2021; BCRC 911074 Food Industry Development Research Institute; August 31, 2021; BCRC 911072 Food Industry Development Research Institute; August 31, 2021; BCRC 911073

Claims (139)

一種藥物組成物的固體劑型，該固體劑型包含： 藥劑，其具有的藥劑總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的70%，其中該藥劑包含細菌和/或微生物胞外囊泡（mEV）；以及 矽化微晶纖維素，其具有的矽化微晶纖維素總質量係該藥物組成物總質量的至少15%且不超過該藥物組成物總質量的85%。 A solid dosage form of a pharmaceutical composition, the solid dosage form comprising: a medicament having a total mass of the medicament of at least 5% and no more than 70% of the total mass of the pharmaceutical composition, wherein the medicament comprises bacterial and/or microbial extracellular vesicles (mEV); and Silicified microcrystalline cellulose, which has a total mass of silicified microcrystalline cellulose that is at least 15% and not more than 85% of the total mass of the pharmaceutical composition. 如請求項1所述之固體劑型，該固體劑型進一步包含交聚維酮，其具有的交聚維酮總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的25%。The solid dosage form as claimed in item 1, the solid dosage form further comprises crospovidone, and the total mass of crospovidone is at least 5% of the total mass of the pharmaceutical composition and no more than 5% of the total mass of the pharmaceutical composition 25%. 如請求項1或2所述之固體劑型，其中該矽化微晶纖維素總質量加上該交聚維酮總質量係該藥物組成物總質量的至少35%。The solid dosage form according to claim 1 or 2, wherein the total mass of the silicified microcrystalline cellulose plus the total mass of crospovidone is at least 35% of the total mass of the pharmaceutical composition. 如請求項1或2所述之固體劑型，其中該矽化微晶纖維素總質量加上該交聚維酮總質量係該藥物組成物總質量的至少70%。The solid dosage form according to claim 1 or 2, wherein the total mass of the silicified microcrystalline cellulose plus the total mass of the crospovidone is at least 70% of the total mass of the pharmaceutical composition. 如請求項1至4中任一項所述之固體劑型，其中該矽化微晶纖維素為HD90級矽化微晶纖維素。The solid dosage form according to any one of claims 1 to 4, wherein the silicified microcrystalline cellulose is HD90 grade silicified microcrystalline cellulose. 如請求項1至5中任一項所述之固體劑型，其中 該矽化微晶纖維素總質量係該藥物組成物總質量的至少15%且不超過該藥物組成物總質量的80%；並且 該交聚維酮總質量係該藥物組成物總質量的至少10%且不超過該藥物組成物總質量的20%。 The solid dosage form according to any one of claims 1 to 5, wherein The total mass of the silicified microcrystalline cellulose is at least 15% and not more than 80% of the total mass of the pharmaceutical composition; and The total mass of crospovidone is at least 10% and no more than 20% of the total mass of the pharmaceutical composition. 如請求項1至6中任一項所述之固體劑型，其中 該矽化微晶纖維素總質量係該藥物組成物總質量的至少48%且不超過該藥物組成物總質量的78%；並且 該交聚維酮總質量係該藥物組成物總質量的至少14%且不超過該藥物組成物總質量的16%。 The solid dosage form according to any one of claims 1 to 6, wherein The total mass of the silicified microcrystalline cellulose is at least 48% and not more than 78% of the total mass of the pharmaceutical composition; and The total mass of crospovidone is at least 14% and not more than 16% of the total mass of the pharmaceutical composition. 如請求項1至7中任一項所述之固體劑型，其中 該矽化微晶纖維素總質量係該藥物組成物總質量的約50%；並且 該交聚維酮總質量係該藥物組成物總質量的約15%。 The solid dosage form according to any one of claims 1 to 7, wherein The total mass of the silicified microcrystalline cellulose is about 50% of the total mass of the pharmaceutical composition; and The total mass of the crospovidone is about 15% of the total mass of the pharmaceutical composition. 如請求項1至6中任一項所述之固體劑型，其中 該矽化微晶纖維素總質量係該藥物組成物總質量的約20%；並且 該交聚維酮總質量係該藥物組成物總質量的約15%。 The solid dosage form according to any one of claims 1 to 6, wherein The total mass of the silicified microcrystalline cellulose is about 20% of the total mass of the pharmaceutical composition; and The total mass of the crospovidone is about 15% of the total mass of the pharmaceutical composition. 如請求項1至6中任一項所述之固體劑型，其中 該矽化微晶纖維素總質量係該藥物組成物總質量的約76.4%； 並且 該交聚維酮總質量係該藥物組成物總質量的約15%。 The solid dosage form according to any one of claims 1 to 6, wherein The total mass of the silicified microcrystalline cellulose is about 76.4% of the total mass of the pharmaceutical composition; and The total mass of the crospovidone is about 15% of the total mass of the pharmaceutical composition. 如請求項1至6中任一項所述之固體劑型，其中 該矽化微晶纖維素總質量係該藥物組成物總質量的約72.5%； 並且 該交聚維酮總質量係該藥物組成物總質量的約15%。 The solid dosage form according to any one of claims 1 to 6, wherein The total mass of the silicified microcrystalline cellulose is about 72.5% of the total mass of the pharmaceutical composition; and The total mass of the crospovidone is about 15% of the total mass of the pharmaceutical composition. 一種藥物組成物的固體劑型，該固體劑型包含藥劑和一種或多種賦形劑，其中該一種或多種賦形劑的總質量係該藥物組成物總質量的至少15%，並且其中該藥劑包含細菌和/或微生物胞外囊泡（mEV）。A solid dosage form of a pharmaceutical composition comprising a medicament and one or more excipients, wherein the total mass of the one or more excipients is at least 15% of the total mass of the pharmaceutical composition, and wherein the medicament comprises bacteria and/or microbial extracellular vesicles (mEVs). 如請求項12所述之固體劑型，其中該一種或多種賦形劑包含矽化微晶纖維素。The solid dosage form according to claim 12, wherein the one or more excipients comprise silicified microcrystalline cellulose. 如請求項13所述之固體劑型，其中該矽化微晶纖維素為HD90級矽化微晶纖維素。The solid dosage form according to claim 13, wherein the silicified microcrystalline cellulose is HD90 grade silicified microcrystalline cellulose. 如請求項13或14所述之固體劑型，其中該矽化微晶纖維素總質量係該藥物組成物總質量的至少15%且不超過該藥物組成物總質量的85%。The solid dosage form according to claim 13 or 14, wherein the total mass of the silicified microcrystalline cellulose is at least 15% and not more than 85% of the total mass of the pharmaceutical composition. 如請求項12至15中任一項所述之固體劑型，其中該一種或多種賦形劑包含交聚維酮。The solid dosage form according to any one of claims 12 to 15, wherein the one or more excipients comprise crospovidone. 如請求項16所述之固體劑型，其中該交聚維酮總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的25%。The solid dosage form according to claim 16, wherein the total mass of crospovidone is at least 5% and no more than 25% of the total mass of the pharmaceutical composition. 如請求項12至17中任一項所述之固體劑型，其中該藥劑總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的70%。The solid dosage form according to any one of claims 12 to 17, wherein the total mass of the medicament is at least 5% and not more than 70% of the total mass of the pharmaceutical composition. 如請求項1至18中任一項所述之固體劑型，其中該藥劑總質量係該藥物組成物總質量的至少15%且不超過該藥物組成物總質量的40%。The solid dosage form according to any one of claims 1 to 18, wherein the total mass of the medicament is at least 15% and no more than 40% of the total mass of the pharmaceutical composition. 如請求項1至16中任一項所述之固體劑型，其中該藥劑總質量係該藥物組成物總質量的至少20%且不超過該藥物組成物總質量的38%。The solid dosage form according to any one of claims 1 to 16, wherein the total mass of the medicament is at least 20% and not more than 38% of the total mass of the pharmaceutical composition. 如請求項1至18中任一項所述之固體劑型，其中該藥劑總質量係該藥物組成物總質量的至少24%且不超過該藥物組成物總質量的35%。The solid dosage form according to any one of claims 1 to 18, wherein the total mass of the medicament is at least 24% and not more than 35% of the total mass of the pharmaceutical composition. 如請求項1至18中任一項所述之固體劑型，其中該藥劑總質量係該藥物組成物總質量的約26.4%-33%。The solid dosage form according to any one of claims 1 to 18, wherein the total mass of the medicament is about 26.4%-33% of the total mass of the pharmaceutical composition. 如請求項1至22中任一項所述之固體劑型，該固體劑型進一步包含硬脂酸鎂，其具有的硬脂酸鎂總質量係該藥物組成物總質量的至少0.01%且不超過該藥物組成物總質量的10%。The solid dosage form as described in any one of claims 1 to 22, the solid dosage form further comprises magnesium stearate, and the total mass of magnesium stearate it has is at least 0.01% of the total mass of the pharmaceutical composition and does not exceed the 10% of the total mass of the pharmaceutical composition. 如請求項1至23中任一項所述之固體劑型，該固體劑型進一步包含膠體二氧化矽，其具有的膠體二氧化矽總質量係該藥物組成物總質量的至少0.01%且不超過該藥物組成物總質量的10%。The solid dosage form as described in any one of claims 1 to 23, the solid dosage form further comprises colloidal silicon dioxide, and the total mass of colloidal silicon dioxide it has is at least 0.01% of the total mass of the pharmaceutical composition and does not exceed the 10% of the total mass of the pharmaceutical composition. 如請求項1至24中任一項所述之固體劑型，其中該藥劑包含細菌。The solid dosage form according to any one of claims 1 to 24, wherein the agent comprises bacteria. 如請求項25所述之固體劑型，其中該細菌係凍乾的細菌。The solid dosage form according to claim 25, wherein the bacteria are freeze-dried bacteria. 如請求項1至26中任一項所述之固體劑型，其中該藥劑包含分離的細菌（例如，來自一種或多種細菌菌株（例如，目的細菌）（例如，其治療有效量））。The solid dosage form of any one of claims 1 to 26, wherein the medicament comprises isolated bacteria (eg, from one or more bacterial strains (eg, bacteria of interest) (eg, a therapeutically effective amount thereof)). 如請求項1至27中任一項所述之固體劑型，其中該藥劑包含細菌，該細菌已經經γ照射、UV照射、熱滅活、酸處理或氧噴射。The solid dosage form according to any one of claims 1 to 27, wherein the medicament comprises bacteria which have been subjected to gamma irradiation, UV irradiation, heat inactivation, acid treatment or oxygen sparging. 如請求項1至27中任一項所述之固體劑型，其中該藥劑包含活細菌。The solid dosage form according to any one of claims 1 to 27, wherein the medicament comprises live bacteria. 如請求項1至27中任一項所述之固體劑型，其中該藥劑包含死細菌。The solid dosage form according to any one of claims 1 to 27, wherein the medicament comprises dead bacteria. 如請求項1至27中任一項所述之固體劑型，其中該藥劑包含非複製型細菌。The solid dosage form according to any one of claims 1 to 27, wherein the medicament comprises non-replicating bacteria. 如請求項1至31中任一項所述之固體劑型，其中該藥劑包含來自一種細菌菌株的細菌。The solid dosage form according to any one of claims 1 to 31, wherein the medicament comprises bacteria from a bacterial strain. 如請求項1至32中任一項所述之固體劑型，其中該細菌被凍乾（例如，凍乾的產物進一步包含藥學上可接受的賦形劑）（例如，粉末形式）。The solid dosage form according to any one of claims 1 to 32, wherein the bacteria are freeze-dried (eg, the freeze-dried product further comprises a pharmaceutically acceptable excipient) (eg, in powder form). 如請求項1至33中任一項所述之固體劑型，其中該細菌經γ照射。The solid dosage form according to any one of claims 1 to 33, wherein the bacteria are gamma irradiated. 如請求項1至33中任一項所述之固體劑型，其中該細菌經UV照射。The solid dosage form according to any one of claims 1 to 33, wherein the bacteria are irradiated with UV. 如請求項1至33中任一項所述之固體劑型，其中該細菌經熱滅活（例如，在50°C下兩小時或在90°C下兩小時）。The solid dosage form according to any one of claims 1 to 33, wherein the bacteria are heat-inactivated (for example, at 50°C for two hours or at 90°C for two hours). 如請求項1至33中任一項所述之固體劑型，其中該細菌經酸處理。The solid dosage form according to any one of claims 1 to 33, wherein the bacteria are acid-treated. 如請求項1至33中任一項所述之固體劑型，其中該細菌經氧噴射（例如，以0.1 vvm持續兩小時）。The solid dosage form according to any one of claims 1 to 33, wherein the bacteria are sparged with oxygen (for example, at 0.1 vvm for two hours). 如請求項1至38中任一項所述之固體劑型，其中該細菌係革蘭氏陽性細菌。The solid dosage form according to any one of claims 1 to 38, wherein the bacteria are Gram-positive bacteria. 如請求項1至38中任一項所述之固體劑型，其中該細菌係革蘭氏陰性細菌。The solid dosage form according to any one of claims 1 to 38, wherein the bacteria are Gram-negative bacteria. 如請求項1至38中任一項所述之固體劑型，其中該細菌係需氧細菌。The solid dosage form according to any one of claims 1 to 38, wherein the bacteria are aerobic bacteria. 如請求項1至38中任一項所述之固體劑型，其中該細菌係厭氧細菌。The solid dosage form according to any one of claims 1 to 38, wherein the bacteria are anaerobic bacteria. 如請求項1至38中任一項所述之固體劑型，其中該細菌係嗜酸細菌。The solid dosage form according to any one of claims 1 to 38, wherein the bacteria are acidophilic bacteria. 如請求項1至38中任一項所述之固體劑型，其中該細菌係嗜鹼細菌。The solid dosage form according to any one of claims 1 to 38, wherein the bacteria are alkaliphilic bacteria. 如請求項1至38中任一項所述之固體劑型，其中該細菌係嗜中性細菌。The solid dosage form according to any one of claims 1 to 38, wherein the bacteria are neutrophils. 如請求項1至38中任一項所述之固體劑型，其中該細菌係難養細菌。The solid dosage form according to any one of claims 1 to 38, wherein the bacteria are fastidious bacteria. 如請求項1至38中任一項所述之固體劑型，其中該細菌係非難養細菌。The solid dosage form according to any one of claims 1 to 38, wherein the bacteria are non-fastidious bacteria. 如請求項25所述之固體劑型，其中該細菌係小韋榮氏球菌細菌。The solid dosage form according to claim 25, wherein the bacteria are Veillonella parvum bacteria. 如請求項48所述之固體劑型，其中該小韋榮氏球菌係與小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）的核苷酸序列包含至少90%的基因組、16S和/或CRISPR序列同一性的菌株。The solid dosage form according to claim 48, wherein the nucleotide sequence of the Veillonella parvum strain and Veillonella parvo strain A (ATCC deposit number PTA-125691) comprises at least 90% of the genome, 16S and/or Strains with CRISPR sequence identity. 如請求項48所述之固體劑型，其中該小韋榮氏球菌係與小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）的核苷酸序列包含至少95%的基因組、16S和/或CRISPR序列同一性的菌株。The solid dosage form as claimed in claim 48, wherein the nucleotide sequence of the Veillonella parvum strain and Veillonella parvo strain A (ATCC deposit number PTA-125691) comprises at least 95% of the genome, 16S and/or Strains with CRISPR sequence identity. 如請求項48所述之固體劑型，其中該小韋榮氏球菌係與小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）的核苷酸序列包含至少99%的基因組、16S和/或CRISPR序列同一性的菌株。The solid dosage form as claimed in claim 48, wherein the nucleotide sequence of the Veillonella parvum strain and Veillonella parvo strain A (ATCC deposit number PTA-125691) comprises at least 99% of the genome, 16S and/or Strains with CRISPR sequence identity. 如請求項48所述之固體劑型，其中該小韋榮氏球菌係與小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）的核苷酸序列包含至少99%的16S序列同一性的菌株。The solid dosage form according to claim 48, wherein the nucleotide sequence of Veillonella parvum strain A (ATCC deposit number PTA-125691) comprises at least 99% of 16S sequence identity . 如請求項48所述之固體劑型，其中該小韋榮氏球菌係小韋榮氏球菌菌株A（ATCC保藏號PTA-125691）。The solid dosage form as described in claim 48, wherein the Veillonella parvum strain is Veillonella parvum strain A (ATCC deposit number PTA-125691). 如請求項48-53中任一項所述之固體劑型，其中該藥物組成物中的至少50%的細菌係小韋榮氏球菌菌株A。The solid dosage form according to any one of claims 48-53, wherein at least 50% of the bacteria in the pharmaceutical composition are Veillonella parvum strain A. 如請求項48-54中任一項所述之固體劑型，其中該藥物組成物中的至少90%的細菌係小韋榮氏球菌菌株A。The solid dosage form according to any one of claims 48-54, wherein at least 90% of the bacteria in the pharmaceutical composition are strain A of Veillonella parvum. 如請求項48-55中任一項所述之固體劑型，其中該藥物組成物中的基本上全部的細菌係小韋榮氏球菌菌株A。The solid dosage form according to any one of claims 48-55, wherein substantially all bacteria in the pharmaceutical composition are strain A of Veillonella parvum. 如請求項48-56中任一項所述之固體劑型，其中該藥物組成物包含至少約1 x 10 7至約2 x 10 12（約3 x 10 10或約1.5 x 10 11或約1.5 x 10 12）個小韋榮氏球菌菌株A細胞。 The solid dosage form according to any one of claims 48-56, wherein the pharmaceutical composition comprises at least about 1 x 10 7 to about 2 x 10 12 (about 3 x 10 10 or about 1.5 x 10 11 or about 1.5 x 10 12 ) Veillonella parvum strain A cells. 如請求項48-57中任一項所述之固體劑型，其中該藥物組成物包含約1.5 x 10 11個小韋榮氏球菌菌株A細胞。 The solid dosage form according to any one of claims 48-57, wherein the pharmaceutical composition comprises about 1.5 x 10 11 Veillonella parvum strain A cells. 如請求項48-57中任一項所述之固體劑型，其中該藥物組成物包含約1.5 x 10 12個小韋榮氏球菌菌株A細胞。 The solid dosage form according to any one of claims 48-57, wherein the pharmaceutical composition comprises about 1.5 x 10 12 Veillonella parvum strain A cells. 如請求項1至25中任一項所述之固體劑型，其中該細菌來自表1、表2、表3或表4中列出的分類學組（例如，綱、目、科、屬、種或菌株）。The solid dosage form according to any one of claims 1 to 25, wherein the bacterium is from a taxonomic group listed in Table 1, Table 2, Table 3 or Table 4 (for example, class, order, family, genus, species or strains). 如請求項1至39中任一項所述之固體劑型，其中該細菌來自表1、表2、表3或表4中列出的細菌菌株。The solid dosage form according to any one of claims 1 to 39, wherein the bacteria are from the bacterial strains listed in Table 1, Table 2, Table 3 or Table 4. 如請求項1至39中任一項所述之固體劑型，其中該細菌來自表J中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌。The solid dosage form according to any one of claims 1 to 39, wherein the bacterium is from a taxonomic group (eg, class, order, family, genus, species or strain) listed in Table J. 如請求項1至39中任一項所述之固體劑型，其中該細菌來自表J中列出的細菌菌株。The solid dosage form according to any one of claims 1 to 39, wherein the bacteria are from the bacterial strains listed in Table J. 如請求項1至63中任一項所述之固體劑型，其中該藥劑包含微生物胞外囊泡（mEV）。The solid dosage form according to any one of claims 1 to 63, wherein the medicament comprises microbial extracellular vesicles (mEV). 如請求項1至64中任一項所述之固體劑型，其中該藥劑包含分離的mEV（例如，來自一種或多種細菌菌株（例如，目的細菌））（例如，其治療有效量）。The solid dosage form of any one of claims 1 to 64, wherein the medicament comprises isolated mEV (eg, from one or more bacterial strains (eg, the bacterium of interest)) (eg, a therapeutically effective amount thereof). 如請求項1至65中任一項所述之固體劑型，其中該藥劑包含mEV，並且該mEV包含分泌型mEV（smEV）。The solid dosage form according to any one of claims 1 to 65, wherein the medicament comprises mEV, and the mEV comprises secreted mEV (smEV). 如請求項1至65中任一項所述之固體劑型，其中該藥劑包含mEV，並且該mEV包含經處理的mEV（pmEV）。The solid dosage form of any one of claims 1 to 65, wherein the medicament comprises mEV, and the mEV comprises processed mEV (pmEV). 如請求項1至65中任一項所述之固體劑型，其中該藥劑包含pmEV，並且該pmEV由已經經γ照射、UV照射、熱滅活、酸處理或氧噴射的細菌產生。The solid dosage form according to any one of claims 1 to 65, wherein the medicament comprises pmEV, and the pmEV is produced by bacteria that have been gamma irradiated, UV irradiated, heat inactivated, acid treated or oxygen sparged. 如請求項1至65中任一項所述之固體劑型，其中該藥劑包含pmEV，並且該pmEV由活細菌產生。The solid dosage form according to any one of claims 1 to 65, wherein the medicament comprises pmEV, and the pmEV is produced by living bacteria. 如請求項1至65中任一項所述之固體劑型，其中該藥劑包含pmEV，並且該pmEV由死細菌產生。The solid dosage form according to any one of claims 1 to 65, wherein the medicament comprises pmEV, and the pmEV is produced by dead bacteria. 如請求項1至65中任一項所述之固體劑型，其中該藥劑包含pmEV，並且該pmEV由非複製型細菌產生。The solid dosage form according to any one of claims 1 to 65, wherein the medicament comprises pmEV, and the pmEV is produced by non-replicating bacteria. 如請求項1至71中任一項所述之固體劑型，其中該藥劑包含mEV，並且該mEV來自一種細菌菌株。The solid dosage form according to any one of claims 1 to 71, wherein the medicament comprises mEV, and the mEV is from a bacterial strain. 如請求項1至72中任一項所述之固體劑型，其中該mEV被凍乾（例如，凍乾的產物進一步包含藥學上可接受的賦形劑）。The solid dosage form according to any one of claims 1 to 72, wherein the mEV is lyophilized (for example, the lyophilized product further comprises a pharmaceutically acceptable excipient). 如請求項1至73中任一項所述之固體劑型，其中該mEV經γ照射。The solid dosage form according to any one of claims 1 to 73, wherein the mEVs are γ-irradiated. 如請求項1至73中任一項所述之固體劑型，其中該mEV經UV照射。The solid dosage form according to any one of claims 1 to 73, wherein the mEV is irradiated with UV. 如請求項1至73中任一項所述之固體劑型，其中該mEV經熱滅活（例如，在50°C下兩小時或在90°C下兩小時）。The solid dosage form of any one of claims 1 to 73, wherein the mEV is heat inactivated (for example, at 50°C for two hours or at 90°C for two hours). 如請求項1至73中任一項所述之固體劑型，其中該mEV經酸處理。The solid dosage form according to any one of claims 1 to 73, wherein the mEV is acid-treated. 如請求項1至77中任一項所述之固體劑型，其中該mEV經氧噴射（例如，以0.1 vvm持續兩小時）。The solid dosage form of any one of claims 1 to 77, wherein the mEV is oxygen sparged (eg, at 0.1 vvm for two hours). 如請求項1至77中任一項所述之固體劑型，其中該mEV來自革蘭氏陽性細菌。The solid dosage form according to any one of claims 1 to 77, wherein the mEV is from Gram-positive bacteria. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自革蘭氏陰性細菌。The solid dosage form according to any one of claims 1 to 77, wherein the mEV is from Gram-negative bacteria. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自需氧細菌。The solid dosage form according to any one of claims 1 to 77, wherein the mEV is derived from aerobic bacteria. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自厭氧細菌。The solid dosage form according to any one of claims 1 to 77, wherein the mEV is derived from anaerobic bacteria. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自嗜酸細菌。The solid dosage form according to any one of claims 1 to 77, wherein the mEV is from acidophilic bacteria. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自嗜鹼細菌。The solid dosage form according to any one of claims 1 to 77, wherein the mEV is from an alkaliphilic bacterium. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自嗜中性細菌。The solid dosage form according to any one of claims 1 to 77, wherein the mEV is from neutrophils. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自難養細菌。The solid dosage form according to any one of claims 1 to 77, wherein the mEV is from fastidious bacteria. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自非難養細菌。The solid dosage form according to any one of claims 1 to 77, wherein the mEV is from non-fastidious bacteria. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自表1、表2、表3或表4中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌。The solid dosage form of any one of claims 1 to 77, wherein the mEV is from a taxonomic group listed in Table 1, Table 2, Table 3, or Table 4 (e.g., class, order, family, genus, species or strains) of bacteria. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自表1、表2、表3或表4中列出的細菌菌株。The solid dosage form according to any one of claims 1 to 77, wherein the mEV is from a bacterial strain listed in Table 1, Table 2, Table 3 or Table 4. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自表J中列出的分類學組（例如，綱、目、科、屬、種或菌株）的細菌。The solid dosage form of any one of claims 1 to 77, wherein the mEV is from a bacterium of a taxonomic group (eg, class, order, family, genus, species, or strain) listed in Table J. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自表J中列出的細菌菌株。The solid dosage form according to any one of claims 1 to 77, wherein the mEV is from the bacterial strains listed in Table J. 如請求項1至77中任一項所述之固體劑型，其中該mEV來自棲組織普雷沃菌細菌。The solid dosage form as described in any one of claims 1 to 77, wherein the mEV is from the Prevotella histotropes bacterium. 如請求項92所述之固體劑型，其中該棲組織普雷沃菌係與普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）的核苷酸序列包含至少90%的基因組、16S和/或CRISPR序列同一性的菌株。The solid dosage form as claimed in claim 92, wherein the nucleotide sequence of the Prevotella strain and Prevotella strain B 50329 (NRRL deposit number B 50329) comprises at least 90% of the genome, 16S and/or or strains with CRISPR sequence identity. 如請求項92所述之固體劑型，其中該棲組織普雷沃菌係與普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）的核苷酸序列包含至少95%的基因組、16S和/或CRISPR序列同一性的菌株。The solid dosage form as claimed in claim 92, wherein the nucleotide sequence of the Prevotella strain and Prevotella strain B 50329 (NRRL deposit number B 50329) comprises at least 95% of the genome, 16S and/or or strains with CRISPR sequence identity. 如請求項92所述之固體劑型，其中該棲組織普雷沃菌係與普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）的核苷酸序列包含至少99%的基因組、16S和/或CRISPR序列同一性的菌株。The solid dosage form as claimed in claim 92, wherein the nucleotide sequence of the Prevotella strain and Prevotella strain B 50329 (NRRL deposit number B 50329) comprises at least 99% of the genome, 16S and/or or strains with CRISPR sequence identity. 如請求項92所述之固體劑型，其中該棲組織普雷沃菌係與普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）的核苷酸序列包含至少99%的16S序列同一性的菌株。The solid dosage form as claimed in claim 92, wherein the nucleotide sequence of the Prevotella strain comprises at least 99% 16S sequence identity to Prevotella strain B 50329 (NRRL deposit number B 50329) strain. 如請求項92所述之固體劑型，其中該棲組織普雷沃菌係普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）。The solid dosage form as claimed in claim 92, wherein the Prevotella histotropes is Prevotella strain B 50329 (NRRL deposit number B 50329). 如請求項92-97中任一項所述之固體劑型，其中該藥物組成物中至少50%的該mEV係普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）。The solid dosage form according to any one of claims 92-97, wherein at least 50% of the mEV in the pharmaceutical composition is Prevotella strain B 50329 (NRRL deposit number B 50329). 如請求項92-98中任一項所述之固體劑型，其中該藥物組成物中至少90%的該mEV係普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）。The solid dosage form according to any one of claims 92-98, wherein at least 90% of the mEV in the pharmaceutical composition is Prevotella strain B 50329 (NRRL deposit number B 50329). 如請求項92-99中任一項所述之固體劑型，其中該藥物組成物中基本上全部的該mEV係普雷沃菌屬菌株B 50329（NRRL保藏號B 50329）。The solid dosage form according to any one of claims 92-99, wherein substantially all of the mEV in the pharmaceutical composition is Prevotella strain B 50329 (NRRL deposit number B 50329). 如請求項1至63中任一項所述之固體劑型，其中該藥劑包含細菌並且細菌的劑量為約1 x 10 7至約2 x 10 12（約3 x 10 10或約1.5 x 10 11或約1.5 x 10 12）個細胞，其中該劑量係按每膠囊或片劑計或按膠囊中的微型片劑的總數計。 The solid dosage form according to any one of claims 1 to 63, wherein the agent comprises bacteria and the dose of bacteria is about 1 x 10 7 to about 2 x 10 12 (about 3 x 10 10 or about 1.5 x 10 11 or about 1.5 x 10 12 ) cells, where the dose is per capsule or tablet or the total number of minitablets in a capsule. 如請求項1至63中任一項所述之固體劑型，其中該藥劑包含細菌並且細菌的劑量為約1 x 10 9、約3 x 10 9、約5 x 10 9、約1.5 x 10 10、約3 x 10 10、約5 x 10 10、約1.5 x 10 11、約1.5 x 10 12、或約2 x 10 12個細胞，其中該劑量係按每膠囊或片劑計或按膠囊中的微型片劑的總數計。 The solid dosage form according to any one of claims 1 to 63, wherein the agent comprises bacteria and the dose of bacteria is about 1 x 10 9 , about 3 x 10 9 , about 5 x 10 9 , about 1.5 x 10 10 , About 3 x 10 10 , about 5 x 10 10 , about 1.5 x 10 11 , about 1.5 x 10 12 , or about 2 x 10 12 cells, wherein the dosage is per capsule or tablet or per micronized capsule Total number of tablets counted. 如請求項1至102中任一項所述之固體劑型，其中該藥劑包含細菌和/或mEV，並且該藥劑（例如細菌和/或mEV）的劑量為約10 mg至約1500 mg，其中該劑量係按每膠囊或片劑計或按膠囊中的微型片劑的總數計。The solid dosage form according to any one of claims 1 to 102, wherein the medicament comprises bacteria and/or mEV, and the dosage of the medicament (such as bacteria and/or mEV) is about 10 mg to about 1500 mg, wherein the The dosage is per capsule or tablet or the total number of minitablets in a capsule. 如請求項1至102中任一項所述之固體劑型，其中該藥劑包含細菌和/或mEV，並且該藥劑（例如細菌和/或mEV）的劑量為約30 mg至約1300 mg（按細菌和/或mEV的重量計）（約25、約30、約35、約50、約75、約100、約120、約150、約250、約300、約350、約400、約500、約600、約700、約750、約800、約900、約1000、約1100、約1200、約1250、約1300、約2000、約2500、約3000、或約3500 mg），其中該劑量係按每膠囊或片劑計或按膠囊中的微型片劑的總數計。The solid dosage form according to any one of claims 1 to 102, wherein the medicament comprises bacteria and/or mEV, and the dosage of the medicament (such as bacteria and/or mEV) is about 30 mg to about 1300 mg (according to bacteria and/or mEV by weight) (about 25, about 30, about 35, about 50, about 75, about 100, about 120, about 150, about 250, about 300, about 350, about 400, about 500, about 600 , about 700, about 750, about 800, about 900, about 1000, about 1100, about 1200, about 1250, about 1300, about 2000, about 2500, about 3000, or about 3500 mg), wherein the dose is based on each capsule Either by tablet or by the total number of microtablets in the capsule. 如請求項1至102中任一項所述之固體劑型，其中該藥劑包含細菌和/或mEV，並且該藥劑（例如細菌和/或mEV）的劑量為約2 x 10 6至約2 x 10 16個顆粒（例如，其中藉由NTA（奈米顆粒跟蹤分析）確定顆粒計數），其中該劑量係按每膠囊或片劑計或按膠囊中的微型片劑的總數計。 The solid dosage form according to any one of claims 1 to 102, wherein the medicament comprises bacteria and/or mEV, and the dosage of the medicament (such as bacteria and/or mEV) is about 2 x 10 6 to about 2 x 10 16 particles (eg, where the particle count is determined by NTA (Nanoparticle Tracking Analysis)), where the dose is per capsule or tablet or the total number of minitablets in the capsule. 如請求項1至102中任一項所述之固體劑型，其中該藥劑包含細菌和/或mEV，並且該藥劑（例如細菌和/或mEV）的劑量為約5 mg至約900 mg總蛋白（例如，其中總蛋白藉由布拉德福德測定或BCA確定），其中該劑量係按每膠囊或片劑計或按膠囊中的微型片劑的總數計。The solid dosage form according to any one of claims 1 to 102, wherein the medicament comprises bacteria and/or mEV, and the dose of the medicament (such as bacteria and/or mEV) is about 5 mg to about 900 mg total protein ( For example, wherein total protein is determined by Bradford assay or BCA), wherein the dosage is per capsule or tablet or the total number of minitablets in a capsule. 如請求項1至106中任一項所述之固體劑型，其中該固體劑型進一步包含一種或多種治療劑。The solid dosage form according to any one of claims 1 to 106, wherein the solid dosage form further comprises one or more therapeutic agents. 如請求項1至107中任一項所述之固體劑型，其中該固體劑型進一步包含賦形劑（例如，本文所述之賦形劑，例如稀釋劑、黏合劑和/或黏結劑、崩散劑、潤滑劑和/或助流劑、著色劑、調味劑和/或甜味劑）。The solid dosage form as described in any one of claims 1 to 107, wherein the solid dosage form further comprises excipients (for example, the excipients described herein, such as diluents, adhesives and/or binding agents, disintegrating agents , lubricants and/or glidants, coloring agents, flavoring agents and/or sweeteners). 如請求項1至108中任一項所述之固體劑型，其中該固體劑型係片劑。The solid dosage form according to any one of claims 1 to 108, wherein the solid dosage form is a tablet. 如請求項109所述之固體劑型，其中片劑係5 mm、5.5 mm、6 mm、6.5 mm、7 mm、7.5 mm、8 mm、8.5 mm、9 mm、9.5 mm、10 mm、11 mm、12 mm、13 mm、14 mm、15 mm、16 mm、17 mm或18 mm片劑。The solid dosage form as described in claim 109, wherein the tablet is 5 mm, 5.5 mm, 6 mm, 6.5 mm, 7 mm, 7.5 mm, 8 mm, 8.5 mm, 9 mm, 9.5 mm, 10 mm, 11 mm, 12 mm, 13 mm, 14 mm, 15 mm, 16 mm, 17 mm or 18 mm tablets. 如請求項1至108中任一項所述之固體劑型，其中該固體劑型係微型片劑。The solid dosage form according to any one of claims 1 to 108, wherein the solid dosage form is a mini-tablet. 如請求項111所述之固體劑型，其中該微型片劑係1 mm微型片劑、1.5 mm微型片劑、2 mm微型片劑、3 mm微型片劑或4 mm微型片劑。The solid dosage form as claimed in claim 111, wherein the minitablet is a 1 mm minitablet, 1.5 mm minitablet, 2 mm minitablet, 3 mm minitablet or 4 mm minitablet. 如請求項111或112所述之固體劑型，其中多個微型片劑包含於膠囊中。The solid dosage form as claimed in claim 111 or 112, wherein a plurality of minitablets are contained in a capsule. 如請求項1至113中任一項所述之固體劑型，該固體劑型進一步包含腸溶衣。The solid dosage form according to any one of claims 1 to 113, further comprising an enteric coating. 如請求項1114所述之固體劑型，其中該腸溶衣係單腸溶衣或多於一個腸溶衣。The solid dosage form of claim 1114, wherein the enteric coating is a single enteric coating or more than one enteric coating. 如請求項114或115所述之固體劑型，其中該腸溶衣包含內部腸溶衣和外部腸溶衣，並且其中該內部和外部腸溶衣不相同。The solid dosage form of claim 114 or 115, wherein the enteric coating comprises an inner enteric coating and an outer enteric coating, and wherein the inner and outer enteric coatings are different. 如請求項114至116中任一項所述之固體劑型，其中該腸溶衣包含甲基丙烯酸丙烯酸乙酯（MAE）共聚物（1 : 1）。The solid dosage form according to any one of claims 114 to 116, wherein the enteric coating comprises ethyl methacrylate (MAE) copolymer (1:1). 如請求項112至117中任一項所述之固體劑型，其中該腸溶衣包含鄰苯二甲酸乙酸纖維素（CAP）、偏苯三酸乙酸纖維素（CAT）、聚醋酸乙烯鄰苯二甲酸酯（PVAP）、羥丙基甲基纖維素鄰苯二甲酸酯（HPMCP）、脂肪酸、蠟、蟲膠（紫膠桐酸的酯）、塑膠、植物纖維、玉米醇溶蛋白、Aqua-Zein（不含醇的水性玉米醇溶蛋白配製物）、直鏈澱粉、澱粉衍生物、糊精、丙烯酸甲酯-甲基丙烯酸共聚物、醋酸琥珀酸纖維素、羥丙基甲基醋酸琥珀酸纖維素（醋酸羥丙甲纖維素琥珀酸酯）、甲基丙烯酸甲酯-甲基丙烯酸共聚物、或海藻酸鈉。The solid dosage form according to any one of claims 112 to 117, wherein the enteric coating comprises cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), polyvinyl acetate phthalate Formate (PVAP), Hydroxypropylmethylcellulose Phthalate (HPMCP), Fatty Acid, Wax, Shellac (Ester of Lacic Acid), Plastic, Vegetable Fiber, Zein, Aqua -Zein (alcohol-free aqueous zein formulation), amylose, starch derivatives, dextrin, methyl acrylate-methacrylic acid copolymer, cellulose acetate succinate, succinate hydroxypropylmethyl acetate cellulose acetate (hypromellose acetate succinate), methyl methacrylate-methacrylic acid copolymer, or sodium alginate. 如請求項114至117中任一項所述之固體劑型，其中該腸溶衣包含陰離子聚合物材料。The solid dosage form according to any one of claims 114 to 117, wherein the enteric coating comprises an anionic polymer material. 一種預防或治療受試者的疾病之方法，該方法包括向該受試者施用如請求項1至119中任一項所述之固體劑型。A method of preventing or treating a disease in a subject, the method comprising administering the solid dosage form according to any one of claims 1 to 119 to the subject. 如請求項1至119中任一項所述之固體劑型用於治療或預防受試者的疾病的用途。Use of the solid dosage form according to any one of claims 1 to 119 for treating or preventing a disease in a subject. 如請求項1至119中任一項所述之固體劑型用於製備藥物的用途，該藥物用於治療或預防受試者的疾病。Use of the solid dosage form as described in any one of claims 1 to 119 for preparing a medicament for treating or preventing a disease in a subject. 如請求項1至119中任一項所述之固體劑型，用於治療或預防受試者的疾病。The solid dosage form according to any one of claims 1 to 119, for treating or preventing a disease in a subject. 如請求項120至123中任一項所述之方法/固體劑型/用途，其中該固體劑型經口服施用（例如用於口服施用）。The method/solid dosage form/use according to any one of claims 120 to 123, wherein the solid dosage form is administered orally (eg for oral administration). 如請求項120至124中任一項所述之方法/固體劑型/用途，其中該固體劑型空腹（例如，進食前一小時或進食後兩小時）施用。The method/solid dosage form/use according to any one of claims 120 to 124, wherein the solid dosage form is administered on an empty stomach (for example, one hour before or two hours after eating). 如請求項120至125中任一項所述之方法/固體劑型/用途，其中每天1、2、3或4次施用（例如，用於施用）該固體劑型（例如，片劑或多個微型片劑（例如，包含在膠囊中））。The method/solid dosage form/use of any one of claims 120 to 125, wherein the solid dosage form (e.g., a tablet or a plurality of miniature tablets (eg, contained in capsules)). 如請求項120至126中任一項所述之方法/固體劑型/用途，其中該固體劑型包含片劑或多個微型片劑（例如，包含在膠囊中）並且每天1、2、3或4次施用（例如，用於施用）1、2、3或4個固體劑型（例如，片劑或多個微型片劑（例如，包含在膠囊中）。The method/solid dosage form/use of any one of claims 120 to 126, wherein the solid dosage form comprises a tablet or a plurality of minitablets (e.g. contained in a capsule) and 1, 2, 3 or 4 1, 2, 3, or 4 solid dosage forms (eg, a tablet or multiple minitablets (eg, contained in a capsule)) per administration (eg, for administration). 如請求項120至127中任一項所述之方法/固體劑型/用途，其中該受試者需要治療（和/或預防）癌症。The method/solid dosage form/use according to any one of claims 120 to 127, wherein the subject needs to treat (and/or prevent) cancer. 如請求項120至127中任一項所述之方法/固體劑型/用途，其中該受試者需要治療（和/或預防）自體免疫性疾病。The method/solid dosage form/use according to any one of claims 120 to 127, wherein the subject needs to treat (and/or prevent) an autoimmune disease. 如請求項120至127中任一項所述之方法/固體劑型/用途，其中該受試者需要治療（和/或預防）炎性疾病。The method/solid dosage form/use according to any one of claims 120 to 127, wherein the subject needs to treat (and/or prevent) an inflammatory disease. 如請求項120至127中任一項所述之方法/固體劑型/用途，其中該受試者需要治療（和/或預防）代謝性疾病。The method/solid dosage form/use according to any one of claims 120 to 127, wherein the subject needs to treat (and/or prevent) a metabolic disease. 如請求項120至127中任一項所述之方法/固體劑型/用途，其中該受試者需要治療（和/或預防）生態失調。The method/solid dosage form/use according to any one of claims 120 to 127, wherein the subject needs to treat (and/or prevent) dysbiosis. 如請求項120至132中任一項所述之方法/固體劑型/用途，其中該固體劑型與治療劑組合施用。The method/solid dosage form/use of any one of claims 120 to 132, wherein the solid dosage form is administered in combination with a therapeutic agent. 一種製備藥物組成物的固體劑型之方法，該方法包括： (a) 將以下組合成藥物組成物： (i) 藥劑，其具有的藥劑總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的70%，其中該藥劑包含細菌和/或微生物胞外囊泡（mEV）； (ii) 矽化微晶纖維素，其具有的矽化微晶纖維素總質量係該藥物組成物總質量的至少15%且不超過該藥物組成物總質量的85%；以及 (b) 將該藥物組成物壓製成固體劑型。 A method for preparing a solid dosage form of a pharmaceutical composition, the method comprising: (a) Combining the following into pharmaceutical compositions: (i) A medicament having a total mass of the medicament of at least 5% and no more than 70% of the total mass of the pharmaceutical composition, wherein the medicament comprises bacteria and/or microbial extracellular vesicles (mEV ); (ii) silicified microcrystalline cellulose having a total mass of silicified microcrystalline cellulose that is at least 15% and not more than 85% of the total mass of the pharmaceutical composition; and (b) Compressing the pharmaceutical composition into a solid dosage form. 如請求項134所述之方法，該方法進一步將以下組合成藥物組成物：交聚維酮，其具有的交聚維酮總質量係該藥物組成物總質量的至少5%且不超過該藥物組成物總質量的25%。The method of claim 134, further combining the following into a pharmaceutical composition: crospovidone having a total mass of crospovidone of at least 5% of the total mass of the pharmaceutical composition and no more than the drug 25% of the total mass of the composition. 如請求項134或135所述之方法，該方法進一步包括將該固體劑型進行腸溶包衣以獲得經腸溶包衣的固體劑型的步驟。The method according to claim 134 or 135, further comprising the step of performing enteric coating on the solid dosage form to obtain an enteric coated solid dosage form. 如請求項134至136中任一項所述之方法，其中該固體劑型係片劑。The method of any one of claims 134 to 136, wherein the solid dosage form is a tablet. 如請求項134或136中任一項所述之方法，其中該固體劑型係微型片劑。The method of any one of claims 134 or 136, wherein the solid dosage form is a minitablet. 如請求項134至138中任一項所述之方法，該方法進一步包括在該組合步驟之前對該藥劑進行濕法製粒的步驟。The method of any one of claims 134 to 138, further comprising the step of wet granulating the medicament prior to the combining step.
TW111108035A 2021-03-05 2022-03-04 Solid dosage forms TW202302125A (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US202163157138P 2021-03-05 2021-03-05
US63/157,138 2021-03-05
US202163234490P 2021-08-18 2021-08-18
US63/234,490 2021-08-18

Publications (1)

Publication Number Publication Date
TW202302125A true TW202302125A (en) 2023-01-16

Family

ID=80952246

Family Applications (1)

Application Number Title Priority Date Filing Date
TW111108035A TW202302125A (en) 2021-03-05 2022-03-04 Solid dosage forms

Country Status (2)

Country Link
TW (1) TW202302125A (en)
WO (1) WO2022187578A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023239728A1 (en) 2022-06-07 2023-12-14 Evelo Biosciences, Inc. Compositions and methods of treating inflammation using prevotella histicola extracellular vesicles
CN115778913B (en) * 2022-10-28 2024-07-02 广西壮族自治区水牛研究所 Effervescent tablet, preparation method and application thereof

Family Cites Families (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4775536A (en) 1986-02-24 1988-10-04 Bristol-Myers Company Enteric coated tablet and process for making
US5292522A (en) 1989-06-20 1994-03-08 Rohm Gmbh Aqueous film coating agent for solid medicaments
US5047258A (en) 1989-07-14 1991-09-10 Sterling Drug Inc. Aqueous spray-coating process
US6623759B2 (en) 1996-06-28 2003-09-23 Astrazeneca Ab Stable drug form for oral administration with benzimidazole derivatives as active ingredient and process for the preparation thereof
DE19631084A1 (en) 1996-08-01 1998-02-05 Basf Ag Use of (meth) acrylic acid copolymers to increase the permeability of the mucosa
US6312728B1 (en) 1998-07-07 2001-11-06 Cascade Development, Inc. Sustained release pharmaceutical preparation
CN1163223C (en) 1998-07-28 2004-08-25 田边制药株式会社 Prepn. capable of releasing drug at target side in intestine
US20040028737A1 (en) 2002-08-12 2004-02-12 Kopran Research Laboratories Limited Enteric coated stable oral pharmaceutical composition of acid unstable drug and process for preparing the same
DE10260919A1 (en) 2002-12-20 2004-07-01 Röhm GmbH & Co. KG Process for the preparation of coated dosage forms and dietary supplements with concentration gradients in the coating
US20070065513A1 (en) 2003-10-31 2007-03-22 Avi Avramoff Stable lansoprazole formulation
US9149439B2 (en) 2005-03-21 2015-10-06 Sandoz Ag Multi-particulate, modified-release composition
DE102005032806A1 (en) 2005-07-12 2007-01-18 Röhm Gmbh Use of a partially neutralized, anionic (meth) acrylate copolymer as a coating for the preparation of a dosage form with a release of active ingredient at reduced pH values
US20150087616A1 (en) * 2011-11-30 2015-03-26 Ritter Pharmaceuticals, Inc. Prebiotic formulations and methods of use
BR112015020836B1 (en) 2013-03-01 2022-09-20 Bpsi Holdings, Llc DELAYED RELEASE FILM COATINGS CONTAINING CALCIUM SILICATE AND SUBSTRATES COATED WITH THE SAME
ES2917415T3 (en) 2017-06-14 2022-07-08 4D Pharma Res Ltd Compositions comprising a bacterial strain
SG11202106230XA (en) 2018-12-12 2021-07-29 4D Pharma Res Ltd Compositions comprising bacterial strains
AU2020225473A1 (en) * 2019-02-22 2021-09-30 Evelo Biosciences, Inc. Bacterial membrane preparations
WO2021146523A1 (en) * 2020-01-17 2021-07-22 Evelo Biosciences, Inc. Solid dosage forms with improved disintegration profiles

Also Published As

Publication number Publication date
WO2022187578A1 (en) 2022-09-09

Similar Documents

Publication Publication Date Title
TW202045192A (en) Bacterial membrane preparations
TW202114718A (en) Processed microbial extracellular vesicles
TW202135783A (en) Solid dosage forms containing bacteria and microbial extracellular vesicles
TW202140051A (en) Solid dosage forms with improved disintegration profiles
TW202228653A (en) Solid dosage forms of bacteria
US20230190831A1 (en) Solid dosage forms with improved disintegration profiles
TW202302125A (en) Solid dosage forms
TW202237155A (en) Extracellular vesicle preparations
TW202216178A (en) Compositions And Methods For Treating Diseases and Disorders UsingMegasphaera sp.
TW202304415A (en) Pharmaceutical agents that contain bacteria
WO2023114296A2 (en) Extracellular vesicle preparations
TW202304486A (en) Fournierella extracellular vesicle preparations
TW202214275A (en) Compositions and methods for treating diseases and disorders using fournierella massiliensis
TW202322787A (en) Solid dosage forms containing bacteria and microbial extracellular vesicles
CN116867502A (en) Solid dosage form of bacteria
CN117615748A (en) Pharmaceutical composition containing bacteria
CN117062913A (en) Extracellular vesicle preparation