WO2022061141A1

WO2022061141A1 - Compositions and methods of treating inflammation using prevotella histicola

Info

Publication number: WO2022061141A1
Application number: PCT/US2021/050913
Authority: WO
Inventors: Mark BODMER; Douglas MASLIN; Duncan MCHALE
Original assignee: Evelo Biosciences, Inc.
Priority date: 2020-09-21
Filing date: 2021-09-17
Publication date: 2022-03-24
Also published as: TW202227112A

Abstract

Provided herein are methods and compositions related to Prevotella bacteria useful as therapeutic agents, e.g., for the treatment of inflammatory disease.

Description

COMPOSITIONS AND METHODS OF TREATING INFLAMMATION

USING PREVOTELLA HISTICOLA

CROSS-REFERENCE TO RELATED APPLICATIONS

[1] This application claims the benefit of the following U.S. Provisional Application serial numbers 63/081,072, filed September 21, 2020, 63/092,191, filed October 15, 2020, and 63/145,790, filed February 4, 2021, the entire contents of each of which are incorporated herein by reference.

SUMMARY

[2] In certain aspects, provided herein are bacterial compositions (e.g, pharmaceutical compositions) comprising Prevotella histicola useful for the treatment and/or prevention of an inflammatory disease. In some embodiments, the inflammatory disease is a Thl, Th2, or Thl7 inflammatory disease. In certain aspects, provided herein are bacterial compositions (e.g, pharmaceutical compositions) comprising Prevotella histicola useful for the treatment and/or prevention of an immune disorder.

[3] In certain aspects, provided herein are bacterial compositions (e.g, pharmaceutical compositions) comprising Prevotella histicola useful for the treatment and/or prevention of psoriasis (e.g, mild to moderate psoriasis) (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g, for the treatment of psoriasis, for the reduction of Lesion Severity Scores (LSS), and/or for the reduction of Psoriasis Area Severity Index (PASI) scores). In some embodiments, the bacterial compositions comprise whole Prevotella histicola bacteria (e.g, live bacteria, killed bacteria, attenuated bacteria).

[4] In certain aspects, provided herein are bacterial compositions (e.g, pharmaceutical compositions) comprising Prevotella histicola useful for the treatment and/or prevention of atopic dermatitis (e.g, mild to moderate atopic dermatitis) (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g, for the treatment of atopic dermatitis). In some embodiments, the bacterial compositions comprise whole Prevotella histicola bacteria (e.g, live bacteria, killed bacteria, attenuated bacteria).

[5] In certain aspects, provided herein are bacterial compositions (e.g, pharmaceutical compositions) comprising Prevotella histicola useful for the treatment and/or prevention of psoriatic arthritis, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g, for the treatment of psoriatic arthritis). In some embodiments, the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, killed bacteria, attenuated bacteria).

[6] In some embodiments, the Prevotella histicola is Prevotella Strain B 50329 (NRRL accession number B 50329; Strain B). In some embodiments, the Prevotella strain is a strain comprising at least at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, 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) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Prevotella Strain B 50329.

[7] In some embodiments, the bacterial composition comprises one strain of bacteria, wherein the one strain of bacteria is a strain comprising at least 99.9% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329). In some embodiments, the bacterial composition comprises one strain of bacteria, wherein the one strain of bacteria is the Prevotella histicola Strain B 50329 (NRRL accession number B 50329).

[8] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about

9.6 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[9] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 12.8 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[10] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 16 x 10" total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[11] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about

9.6 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[12] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about

9.6 x 10¹¹ to about 12.8 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. [13] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 12.8 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[14] In certain embodiments, provided herein are solid dosage forms comprising the Prevotella histicola bacteria. In some embodiments, the solid dosage form comprises an enteric coating. In some embodiments, the solid dosage form is a tablet, e.g., an enteric coated tablet. In some embodiments, each tablet comprises about 3.2 x 10¹¹ total cells of the Prevotella histicola bacteria. In some embodiments, the solid dosage form is a capsule e.g., an enteric coated capsule. In some embodiments, each capsule comprises about 3.2 x 10¹¹ total cells (e.g., 3.35 x 10¹¹ total cells) of the Prevotella histicola bacteria.

[15] In some embodiments, 1 solid dosage form (e.g., tablet or capsule) is administered (e.g., is for administration) per day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 2 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per day, wherein the solid dosage form (e.g., each solid dose form) comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 3 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 4 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 5 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. For clarity, about 3.2 x 10¹¹ total cells includes total cell counts within ±5% of 3.2 x 10¹¹ total cells e.g., 3.35 x 10¹¹ total cells.

[16] In some embodiments, a dose of Prevotella histicola bacteria of about 9.6 x 10¹¹ total cells are administered (e.g., are for administration) per day.

[17] In some embodiments, a dose of Prevotella histicola bacteria of about 12.8 x 10¹¹ total cells are administered (e.g., are for administration) per day.

[18] In some embodiments, a dose of Prevotella histicola bacteria of about 16 x 10¹¹ total cells are administered (e.g., are for administration) per day.

[19] In some embodiments, the solid dosage form is a tablet. In some embodiments, the tablet is an enteric coated tablet. In some embodiments, the enteric coated tablet is from 5mm to 18mm in diameter. In some embodiments, the tablet comprises about 3.2 x 10¹¹ total cells of the Prevotella bacteria. In some embodiments, the Prevotella bacteria in the tablet are lyophilized.

[20] In some embodiments, the solid dosage form is a capsule. In some embodiments, the capsule is an enteric coated capsule. In some embodiments, the enteric coated capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule. In some embodiments, the capsule is a size 0 capsule. In some embodiments, the capsule comprises about 3.2 x 10¹¹ total cells of the Prevotella bacteria. In some embodiments, the Prevotella bacteria in the capsule are lyophilized.

[21] In certain embodiments, provided herein are solid dosage forms comprising the Prevotella bacteria. In some embodiments, the solid dosage form is a tablet, e.g., an enteric coated tablet. In some embodiments, the solid dosage form is a capsule, e.g., an enteric coated capsule. In some embodiments, the enteric coating comprises a polymethacrylate-based copolymer. In some embodiments, the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1). In some embodiments, the enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P or Eudragit L30-D55).

[22] In some embodiments, each tablet comprises about 3.2 x 10¹¹ total cells of the Prevotella bacteria. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tablets are administered, e.g., once or twice daily to a subject. In some embodiments, 3 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 4 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 5 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, the Prevotella bacteria in the tablet are lyophilized (e.g., in a powder). In some embodiments, the Prevotella bacteria in the tablet are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.

[23] In some embodiments, each capsule comprises about 3.2 x 10¹¹ total cells of the Prevotella bacteria. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered, e.g., once or twice daily to a subject. In some embodiments, 3 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 4 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 5 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, the Prevotella bacteria in the capsule are lyophilized (e.g., in a powder). In some embodiments, the Prevotella bacteria in the capsule are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.

[24] In some embodiments, the bacterial composition comprising Prevotella bacteria is prepared as a solid dose form, such as a tablet, capsule, or a powder. The powder can comprise lyophilized bacteria. In some embodiments, the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide. In some embodiments, the bacterial composition comprises a powder comprising Prevotella bacteria. In some embodiments, the powder comprising Prevotella bacteria (e.g., at a dose provided herein) is resuspended (e.g., in a liquid such as a solution, buffer, water or other beverage, or a food), e.g., for use in the methods provided herein.

[25] In some embodiments, the bacterial composition is administered orally. In some embodiments, the administration to the subject once daily.

[26] In some embodiments, the bacterial composition is administered once daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days. In some embodiments, the bacterial composition is administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered once daily for at least 8 weeks. In some embodiments, the bacterial composition is administered once daily for at least 16 weeks.

[27] In some embodiments, the bacterial composition comprises lyophilized Prevotella bacteria, e.g., in a powder. In certain embodiments, the lyophilized Pre votella bacteria is formulated into a solid dose form, such as a tablet or capsule. In some embodiments, the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.

[28] In some embodiments, the bacterial composition is formulated as a tablet. In some embodiments, the bacterial formulation e.g., composition) comprises an enteric coating or micro encapsulation. [29] In some embodiments, the bacterial composition is formulated as a capsule. In some embodiments, the bacterial formulation (e.g, composition) comprises an enteric coating or micro encapsulation.

[30] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is anon-human mammal (e.g., a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee).

[31] In certain embodiments, provided herein are methods of treating a subject who has a Thl mediated inflammatory disease comprising administering to the subject a bacterial composition described herein.

[32] In embodiments, provided herein is a method of treating a Thl mediated inflammatory disease comprising administering (e.g, orally administering) to a human subject (e.g., a subject with a Thl mediated inflammatory disease) a strain of a Prevoiella histicola and/or a composition (e.g, a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Prevoiella histicola provided herein.

[33] In certain embodiments, provided herein are methods of treating a subject who has a Th2 mediated inflammatory disease (such as asthma or atopic dermatitis) comprising administering to the subject a bacterial composition described herein.

[34] In embodiments, provided herein is a method of treating a Th2 mediated inflammatory disease (such as asthma or atopic dermatitis) comprising administering (e.g, orally administering) to a human subject (e.g., a subject with a Th2 mediated inflammatory disease (such as asthma or atopic dermatitis)) a strain of a Prevoiella histicola and/or a composition (e.g, a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Prevotella histicola provided herein.

[35] In certain embodiments, provided herein are methods of treating a subject who has a Thl7 mediated inflammatory disease (such as psoriasis) comprising administering to the subject a bacterial composition described herein.

[36] In embodiments, provided herein is a method of treating a Thl7 mediated inflammatory disease (such as psoriasis) comprising administering (e.g, orally administering) to a human subject (e.g., a subject with a Thl7 mediated inflammatory disease (such as psoriasis)) a strain of a Prevotella histicola and/or a composition (e.g, a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Prevotella histicola provided herein. [37] In certain embodiments, provided herein are methods of treating a subject who has psoriasis (e.g, mild to moderate psoriasis) comprising administering to the subject a bacterial composition (e.g., pharmaceutical composition) described herein.

[38] In certain embodiments, provided herein are methods of decreasing Lesion Severity Score (LSS) (e.g, mean LSS) (e.g, as compared to baseline or placebo control) in a subject (e.g, a subject with psoriasis) comprising administering to the subject a bacterial composition described herein. In certain embodiments, the LSS in the subject is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more (e.g, by day 7, 14, 21, 28, or 35 of treatment). In certain embodiments, the LSS in the subject is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more after dosing is stopped (e.g, 14 days after treatment has stopped).

[39] In certain embodiments, provided herein are methods of decreasing Psoriasis Area and Severity Index (PASI) score (e.g, mean PASI score) (e.g, as compared to baseline or placebo control) in a subject (e.g, a subject with psoriasis) comprising administering to the subject a bacterial composition described herein. In certain embodiments, the PASI score in the subject is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more (e.g, by day 7, 14, 21, 28, or 35 of treatment). In certain embodiments, the PASI score in the subject is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more after dosing is stopped (e.g, 14 days after treatment has stopped).

[40] In certain embodiments, provided herein are methods of increasing a sustained clinical effect (e.g, continued reductions from baseline (or placebo) in mean LSS and/or PASI, e.g, 1, 2, 3, 4, 5, 6 or more weeks after completion of dosing) in a subject (e.g, a subject with psoriasis) comprising administering to the subject a bacterial composition described herein. In certain embodiments, the LSS and/or PASI score in the subject is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more (e.g, by day 7, 14, 21, 28, or 35 of treatment).

[41] In certain embodiments, provided herein are methods of enhancing anti-inflammatory cytokine production (e.g., increasing as compared to amount produced (e.g., mRNA and/or protein) in the absence of the bacterial composition) in a subject, the method comprising administering a bacterial composition described herein. In some embodiments, the antiinflammatory cytokine is IL-10, IL-27, and/or IL1RA. In certain embodiments, the antiinflammatory cytokine is expressed by Ml-type APCs. In some embodiments, enhancing anti-inflammatory cytokine production comprises an increase in anti-inflammatory cytokine (e.g., IL-10, IL-27, and/or IL1RA) mRNA levels (e.g., in skin biopsies). In some embodiments, enhancing anti-inflammatory cytokine production comprises an increase in anti-inflammatory cytokine (e.g., IL-10, IL-27, and/or IL1RA) protein levels (e.g., in blood samples).

[42] In certain embodiments, provided herein are methods of inhibiting pro-inflammatory cytokine production (e.g., decreasing as compared to amount produced (e.g., mRNA and/or protein) in the absence of the bacterial composition) in a subject, the method comprising administering a bacterial composition described herein. In some embodiments, the pro- inflammatory cytokine is GM-CSF, IL-17A, and/or IL-13. In some embodiments, the pro- inflammatory cytokine is IL-6, TNF, and/or IL-12p70. In some embodiments, the pro- inflammatory cytokine is IL23p40, IL17, IL-6, TNF, and/or IL-13. In some embodiments, inhibiting pro-inflammatory cytokine production comprises inhibiting pro-inflammatory cytokine production in a draining lymph node (e.g., cervical lymph node). In some embodiments, inhibiting pro-inflammatory cytokine production comprises inhibiting pro- inflammatory cytokine production in the spleen. In some embodiments, inhibiting pro- inflammatory cytokine production comprises a decrease in pro-inflammatory cytokine (e.g., 1117a) mRNA levels (e.g., in skin biopsies). In some embodiments, inhibiting pro- inflammatory cytokine production comprises a decrease in pro-inflammatory cytokine (e.g., IL-17A) protein levels (e.g., in blood samples).

[43] In certain embodiments, provided herein are methods of inhibiting pro-inflammatory chemokines production (e.g., decreasing as compared to amount produced (e.g., mRNA and/or protein) in the absence of the bacterial composition) in a subject, the method comprising administering a bacterial composition described herein. In some embodiments, the pro-inflammatory chemokine is keratinocyte chemoattractant (KC).

[44] In certain embodiments, provided herein are methods of altering cytokine production or chemokine production (e.g., altering as compared to amount produced (e.g., mRNA and/or protein) in the absence of the bacterial composition) in a subject, the method comprising administering a bacterial composition described herein. In some embodiments, blood samples from the subject are stimulated ex vivo and analyzed for levels of cytokines and/or chemokines. In some embodiments, the level of IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL- 12p40, IL-17A, TNFa, and/or IFNy is analyzed.

[45] In embodiments, provided herein is a method of treating psoriasis comprising administering e.g., orally administering) to a human subject a strain of a Prevotella histicola and/or a composition (e.g., a pharmaceutical composition and/or a solid dosage form) comprising a strain of aPrevotella histicola provided herein. In some embodiments, the human subject has a confirmed diagnosis of mild to moderate plaque-type psoriasis for at least 6 months involving no more than 10% of body surface area (BSA) (excluding the scalp). In some embodiments, the human subject has a minimum of 2 psoriatic lesions. In some embodiments, the subject has not received systemic non-biologic psoriasis therapy (methotrexate [MTX], steroids, cyclophosphamide) or psoralen plus ultraviolet A (PUVA)/ultraviolet A (UVA) phototherapy within 4 weeks prior to dosing. In some embodiments, subject has not received treatment with biologic agents within 12 months prior to first dose. In some embodiments, the subject is not continuing use of topical or oral pharmacologically active agents 2 weeks prior to the start of dosing. In some embodiments, the human subject has a documented diagnosis of plaque psoriasis for >6 months.

[46] In some embodiments, the human subject has had mild to moderate plaque psoriasis with plaque covering BSA of >3% and <10% and meet both of the following additional criteria: (i) PASI score of >6 and <15, and (ii) PGA score of 2 or 3.

[47] In some embodiments, the method decreases the PASI (Psoriasis Area and Severity Index) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s PASI score prior to the commencement of treatment).

[48] In some embodiments, the method increases a PASI percentage response rate (e.g., PASI-50, PASI-75, PASI-90, or PASI-100), e.g., as described herein. For example, the percentage of subjects who achieve a 75% or greater reduction in PASI score from baseline is represented by the PASI-75 value, e.g., after 16 weeks of treatment.

[49] In some embodiments, the method decreases the LSS (Lesion Severity Score) in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s LSS prior to the commencement of treatment), e.g., as described herein.

[50] In some embodiments, the method decreases the PGA (Physician’s Global Assessment) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s PGA score prior to the commencement of treatment), e.g., as described herein.

[51] In some embodiments, the method decreases the percent of BSA (Body Surface Area) involvement in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s percent involvement prior to the commencement of treatment), e.g., as described herein. [52] In some embodiments, the method decreases the mNAPSI (Modified Nail Psoriasis Severity Index) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s mNAPSI score prior to the commencement of treatment), e.g., as described herein.

[53] In some embodiments, the method improves (e.g., decreases) the DLQI (Dermatology Life Quality Index) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s DLQI score prior to the commencement of treatment), e.g., as described herein.

[54] In some embodiments, the method improves the product of PGA and BSA in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s product of PGA and BSA prior to the commencement of treatment), e.g., as described herein.

[55] In some embodiments, the method improves (e.g., decreases) the PSI (Psoriasis Symptom Inventory) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s PSI score prior to the commencement of treatment), e.g., as described herein.

[56] In some embodiments, the method decreases pain in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s pain prior to the commencement of treatment), e.g., as described herein. For example, pain can be assessed by the SF-36 Bodily Pain Scale (SF-36 BPS) or the VAS Pain.

[57] In some embodiments, the method decreases fatigue in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s fatigue prior to the commencement of treatment), e.g., as described herein.

[58] In certain embodiments, provided herein are methods of treating a subject who has atopic dermatitis (e.g., mild to moderate atopic dermatitis) comprising administering to the subject a bacterial composition described herein.

[59] In embodiments, provided herein is a method of treating atopic dermatitis comprising administering (e.g, orally administering) to a human subject a strain of a Prevotella histicola and/or a composition (e.g, a pharmaceutical composition and/or a solid dosage form) comprising a strain of a Prevotella histicola. In some embodiments, the human subject has a confirmed diagnosis of mild to moderate atopic dermatitis for at least 6 months involving a minimum of 3% to a maximum of 15% body surface area. In some embodiments, the subject has had a confirmed diagnosis of mild to moderate atopic dermatitis with an IGA score of 2 or 3. In some embodiments, the human subject has moderate atopic dermatitis with a minimum of 5% and a maximum of 40% BSA involvement, and an IGA score of 2 or 3. In some embodiments, the subject has at least 2 atopic dermatitis lesions with at least 1 in a site suitable for biopsy. In some embodiments, the subject is not receiving systemic non-biologic atopic dermatitis therapy (methotrexate (MTX), steroids, cyclophosphamide) or has received therapy within 4 weeks prior to dosing. In some embodiments, wherein the human subject is not receiving treatment with biologic agents within 12 months prior to first dose. In some embodiments, wherein the human subject is not continuing to use topical or oral pharmacologically active agents 2 weeks prior to the start of dosing.

[60] In some embodiments, the method decreases the EASI (Eczema Area and Severity Index) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s EASI score prior to the commencement of treatment), e.g., as described herein.

[61] In some embodiments, the method decreases the SCORAD (SCORing Atopic Dermatitis) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s SCORAD score prior to the commencement of treatment), e.g., as described herein.

[62] In some embodiments, the method decreases the IGA (Investigator’s Global Assessment) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s IGA score prior to the commencement of treatment), e.g., as described herein.

[63] In some embodiments, the method decreases the Percentage of Body Surface Area (BSA) affected by disease in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s BSA percentage prior to the commencement of treatment), e.g., as described herein.

[64] In some embodiments, the method improves the product of IGA and BSA in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s IGA x BSA prior to the commencement of treatment), e.g., as described herein.

[65] In some embodiments, the method improves the Dermatology Life Quality Index (DLQI) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s DLQI score prior to the commencement of treatment), e.g., as described herein.

[66] In some embodiments, the method improves the Patient-Oriented Eczema Measure (POEM) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s POEM score prior to the commencement of treatment), e.g., as described herein.

[67] In some embodiments, the method improves the Pruritus Numerical Rating Scale (Pruritus NRS) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s Pruritus NRS score prior to the commencement of treatment), e.g., as described herein.

[68] In some embodiments, the method improves the blood eosinophils in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s blood eosinophils prior to the commencement of treatment), e.g., as described herein. [69] In certain embodiments, provided herein are methods of treating a subject who has psoriatic arthritis comprising administering to the subject a bacterial composition described herein.

[70] In embodiments, provided herein is a method of treating psoriatic arthritis comprising administering (e.g., orally administering) to a human subject (e.g., a subject with psoriatic arthritis) a strain of a Prevoiella histicola and/or a composition (e.g., a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Prevotella histicola provided herein.

[71] In some embodiments, the method improves (e.g., increases) the percentage of subjects with an ACR20 response, e.g., after 8 or 16 weeks of treatment (e.g., as compared to the percentage prior to the commencement of treatment), e.g., as described herein.

[72] In some embodiments, the method improves (e.g., increases) the percentage of subjects with an ACR50 response, e.g., after 8 or 16 weeks of treatment (e.g., as compared to the percentage prior to the commencement of treatment), e.g., as described herein.

[73] In some embodiments, the method improves (e.g., increases) the percentage of subjects with an ACR70 response, e.g., after 8 or 16 weeks of treatment (e.g., as compared to the percentage prior to the commencement of treatment), e.g., as described herein.

[74] In some embodiments, the method improves (e.g., increases) the Modified Psoriatic Arthritis Response Criteria (PsARC) score in the subject, e.g., after 8 or 16 weeks of treatment (e.g., as compared to the subject’s PsARC prior to the commencement of treatment), e.g., as described herein.

[75] In some embodiments, the method decreases the dactylitis severity score in the subject, e.g., after 8 or 16 weeks of treatment (e.g., as compared to the subject’s dactylitis severity score prior to the commencement of treatment), e.g., as described herein.

[76] In some embodiments, the method decreases the Clinical Disease Activity Index (CD Al) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s CD Al prior to the commencement of treatment), e.g., as described herein.

[77] In some embodiments, the method decreases the DAS28 score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s DAS28 prior to the commencement of treatment), e.g., as described herein.

[78] In some embodiments, the method decreases the Maastricht Ankylosing Spondylitis Enthesis Score (MASES) in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s MASES prior to the commencement of treatment), e.g., as described herein. [79] In some aspects, the disclosure provides a bacterial composition described herein (e.g, in an amount described herein) for use in treating psoriasis (e.g, mild to moderate psoriasis).

[80] In some aspects, the disclosure provides a bacterial composition described herein (e.g, in an amount described herein) for use in treating atopic dermatitis (e.g, mild to moderate atopic dermatitis).

[81] In some aspects, the disclosure provides a bacterial composition described herein (e.g, in an amount described herein) for use in treating psoriatic arthritis.

[82] In some aspects, the disclosure provides use of a bacterial composition described herein (e.g, in an amount described herein) for the preparation of a medicament for the treatment of psoriasis (e.g, mild to moderate psoriasis).

[83] In some aspects, the disclosure provides use of a bacterial composition described herein (e.g, in an amount described herein) for the preparation of a medicament for the treatment of atopic dermatitis (e.g, mild to moderate atopic dermatitis).

[84] In some aspects, the disclosure provides use of a bacterial composition described herein (e.g, in an amount described herein) for the preparation of a medicament for the treatment of psoriatic arthritis.

[85] In some aspects, the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in treating an inflammatory disease. In some embodiments, the inflammatory disease is a Thl, Th2, or Thl7 inflammatory disease. In some aspects, the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in treating an immune disorder.

[86] In some aspects, the disclosure provides use of a bacterial composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of an inflammatory disease. In some embodiments, the inflammatory disease is a Thl, Th2, or Thl7 inflammatory disease. In some aspects, the disclosure provides use of a bacterial composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of an immune disorder.

[87] In certain embodiments, provided herein are methods of decreasing inflammation in a subject (e.g., a subject who has psoriasis (e.g., mild to moderate psoriasis) comprising administering to the subject a bacterial composition described herein, wherein administration of the bacterial composition results in increased efficacy after 30 days of dosing in the subject (e.g., as compared to the level of efficacy after 15 days of dosing). Efficacy can be determined by the decrease in the level of inflammation being greater after 30 days of dosing than the level of inflammation after 15 days of dosing.

[88] In certain embodiments, provided herein are methods of decreasing inflammation in a subject (e.g., a subject who has psoriasis (e.g., mild to moderate psoriasis) and/or atopic dermatitis (e.g., mild to moderate atopic dermatitis)) and/or psoriatic arthritis comprising administering to the subject a bacterial composition described herein, wherein the effects on inflammation of the administration of the bacterial composition persist for at least 14 days after last dosing the subject (e.g., the level of inflammation is lower 14 days after last dosing the subject, as compared to the level of inflammation prior to commencement of dosing the subject ). Persistence can be determined by the decrease in the level of inflammation being greater at 14 days after last dosing the subject than the level of inflammation prior to commencement of dosing the subject.

DETAILED DESCRIPTION

[89] Prevotella histicola is a natural human commensal organism, commonly found on oral, nasopharyngeal, gastrointestinal (GI), and genito-urinary mucosal surfaces. Preclinical studies using Prevotella histicola Strain B have been carried out across a range of human and mouse primary cell in vitro assays, which support the use of this agent in the treatment of psoriasis, atopic dermatitis and psoriatic arthritis.

[90] In certain aspects, described herein is an oral therapy for treating an inflammatory disease with Prevotella histicola Strain B. In some embodiments, the inflammatory disease is a Thl, Th2, or Thl7 inflammatory disease. In certain aspects, described herein is an oral therapy for treating an immune disorder with Prevotella histicola Strain B.

[91] In certain aspects, described herein is an oral therapy for treating psoriasis with Prevotella histicola Strain B.

[92] In certain aspects, described herein is an oral therapy for treating atopic dermatitis with Prevotella histicola Strain B.

[93] In certain aspects, described herein is an oral therapy for treating psoriatic arthritis with Prevotella histicola Strain B.

Definitions

[94] The term “about” when used before a numerical value indicates that the value may vary within a reasonable range, such as within ±10%, ±5% or ±1% of the stated value.

[95] “Adjuvant” or “Adjuvant therapy” broadly refers to an agent that affects an immunological or physiological response in a patient or subject. For example, an adjuvant might increase the presence of an antigen over time or help absorb an antigen presenting cell antigen, activate macrophages and lymphocytes and support the production of cytokines. By changing an immune response, an adjuvant might permit a smaller dose of an immune interacting agent to increase the effectiveness or safety of a particular dose of the immune interacting agent. For example, an adjuvant might prevent T cell exhaustion and thus increase the effectiveness or safety of a particular immune interacting agent.

[96] ‘ ‘Administration” broadly refers to a route of administration of a composition 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), and subcutaneous (SC) administration. The bacterial compositions described herein can be administered in any form by any effective route, including but not limited to oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g, using any standard patch), intradermal, ophthalmic, (intra)nasally, local, non-oral, such as aerosol, inhalation, subcutaneous, intramuscular, buccal, sublingual, (trans )rectal, vaginal, intra-arterial, and intrathecal, transmucosal (e.g, sublingual, lingual, (trans)buccal, (trans)urethral, vaginal (e.g, trans- and perivaginally), implanted, intravesical, intrapulmonary, intraduodenal, intragastrical, and intrabronchial. In preferred embodiments, the bacterial compositions described herein are administered orally, rectally, topically, intravesically, by injection into or adjacent to a draining lymph node, intravenously, by inhalation or aerosol, or subcutaneously. In some preferred embodiments, the bacterial compositions described herein are administered orally.

[97] ‘ ‘Cellular augmentation” broadly refers to the influx of cells or expansion of cells in an environment that are not substantially present in the environment prior to administration of a composition and not present in the composition itself. Cells that augment the environment include immune cells, stromal cells, bacterial and fungal cells.

[98] ‘ ‘Clade” refers to the OTUs or members of a phylogenetic tree that are downstream of a statistically valid node in a phylogenetic tree. The clade comprises a set of terminal leaves in the phylogenetic tree that is a distinct monophyletic evolutionary unit and that share some extent of sequence similarity. “Operational taxonomic units,” “OTU” (or plural, “OTUs”) refer to a terminal leaf in a phylogenetic tree and is defined by a nucleic acid sequence, e.g, the entire genome, or a specific genetic sequence, and all sequences that share sequence identity to this nucleic acid sequence at the level of species. In some embodiments the specific genetic sequence may be the 16S sequence or a portion of the 16S sequence. In other embodiments, the entire genomes of two entities are sequenced and compared. In another embodiment, select regions such as multilocus sequence tags (MLST), specific genes, or sets of genes may be genetically compared. In 16S embodiments, OTUs that share ^97% average nucleotide identity across the entire 16S or some variable region of the 16S are considered the same OTU (see e.g. Claesson M J, Wang Q, O'Sullivan O, Greene-Diniz R, Cole J R, Ros R P, and O'Toole P W. 2010. Comparison of two next-generation sequencing technologies for resolving highly complex microbiota composition using tandem variable 16S rRNA gene regions. Nucleic Acids Res 38: e200. Konstantinidis K T, Ramette A, and Tiedje J M. 2006. The bacterial species definition in the genomic era. Philos Trans R Soc Land B Biol Sci 361 : 1929-1940.). In embodiments involving the complete genome, MLSTs, specific genes, or sets of genes OTUs that share =195% average nucleotide identity are considered the same OTU (see e.g. Achtman M, and Wagner M. 2008. Microbial diversity and the genetic nature of microbial species. Nat. Rev. Microbiol. 6: 431-440. Konstantinidis K T, Ramette A, and Tiedje J M. 2006. The bacterial species definition in the genomic era. Philos Trans R Soc LondB Biol Sci 361: 1929-1940.). OTUs are frequently defined by comparing sequences between organisms. Generally, sequences with less than 95% sequence identity are not considered to form part of the same OTU. OTUs may also be characterized by any combination of nucleotide markers or genes, in particular highly conserved genes (e.g, “house-keeping” genes), or a combination thereof. Such characterization employs, e.g., WGS data or a whole genome sequence.

[99] A “combination” of two or more monoclonal microbial strains includes the physical co-existence of the two monoclonal microbial strains, either in the same material or product or in physically connected products, as well as the temporal co-administration or colocalization of the monoclonal microbial strains.

[100] The term “decrease” or “deplete” means a change, such that the difference is, depending on circumstances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 1/100, 1/1000, 1/10,000, 1/100,000, 1/1,000,000 or undetectable after treatment when compared to a pre-treatment state. Properties that may be decreased include the number of immune cells, bacterial cells, stromal cells, myeloid derived suppressor cells, fibroblasts, metabolites; the level of a cytokine; or another physical parameter (such as ear thickness (e.g., in a DTH animal model) or tumor size (e.g., in an animal tumor model)).

[101] As used herein, “engineered bacteria” are any bacteria that have been genetically altered from their natural state by human intervention and the progeny of any such bacteria. Engineered bacteria include, for example, the products of targeted genetic modification, the products of random mutagenesis screens and the products of directed evolution. [102] The term “epitope” means a protein determinant capable of specific 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 a particular sequence of amino acids to which an antibody is capable of binding.

[103] The term “gene” is used broadly to refer to any nucleic acid associated with a biological function. The term “gene” applies to a specific genomic sequence, as well as to a cDNA or an mRNA encoded by that genomic sequence.

[104] “Identity” as between nucleic acid sequences of two nucleic acid molecules can be determined as a percentage of identity using known computer algorithms such as the “FASTA” program, using for example, the default parameters as in Pearson etal. (1988) Proc. Natl. Acad. Sci. USA 85:2444 (other programs include the GCG program package (Devereux, J., et al. , 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, Martin J. Bishop, ed., Academic Press, San Diego, 1994, and Carillo et al. (1988) SIAM J Applied Math 48: 1073). For example, the BLAST function of the National Center for Biotechnology Information database can be used to determine identity. Other commercially or publicly available programs include, DNAStar “MegAlign” program (Madison, Wis.) and the University of Wisconsin Genetics Computer Group (UWG) “Gap” program (Madison Wis.)).

[105] As used herein, the term “immune disorder” refers to any disease, disorder or disease symptom caused by an activity of the immune system, including autoimmune diseases, inflammatory diseases and allergies. Immune disorders include, but are not limited to, autoimmune diseases (e.g., Lupus, Scleroderma, hemolytic anemia, vasculitis, type one diabetes, Grave’s disease, rheumatoid arthritis, multiple sclerosis, Goodpasture’s syndrome, pernicious anemia and/or myopathy), inflammatory diseases (e.g., acne vulgaris, asthma, celiac disease, chronic prostatitis, glomerulonephritis, inflammatory bowel disease, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis and/or interstitial cystitis), and/or an allergies (e.g., food allergies, drug allergies and/or environmental allergies).

[106] “Immunotherapy” is treatment that uses a subject’s immune system to treat disease (e.g, immune disease) and includes, for example, checkpoint inhibitors, cytokines, cell therapy, CAR-T cells, and dendritic cell therapy.

[107] The term “increase” means a change, such that the difference is, depending on circumstances, at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 2-fold, 4-fold, 10- fold, 100-fold, 10^A3 fold, 10^A4 fold, 10^A5 fold, 10^A6 fold, and/or 10^A7 fold greater after treatment when compared to a pre-treatment state. Properties that may be increased include the number of immune cells, bacterial cells, stromal cells, myeloid derived suppressor cells, fibroblasts, metabolites; the level of a cytokine; or another physical parameter (such as ear thickness (e.g., in a DTH animal model) or tumor size (e.g., in an animal tumor model).

[108] ‘ ‘Innate immune agonists” or “immuno-adjuvants” are small molecules, proteins, or other agents that specifically target innate immune receptors including Toll-Like Receptors (TLR), NOD receptors, RLRs, C-type lectin receptors, STING-cGAS Pathway components, inflammasome complexes. For example, LPS is a TLR-4 agonist that is bacterially derived or synthesized and aluminum can be used as an immune stimulating adjuvant. Immuno- adjuvants are a specific class of broader adjuvant or adjuvant therapy. 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 the bis-phosphorothioate analog of 2'3'-cGAMP). Examples of TLR agonists include, but are not limited to, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR1O and TLRI 1. Examples of NOD agonists include, but are not limited to, N-acetylmuramyl-L-alanyl-D-isoglutamine (muramyldipeptide (MDP)), gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP), and desmuramylpeptides (DMP).

[109] The term “isolated” or “enriched” encompasses a microbe, bacteria or other entity or substance that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature or in an experimental setting), and/or (2) produced, prepared, purified, and/or manufactured by the hand of man. Isolated microbes may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated. In some embodiments, isolated microbes are more 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, e.g., substantially free of other components. The terms “purify,” “purifying” and “purified” refer to a microbe or other material that has been separated from at least some of the components with which it was associated either when initially produced or generated (e.g., whether in nature or in an experimental setting), or during any time after its initial production. A microbe or a microbial population may be considered purified if it is isolated at or after production, such as from a material or environment containing the microbe or microbial population, and a purified microbe or microbial population may contain other materials up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or above about 90% and still be considered “isolated.” In some embodiments, purified microbes or microbial population are more 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. In the instance of microbial compositions provided herein, the one or more microbial types present in the composition can be independently purified from one or more other microbes produced and/or present in the material or environment containing the microbial type. Microbial compositions and the microbial components thereof are generally purified from residual habitat products.

[HO] ‘ ‘Metabolite” as used herein refers to any and all molecular compounds, compositions, molecules, ions, co-factors, catalysts or nutrients used as substrates in any cellular or microbial metabolic reaction or resulting as product compounds, compositions, molecules, ions, co-factors, catalysts or nutrients from any cellular or microbial metabolic reaction.

[Hl] ‘ ‘Microbe” refers to any natural or engineered organism characterized as a bacterium, fungus, microscopic alga, protozoan, and the stages of development or life cycle stages (e.g, vegetative, spore (including sporulation, dormancy, and germination), latent, biofilm) associated with the organism.

[112] ‘ ‘Microbiome” broadly refers to the microbes residing on or in body site of a subject or patient. Microbes in a microbiome may include bacteria, viruses, eukaryotic microorganisms, and/or viruses. Individual microbes in a microbiome may be metabolically active, dormant, latent, or exist as spores, may exist planktonically or in biofilms, or may be present in the microbiome in sustainable or transient manner. The microbiome may be a commensal or healthy-state microbiome or a disease-state microbiome. The microbiome may be native to the subject or patient, or components of the microbiome may be modulated, introduced, or depleted due to changes in health state or treatment conditions (e.g, antibiotic treatment, exposure to different microbes). In some aspects, the microbiome occurs at a mucosal surface. In some aspects, the microbiome is a gut microbiome.

[113] A “microbiome profile” or a “microbiome signature” of a tissue or sample refers to an at least partial characterization of the bacterial makeup of a microbiome. In some embodiments, a 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 or absent in a microbiome. In some embodiments, a 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 a sample. In some embodiments, the microbiome profile indicates the relative or absolute amount of each bacterial strain detected in the sample.

[114] ‘ ‘Modified” in reference to a bacteria broadly refers to a bacteria that has undergone a change from its wild-type form. Examples of bacterial modifications include genetic modification, gene expression, phenotype modification, formulation, chemical modification, and dose or concentration. Examples of improved properties are described throughout this specification and include, e.g, attenuation, auxotrophy, homing, or antigenicity. Phenotype modification might include, by way of example, bacteria growth in media that modify the phenotype of a bacterium that increase or decrease virulence.

[115] As used herein, a gene is “overexpressed” in a bacteria if it is expressed at a higher level in an engineered bacteria under at least some conditions than it is expressed by a wildtype bacteria of the same species under the same conditions. Similarly, a gene is “underexpressed” in a bacteria if it is expressed at a lower level in an engineered bacteria under at least some conditions than it is expressed by a wild-type bacteria of the same species under the same conditions.

[116] The terms “polynucleotide”, and “nucleic acid” are used interchangeably. They refer to a polymeric form of nucleotides of any length, either deoxyribonucleotides or ribonucleotides, or analogs thereof. Polynucleotides may have any three-dimensional structure, and may perform any function. The following are non-limiting examples of polynucleotides: coding or non-coding regions of a gene or gene fragment, loci (locus) defined from linkage analysis, exons, introns, messenger RNA (mRNA), micro RNA (miRNA), silencing RNA (siRNA), transfer RNA, ribosomal RNA, ribozymes, cDNA, recombinant polynucleotides, branched polynucleotides, plasmids, 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. If present, modifications to the nucleotide structure may be imparted before or after assembly of the polymer. A polynucleotide may be further modified, such as by conjugation with a labeling component. In all nucleic acid sequences provided herein, U nucleotides are interchangeable with T nucleotides.

[117] “Operational taxonomic units” and “OTU(s)” refer to a terminal leaf in a phylogenetic tree and is defined by a nucleic acid sequence, e.g., the entire genome, or a specific genetic sequence, and all sequences that share sequence identity to this nucleic acid sequence at the level of species. In some embodiments the specific genetic sequence may be the 16S sequence or a portion of the 16S sequence. In other embodiments, the entire genomes of two entities are sequenced and compared. In another embodiment, select regions such as multilocus sequence tags (MLST), specific genes, or sets of genes may be genetically compared. For 16S, OTUs that share > 97% average nucleotide identity across the entire 16S or some variable region of the 16S are considered the same OTU. See e.g. 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. Nucleic Acids Res 38: e200. Konstantinidis KT, Ramette A, and Tiedje JM. 2006. The bacterial species definition in the genomic era. Philos Trans R Soc Lond B Biol Sci 361 : 1929-1940. For complete genomes, MLSTs, specific genes, other than 16S, or sets of genes OTUs that share > 95% average nucleotide identity are considered the same OTU. See e.g, 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 361 : 1929-1940. OTUs are frequently defined by comparing sequences between organisms. Generally, sequences with less than 95% sequence identity are not considered to form part of the same OTU. OTUs may also be characterized by any combination of nucleotide markers or genes, in particular highly conserved genes (e.g., “house-keeping” genes), or a combination thereof. Operational Taxonomic Units (OTUs) with taxonomic assignments made to, e.g., genus, species, and phylogenetic clade are provided herein.

[118] As used herein, a substance is “pure” if it is substantially free of other components. The terms “purify,” “purifying” and “purified” refer to a microbe or other material that has been separated from at least some of the components with which it was associated either when initially produced or generated (e.g, whether in nature or in an experimental setting), or during any time after its initial production. A microbe may be considered purified if it is isolated at or after production, such as from one or more other bacterial components, and a purified microbe or microbial population may contain other materials up to about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or above about 90% and still be considered “purified.” In some embodiments, purified microbes are more 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. Bacterial compositions and the microbial components thereof are, e.g., purified from residual habitat products. [119] ‘ ‘Residual habitat products” refers to material derived from the habitat for microbiota within or on a subject. For example, microbes live in feces in the gastrointestinal tract, on the skin itself, in saliva, mucus of the respiratory tract, or secretions of the genitourinary tract (i.e., biological matter associated with the microbial community). Substantially free of residual habitat products means that the microbial composition no longer contains the biological matter associated with the microbial environment on or in the human or animal subject and is 100% free, 99% free, 98% free, 97% free, 96% free, or 95% free of any contaminating biological matter associated with the microbial community. Residual habitat products can include abiotic materials (including undigested food) or it can include unwanted microorganisms. Substantially free of residual habitat products may also mean that the microbial composition contains no detectable cells from a human or animal and that only microbial cells are detectable. In one embodiment, substantially free of residual habitat products may also mean that the microbial composition contains no detectable viral (including microbial viruses (e.g, phage)), fungal, mycoplasmal contaminants. In another embodiment, it means that fewer than 1x10-2%, 1x10-3%, 1x10-4%, 1x10-5%, 1x10-6%, 1x10-7%, 1x10-8% of the viable cells in the microbial composition are human or animal, as compared to microbial cells. There are multiple ways to accomplish this degree of purity, none of which are limiting. Thus, contamination may be reduced by isolating desired constituents through multiple steps of streaking to single colonies on solid media until replicate (such as, but not limited to, two) streaks from serial single colonies have shown only a single colony morphology. Alternatively, reduction of contamination can be accomplished by multiple rounds of serial dilutions to single desired cells (e.g, a dilution of 10-8 or 10-9), such as through multiple 10-fold serial dilutions. This can further be confirmed by showing that multiple isolated colonies have similar cell shapes and Gram staining behavior. Other methods for confirming adequate purity include genetic analysis (e.g, PCR, DNA sequencing), serology and antigen analysis, enzymatic and metabolic analysis, and methods using instrumentation such as flow cytometry with reagents that distinguish desired constituents from contaminants.

[120] The terms “subject” or “patient” refers to any animal. A subject or a patient described as “in need thereof’ refers to one in need of a treatment for a disease. Mammals (i.e., mammalian animals) include humans, laboratory animals (e.g, primates, rats, mice), livestock (e.g, cows, sheep, goats, pigs), and household pets (e.g, dogs, cats, rodents). For example, the subject may be a non-human mammal including but not limited to of a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee.

[121] ‘ ‘Strain” refers to a member of a bacterial species with a genetic signature such that it may be differentiated from closely-related members of the same bacterial species. The genetic signature may be the absence of all or part of at least one gene, the absence of all or part of at least on regulatory region (e.g., a promoter, a terminator, a riboswitch, a ribosome binding site), the absence (“curing”) of at least one native plasmid, the presence of at least one recombinant gene, the presence of at least one mutated gene, the presence of at least one foreign gene (a gene derived from another species), the presence at least one mutated regulatory region (e.g, a promoter, a terminator, a riboswitch, a ribosome binding site), the presence of at least one non-native plasmid, the presence of at least one antibiotic resistance cassette, or a combination thereof. Genetic signatures between different strains may be identified by PCR amplification optionally followed by DNA sequencing of the genomic region(s) of interest or of the whole genome. In the case in which one strain (compared with another of the same species) has gained or lost antibiotic resistance or gained or lost a biosynthetic capability (such as an auxotrophic strain), strains may be differentiated by selection or counter-selection using an antibiotic or nutrient/metabolite, respectively.

[122] As used herein, the term “treating” a disease in a subject or “treating” a subject having or suspected of having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of one or more agents, such that at least one symptom of the disease is decreased or prevented from worsening. Thus, in one embodiment, “treating” refers inter aha to delaying progression, expediting remission, inducing remission, augmenting remission, speeding recovery, increasing efficacy of or decreasing resistance to alternative therapeutics, or a combination thereof.

Bacteria

[123] In certain aspects, provided herein are bacterial compositions (e.g, pharmaceutical compositions) comprising Prevotella histicola useful for the treatment and/or prevention of an inflammatory disease and methods of using such bacterial compositions (e.g., for the treatment of an inflammatory disease), e.g., in a subject, e.g., in a human subject. In some embodiments, the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises only one strain of bacteria, e.g., Prevotella histicola. In some embodiments, the inflammatory disease is a Thl, Th2, or Thl7 inflammatory disease.

[124] In certain aspects, provided herein are bacterial compositions (e.g, pharmaceutical compositions) comprising Prevotella histicola useful for the treatment and/or prevention of an immune disorder and methods of using such bacterial compositions (e.g, for the treatment of an immune disorder), e.g., in a subject, e.g., in a human subject. In some embodiments, the bacterial compositions comprise whole Prevotella histicola bacteria (e.g, live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises only one strain of bacteria, e.g., Prevotella histicola.

[125] In certain aspects, provided herein are bacterial compositions (e.g, pharmaceutical compositions) comprising Prevotella histicola useful for the treatment and/or prevention of psoriasis (e.g, mild to moderate psoriasis) and methods of using such bacterial compositions (e.g, for the treatment of psoriasis), e.g., in a subject, e.g., in a human subject. In some embodiments, the bacterial compositions comprise whole Prevotella histicola bacteria (e.g, live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises only one strain of bacteria, e.g, Prevotella histicola.

[126] In certain aspects, provided herein are bacterial compositions (e.g, pharmaceutical compositions) comprising Prevotella histicola useful for the treatment and/or prevention of atopic dermatitis (e.g, mild to moderate atopic dermatitis) and methods of using such bacterial compositions (e.g, for the treatment of atopic dermatitis), e.g., in a subject, e.g., in a human subject. In some embodiments, the bacterial compositions comprise whole Prevotella histicola bacteria (e.g, live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises only one strain of bacteria, e.g., Prevotella histicola.

[127] In certain aspects, provided herein are bacterial compositions (e.g, pharmaceutical compositions) comprising Prevotella histicola useful for the treatment and/or prevention of psoriatic arthritis and methods of using such bacterial compositions (e.g, for the treatment of psoriatic arthritis), e.g., in a subject, e.g., in a human subject. In some embodiments, the bacterial compositions comprise whole Prevotella histicola bacteria (e.g, live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises only one strain of bacteria, e.g., Prevotella histicola.

[128] In some embodiments, the Prevotella histicola is Prevotella Strain B 50329 (NRRL accession number B 50329) (also referred to as "Prevotella histicola Strain B” or ""Prevotella Strain B”). In some embodiments, the Prevotella strain is a strain comprising at least at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, 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) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Prevotella Strain B 50329.

[129] Prevotella histicola Strain B can be cultured according to methods known in the art. For example, Prevotella histicola can be grown in ATCC Medium 2722, ATCC Medium 1490, or other medium using methods disclosed, for example in Caballero et al., 2017. “Cooperating Commensals Restore Colonization Resistance to Vancomycin-Resistant Enterococcus faecium” Cell Host & Microbe 21:592-602, which is hereby incorporated by reference in its entirety.

[130] In some embodiments, the Prevotella bacteria is quantified based on total cells, e.g., total cell count (TCC) (e.g., determined by Coulter counter).

[131] In some embodiments, the bacterial composition is administered once daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.

[132] In some embodiments, the bacterial composition is administered twice daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.

[133] In some embodiments, the bacterial composition is administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered once daily for at least 8 weeks. In some embodiments, the bacterial composition is administered once daily for at least 16 weeks.

[134] In some embodiments, the bacterial composition is administered twice daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered twice daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered twice daily for at least 8 weeks. In some embodiments, the bacterial composition is administered twice daily for at least 16 weeks.

[135] In some embodiments, the bacterial composition is formulated as a capsule or a tablet. In some embodiments, the bacterial formulation (e.g., composition) comprises an enteric coating or micro encapsulation. In some embodiments, the capsule is an enteric coated capsule. In some embodiments, the tablet is an enteric coated tablet. In some embodiments, the enteric coating allows release of the bacterial composition in the small intestine, e.g., in the upper small intestine, e.g., in the duodenum.

[136] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal (e.g., a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee).

Bacterial Compositions

[137] In certain embodiments, the methods provided herein comprise use of bacterial compositions e.g., pharmaceutical compositions) comprising Prevotella histicola bacteria provided herein.

[138] In some embodiments, the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the Prevotella histicola bacteria are non-viable. In some embodiments, the Prevotella histicola bacteria have been gamma irradiated (e.g., according to a method described herein). In some embodiments, the Prevotella histicola bacteria are live.

[139] In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises only one strain of bacteria, e.g., Prevotella histicola.

[140] In some embodiments, the Prevotella histicola is Prevotella Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella strain is a strain comprising at least at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, 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) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Prevotella Strain B 50329. [141] In some embodiments, the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, killed bacteria, attenuated bacteria).

[142] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about

[143] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 12.8 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[144] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 16 x 10" total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[145] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about

[146] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about

9.6 x 10¹¹ to about 12.8 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[147] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 12.8 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[148] In some embodiments, the bacterial composition, e.g., pharmaceutical composition is prepared as a solid dosage form. In certain embodiments, provided herein are solid dosage forms comprising the Prevotella histicola bacteria. In some embodiments, the solid dosage form comprises an enteric coating. In some embodiments, the solid dosage form is a tablet, e.g., an enteric coated tablet. In some embodiments, each tablet comprises about 3.2 x 10¹¹ total cells of the Prevotella histicola bacteria. In some embodiments, the solid dosage form is a capsule, e.g., an enteric coated capsule. In some embodiments, each capsule comprises about 3.2 x 10¹¹ total cells of the Prevotella histicola bacteria.

[149] In some embodiments, 1 solid dosage form (e.g., tablet or capsule) is administered (e.g., is for administration) per day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 2 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 3 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 4 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 5 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells.

[150] In some embodiments, the bacterial composition, e.g., pharmaceutical composition is a powder. The powder can be resuspended (e.g., in a liquid such as a solution, buffer, water or other beverage or a food), e.g., for administration to a subject.

[151] In some embodiments, a dose of Prevotella histicola bacteria of about 9.6 x 10^ total cells are administered (e.g., are for administration) per day.

[152] In some embodiments, a dose of Prevotella histicola bacteria of about 12.8 x 10¹¹ total cells are administered (e.g., are for administration) per day.

[153] In some embodiments, a dose of Prevotella histicola bacteria of about 16 x 10¹¹ total cells are administered (e.g., are for administration) per day.

[154] In some embodiments, the solid dosage form is a tablet. In some embodiments, the tablet is an enteric coated tablet. In some embodiments, the enteric coated tablet is from 5mm to 18mm in diameter (size refers to size prior to application of enteric coat). In some embodiments, the tablet comprises about 3.2 x 10¹¹ total cells of the Prevotella histicola bacteria. In some embodiments, the Prevotella histicola bacteria in the tablet are lyophilized.

[155] In some embodiments, the solid dosage form is a capsule. In some embodiments, the capsule is an enteric coated capsule. In some embodiments, the enteric coated capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule. In some embodiments, the capsule is a size 0 capsule. In some embodiments, the capsule comprises about 3.2 x 10¹¹ total cells of the Prevotella histicola bacteria. In some embodiments, the Prevotella histicola bacteria in the capsule are lyophilized.

[156] In certain embodiments, provided herein are solid dosage forms comprising the Prevotella bacteria. In some embodiments, the solid dosage form is a tablet, e.g., an enteric coated tablet. In some embodiments, the solid dosage form is a capsule, e.g., an enteric coated capsule. In some embodiments, the enteric coating comprises a polymethacrylate- based copolymer. In some embodiments, the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1). In some embodiments, the enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P or Eudragit L30-D55).

[157] In some embodiments, each tablet comprises about 3.2 x 10¹¹ total cells of the Prevotella bacteria. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tablets are administered, e.g., once or twice daily to a subject. In some embodiments, 1 tablet (e.g., comprising about 3.2 x 10¹¹ total cells) is administered, e.g., once or twice daily to a subject. In some embodiments, 2 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 3 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 4 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 6 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 8 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 10 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, the Prevotella histicola bacteria in the tablet are lyophilized (e.g., in a powder). In some embodiments, the Prevotella histicola bacteria in the tablet are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.

[158] In some embodiments, each capsule comprises about 3.2 x 10¹¹ total cells of the Prevotella bacteria. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered, e.g., once or twice daily to a subject. In some embodiments, 1 capsule (e.g., comprising about 3.2 x 10¹¹ total cells) is administered, e.g., once or twice daily to a subject. In some embodiments, 2 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 3 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 4 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 6 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 8 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 10 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, the Prevotella histicola bacteria in the capsule are lyophilized (e.g., in a powder). In some embodiments, the Prevotella histicola bacteria in the capsule are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.

[159] In some embodiments, the Prevotella histicola bacteria may be quantified based on total cells, e.g., total cell count (TCC) (e.g., determined by Coulter counter).

[160] In some embodiments, the bacterial composition is administered orally. In some embodiments, the administration to the subject once daily. In some embodiments, the bacterial composition is administered in 2 or more doses (e.g., 3 or more, 4 or more or 5 or more doses). In some embodiments, the administration to the subject of the two or more doses are separated by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days.

[161] In some embodiments, the bacterial composition is administered once daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.

[162] In some embodiments, the bacterial composition is administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks.

[163] In some embodiments, the bacterial composition is formulated as a tablet. In some embodiments, the bacterial composition is formulated as a capsule. In some embodiments, the bacterial formulation e.g., composition) comprises an enteric coating or micro encapsulation. In some embodiments, the enteric coating allows release of the bacterial composition in the small intestine, e.g., in the upper small intestine, e.g., in the duodenum.

[164] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human mammal (e.g., a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee). [165] In some embodiments, the bacterial composition comprises an enteric coating or micro encapsulation. In certain embodiments, the enteric coating or micro encapsulation improves targeting to a desired region of the gastrointestinal tract. For example, in certain embodiments, the bacterial composition comprises an enteric coating and/or microcapsules that dissolves at a pH associated with a particular region of the gastrointestinal tract. In some embodiments, the enteric coating and/or microcapsules dissolve at a pH of about 5.5 - 6.2 to release in the duodenum, at a pH value of about 7.2 - 7.5 to release in the ileum, and/or at a pH value of about 5.6 - 6.2 to release in the colon. Exemplary enteric coatings and microcapsules are described, for example, in U.S. Pat. Pub. No. 2016/0022592, which is hereby incorporated by reference in its entirety.

[166] In certain aspects, provided are bacterial compositions for administration subjects. In some embodiments, the bacterial compositions are combined with additional active and/or inactive materials in order to produce a final product, which may be in single dosage unit or in a multi-dose format. In some embodiments, the bacterial compositions is combined with an adjuvant such as an immuno-adjuvant (e.g, STING agonists, TLR agonists, NOD agonists).

[167] In some embodiments the composition comprises at least one carbohydrate. A “carbohydrate” refers to a sugar or polymer of sugars. The terms “saccharide,” “polysaccharide,” “carbohydrate,” and “oligosaccharide” may be 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_nH2nOn. A carbohydrate may be a monosaccharide, a disaccharide, trisaccharide, oligosaccharide, or polysaccharide. The most basic carbohydrate is a monosaccharide, 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, an oligosaccharide includes between three and six monosaccharide units (e.g, raffinose, stachyose), and polysaccharides include six or more monosaccharide units. Exemplary polysaccharides include starch, glycogen, and cellulose. Carbohydrates may contain modified saccharide units such as 2’ -deoxyribose wherein a hydroxyl group is removed, 2 ’-fluororibose wherein a hydroxyl group is replaced with a fluorine, or N- acetylglucosamine, a nitrogen-containing form of glucose (e.g, 2 ’-fluororibose, deoxyribose, and hexose). Carbohydrates may exist in many different forms, for example, conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers, and isomers.

[168] In some embodiments the composition comprises at least one lipid. As used herein a “lipid” includes fats, oils, triglycerides, cholesterol, phospholipids, 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). In some embodiments the lipid comprises at least one fatty acid selected from lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16:1), margaric acid (17:0), heptadecenoic acid (17:1), stearic acid (18:0), oleic acid (18:1), linoleic acid (18:2), linolenic acid (18:3), octadecatetraenoic acid (18:4), arachidic acid (20:0), eicosenoic acid (20:1), eicosadienoic acid (20:2), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5) (EP A), docosanoic acid (22:0), docosenoic acid (22:1), docosapentaenoic acid (22:5), docosahexaenoic acid (22:6) (DHA), and tetracosanoic acid (24:0). In some embodiments the composition comprises at least one modified lipid, for example a lipid that has been modified by cooking.

[169] In some embodiments the composition comprises at least one supplemental mineral or mineral source. Examples of minerals include, without limitation: 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 combinations thereof.

[170] In some embodiments the composition comprises at least one supplemental vitamin. The at least one vitamin can be fat-soluble or water-soluble vitamins. 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 salts of the vitamin, derivatives of the vitamin, compounds having the same or similar activity of the vitamin, and metabolites of the vitamin.

[171] In some embodiments the composition comprises an excipient. Non-limiting examples of suitable excipients include a buffering agent, a preservative, a stabilizer, a binder, a compaction agent, a lubricant, a dispersion enhancer, a disintegration agent, a flavoring agent, a sweetener, and a coloring agent.

[172] In some embodiments the excipient is a buffering agent. Non-limiting examples of suitable buffering agents include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate.

[173] In some embodiments the excipient comprises a preservative. Non-limiting examples of suitable preservatives include antioxidants, such as alpha-tocopherol and ascorbate, and antimicrobials, such as parabens, chlorobutanol, and phenol. [174] In some embodiments the composition comprises a binder as an excipient. Nonlimiting examples of suitable binders include starches, pregelatinized starches, gelatin, polyvinylpyrolidone, cellulose, methylcellulose, sodium carboxymethylcellulose, ethylcellulose, polyacrylamides, polyvinyloxoazolidone, polyvinylalcohols, C12-C18 fatty acid alcohol, polyethylene glycol, polyols, saccharides, oligosaccharides, and combinations thereof.

[175] In some embodiments the composition comprises a lubricant as an excipient. Nonlimiting examples of suitable lubricants include magnesium stearate, calcium stearate, zinc stearate, hydrogenated vegetable oils, sterotex, polyoxyethylene monostearate, talc, polyethyleneglycol, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, and light mineral oil.

[176] In some embodiments the composition comprises a dispersion enhancer as an excipient. Non-limiting examples of suitable dispersants include starch, alginic acid, polyvinylpyrrolidones, guar gum, kaolin, bentonite, purified wood cellulose, sodium starch glycolate, isoamorphous silicate, and microcrystalline cellulose as high HLB emulsifier surfactants.

[177] In some embodiments the composition comprises a disintegrant as an excipient. In some embodiments the disintegrant is a non-effervescent disintegrant. Non-limiting examples of suitable non-effervescent disintegrants include starches such as com starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, microcrystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth. In some embodiments the disintegrant is an effervescent disintegrant. Non-limiting examples of suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.

[178] In some embodiments, the composition is a food product (e.g., a food or beverage) such as a health food or beverage, a food or beverage for infants, a food or beverage for pregnant women, athletes, senior citizens or other specified group, a functional food, a beverage, a food or beverage for specified health use, a dietary supplement, a food or beverage for patients, or an animal feed. Specific examples of the foods and beverages include various beverages such as juices, refreshing beverages, tea beverages, drink preparations, jelly beverages, and functional beverages; alcoholic beverages such as beers; carbohydrate-containing foods such as rice food products, noodles, breads, and pastas; paste products such as fish hams, sausages, paste products of seafood; retort pouch products such as curries, food dressed with a thick starchy sauces, and Chinese soups; soups; dairy products such as milk, dairy beverages, ice creams, cheeses, and yogurts; fermented products such as fermented soybean pastes, yogurts, fermented beverages, and pickles; bean products; various confectionery products, including biscuits, cookies, and the like, candies, chewing gums, gummies, cold desserts including jellies, cream caramels, and frozen desserts; instant foods such as instant soups and instant soy-bean soups; microwavable foods; and the like. Further, the examples also include health foods and beverages prepared in the forms of powders, granules, tablets, capsules, liquids, pastes, and jellies.

[179] In some embodiments the composition is a food product for animals, including humans. The animals, other than humans, are not particularly limited, and the composition can be used for various livestock, poultry, pets, experimental animals, and the like. Specific examples of the animals include pigs, cattle, horses, sheep, goats, chickens, wild ducks, ostriches, domestic ducks, dogs, cats, rabbits, hamsters, mice, rats, monkeys, and the like, but the animals are not limited thereto.

Dose Forms

[180] Dose forms comprising Prevotella histicola bacteria are also provided herein, e.g., for use in methods to treat or prevent inflammation (such as inflammation associated with psoriasis or atopic dermatitis or psoriatic arthritis) in a subject (e.g., a human subject). A bacterial composition (e.g., pharmaceutical composition) comprising Prevotella histicola bacteria can be formulated as a solid dose form, e.g., for oral administration. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprising Prevotella histicola bacteria is prepared as a powder (e.g, for resuspension or for use in a solid dose form (such as a capsule)) or as a solid dose form, such as a tablet, a mini-tablet, a capsule, or a powder; or a combination of these forms (e.g., mini-tablets comprised in a capsule)). The powder can comprise lyophilized bacteria. In some embodiments, the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide. In some embodiments, the Prevotella histicola bacteria are gamma irradiated.

[181] The solid dose form (also referred to as solid dosage form herein) can comprise one or more excipients, e.g., pharmaceutically acceptable excipients. The Prevotella histicola bacteria in the solid dose form can be isolated Prevotella histicola bacteria. Optionally, the Prevotella histicola bacteria in the solid dose form can be lyophilized. Optionally, the Prevotella histicola bacteria in the solid dose form are live. Optionally, the Prevotella histicola bacteria in the solid dose form are gamma irradiated. The solid dose form can comprise a tablet The solid dose form can comprise a capsule. The solid dose form can comprise a tablet, a mini -tablet, a capsule, or a powder; or a combination of these forms (e.g, mini-tablets comprised in a capsule).

[182] The Prevotella histicola bacteria in the solid dose form can be in a powder (e.g., the powder comprises lyophilized Prevotella histicola bacteria). In some embodiments, the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide. In some embodiments, the powder further comprises mannitol, magnesium stearate, and colloidal silicon dioxide. Optionally, the Prevotella histicola bacteria in the powder can be lyophilized. Optionally, the Prevotella histicola bacteria in the powder are live. Optionally, the Prevotella histicola bacteria in the powder are gamma irradiated.

[183] In some embodiments, the lyophilized Pre votella histicola bacteria (e.g., powder) is resuspended (e.g., in a liquid such as a solution, buffer, water or other beverage or a food), e.g., for administration to a subject.

[184] In certain embodiments, the bacterial composition (e.g., pharmaceutical composition) provided herein is prepared as a solid dosage form comprising Prevotella histicola bacteria and a pharmaceutically acceptable carrier.

[185] In certain embodiments, the bacterial composition (e.g., pharmaceutical composition) provided herein is prepared as a solid dosage form comprising Prevotella histicola bacteria and a pharmaceutically acceptable carrier. The solid dosage form can comprise a tablet, a mini-tablet, a capsule, a pill, or a powder; or a combination of these forms (e.g, mini-tablets comprised in a capsule).

[186] In some embodiments, the solid dosage form comprises a capsule. The capsule can comprise an enteric coating. The capsule can be a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule.

[187] In some embodiments, the solid dosage form comprises a tablet (> 4mm) (e.g, 5 mm- 18mm). For example, the tablet is a 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm or 18mm tablet. The size refers to the diameter of the tablet, as is known in the art.

[188] As used herein, the size of the tablet refers to the size of the tablet, mini-tablet or capsule prior to application of an enteric coating.

[189] In some embodiments, the solid dosage form comprises a mini-tablet. The mini-tablet can be in the size range of lmm-4 mm range. E.g., the mini -tablet can be a 1mm mini-tablet, 1.5 mm mini -tablet, 2mm mini -tablet, 3mm mini -tablet, or 4mm mini -tablet. The size refers to the diameter of the mini-tablet, as is known in the art. As used herein, the size of the mini-tablet refers to the size of the mini-tablet prior to application of an enteric coating.

[190] The mini-tablets can be in a capsule. The capsule can be a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule. The capsule that contains the mini -tablets can comprise a single layer coating, e.g, anon-enteric coating such as gelatin or HPMC. The mini-tablets can be inside a capsule: the number of mini-tablets inside a capsule will depend on the size of the capsule and the size of the mini -tablets. As an example, a size 0 capsule can contain 31-35 (an average of 33) mini-tablets that are 3mm mini-tablets.

[191] The solid dosage form (e.g, tablet, mini-tablet, or capsule) described herein can be enterically coated. In some embodiments, the enteric coating comprises a polymethacrylate- based copolymer. In some embodiments, the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1). In some embodiments, the enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P).

[192] The solid dose form can comprise a coating. The solid dose form can comprise a single layer coating, e.g, enteric coating, e.g., a Eudragit-based coating, e.g, EUDRAGIT L30 D-55, triethylcitrate, and talc. The solid dose form can comprise two layers of coating. For example, an inner coating can comprise, e.g, EUDRAGIT L30 D-55, triethylcitrate, talc, citric acid anhydrous, and sodium hydroxide, and an outer coating can comprise, e.g., EUDRAGIT L30 D-55, triethylcitrate, and talc. EUDRAGIT is the brand name for a diverse range of polymethacrylate-based copolymers. It includes anionic, cationic, and neutral copolymers based on methacrylic acid and methacry lie/ aery lie esters or their derivatives. Eudragits are amorphous polymers having glass transition temperatures between 9 to > 150°C. Eudragits are non-biodegradable, nonabsorbable, and nontoxic. Anionic Eudragit L dissolves at pH > 6 and is used for enteric coating, while Eudragit S, soluble at pH > 7 is used for colon targeting. Eudragit RL and RS, having quaternary ammonium groups, are water insoluble, but swellable/permeable polymers which are suitable for the sustained release film coating applications. Cationic Eudragit E, insoluble at pH > 5, can prevent drug release in saliva.

Dosage

[193] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 9.6 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. [194] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 12.8 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[195] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 16 x IO^{1 1} total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[196] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 9.6 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[197] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 9.6 x 10¹¹ to about 12.8 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[198] In some embodiments, the bacterial composition, e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 12.8 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.

[199] In certain embodiments, provided herein are solid dosage forms comprising the Prevotella histicola bacteria. In some embodiments, the solid dosage form comprises an enteric coating. In some embodiments, the solid dosage form is a tablet, e.g., an enteric coated tablet. In some embodiments, each tablet comprises about 3.2 x 10¹¹ total cells of the Prevotella histicola bacteria. In some embodiments, the solid dosage form is a mini-tablet, e.g., an enteric coated mini-tablet. In some embodiments, the total dose of a plurality of minitablets (e.g., mini-tablets contained in a capsule) comprises about 3.2 x 10¹¹ total cells of the Prevotella histicola bacteria. In some embodiments, the solid dosage form is a capsule, e.g., an enteric coated capsule. In some embodiments, each capsule comprises about 3.2 x 10¹¹ total cells of the Prevotella histicola bacteria. For clarity, about 3.2 x 10¹¹ total cells includes total cell counts within ±5% of 3.2 x 10¹¹ total cells e.g., 3.35 x 10¹¹ total cells.

[200] In some embodiments, the mini-tablets (e.g, enteric coated mini-tablets) are contained in a capsule. 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 capsule comprises anon-enteric coating (e.g, gelatin) (e.g, is coated with a non-enteric coating). In some embodiments, the capsule comprises a non-enteric coating. In some embodiments, the capsule comprises gelatin. In some embodiments, the capsule comprises HPMC. In some embodiments, the total dose of a plurality of mini -tablets (e.g., mini -tablets contained in a capsule (e.g., enteric coated mini-tablets in anon-enteric coated capsule)) comprises about 3.2 x 10¹¹ total cells of the Prevotella histicola bacteria.

[201] In some embodiments, 1 solid dosage form (e.g., tablet or capsule) is administered (e.g., is for administration) per day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 2 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per day, wherein the solid dosage form (e.g., each solid dosage form) comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 3 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 4 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 5 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 6 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 8 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells. In some embodiments, 10 solid dosage forms (e.g., tablets or capsules) are administered (e.g., are for administration) per a day, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10¹¹ total cells.

[202] The capsule can be, for example, a capsule (e.g., enteric coated capsule) comprising Prevotella histicola bacteria (e.g., a powder thereof); the capsule can be, for example, a capsule (non-enteric coated) that contains mini -tablets (e.g., enteric coated mini -tablets) comprising Prevotella histicola bacteria.

[203] In some embodiments, a dose of Prevotella histicola bacteria of about 9.6 x 10^ total cells are administered (e.g., are for administration) per day.

[204] In some embodiments, a dose of Prevotella histicola bacteria of about 12.8 x 10¹¹ total cells are administered (e.g., are for administration) per day.

[205] In some embodiments, a dose of Prevotella histicola bacteria of about 16 x 10¹¹ total cells are administered (e.g., are for administration) per day. [206] In some embodiments, the solid dosage form is a tablet. In some embodiments, the tablet is an enteric coated tablet. In some embodiments, the enteric coated tablet is from 5mm to 18mm in diameter. In some embodiments, the tablet comprises about 3.2 x 10¹¹ total cells of the Prevotella histicola bacteria. In some embodiments, the Prevotella histicola bacteria in the tablet are lyophilized.

[207] In some embodiments, the solid dosage form is a capsule. In some embodiments, the capsule is an enteric coated capsule. In some embodiments, the enteric coated capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule. In some embodiments, the capsule is a size 0 capsule. In some embodiments, the capsule comprises about 3.2 x 10¹¹ total cells of the Prevotella histicola bacteria. In some embodiments, the Prevotella histicola bacteria in the capsule are lyophilized.

[208] In certain embodiments, provided herein are solid dosage forms comprising the Prevotella histicola bacteria. In some embodiments, the solid dosage form is a tablet, e.g., an enteric coated tablet. In some embodiments, the solid dosage form is a tablet, e.g., an enteric coated mini -tablet. In some embodiments, the solid dosage form is a capsule, e.g., an enteric coated capsule. In some embodiments, the enteric coating comprises a polymethacrylate- based copolymer. In some embodiments, the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1). In some embodiments, the enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1:1) (such as Kollicoat MAE 100P or Eudragit L30-D55).

[209] In some embodiments, each tablet comprises about 3.2 x 10¹¹ total cells of the Prevotella histicola bacteria. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tablets are administered, e.g., once or twice daily to a subject. In some embodiments, 1 tablet (e.g., comprising about 3.2 x 10¹¹ total cells) is administered, e.g., once or twice daily to a subject. In some embodiments, 2 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 3 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 4 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 6 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 8 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 10 tablets (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, the Prevotella histicola bacteria in the tablet are lyophilized (e.g., in a powder). In some embodiments, the Prevotella histicola bacteria in the tablet are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.

[210] In some embodiments, each capsule comprises about 3.2 x 10¹¹ total cells of the Prevotella bacteria. In some embodiments, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered, e.g., once or twice daily to a subject. In some embodiments, 1 capsule (e.g., comprising about 3.2 x 10¹¹ total cells) is administered, e.g., once or twice daily to a subject. In some embodiments, 2 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 3 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 4 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 6 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 8 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 10 capsules (e.g., each comprising about 3.2 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, the Prevotella bacteria in the capsule are lyophilized (e.g., in a powder). In some embodiments, the Prevotella bacteria in the capsule are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.

[2H] In some embodiments, the Prevotella histicola bacteria are quantified based on total cells, e.g., total cell count (TCC) (e.g., determined by Coulter counter).

Gamma-irradiation

[212] Powders (e.g., of Prevotella histicola bacteria) can be gamma-irradiated at 17.5 kGy radiation unit at ambient temperature.

[213] Frozen biomasses (e.g., of Prevotella histicola bacteria) can be gamma-irradiated at 25 kGy radiation unit in the presence of dry ice.

Therapeutic Agents

[214] In certain aspects, the methods provided herein include the administration to a subject of a bacterial composition described herein either alone or in combination with an additional therapeutic. In some embodiments, the additional therapeutic is an immunosuppressant, or a steroid. [215] In some embodiments the Prevotella histicola bacteria is administered to the subject before the therapeutic is administered (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 before 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 before). In some embodiments the Prevotella histicola bacteria is administered to the subject after the therapeutic is administered (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 after 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 after). In some embodiments, the Prevotella histicola bacteria and the therapeutic are administered to the subject simultaneously or nearly simultaneously (e.g, administrations occur within an hour of each other). In some embodiments, the subject is administered an antibiotic before the Prevotella bacteria is administered to the subject (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 before 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 before).In some embodiments, the subject is administered an antibiotic after the Prevotella bacteria is administered to the subject (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 before 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 after). In some embodiments, the Prevotella bacteria and the antibiotic are administered to the subject simultaneously or nearly simultaneously (e.g, administrations occur within an hour of each other).

[216] In some aspects, antibiotics can be selected based on their bactericidal or bacteriostatic properties. Bactericidal antibiotics include mechanisms of action that disrupt the cell wall (e.g., (3-lactams), the cell membrane (e.g., daptomycin), or bacterial DNA (e.g, fluoroquinolones). Bacteriostatic agents inhibit bacterial replication and include sulfonamides, tetracyclines, and macrolides, and act by inhibiting protein synthesis. Furthermore, while some drugs can be bactericidal in certain organisms and bacteriostatic in others, knowing the target organism allows one skilled in the art to select an antibiotic with the appropriate properties. In certain treatment conditions, bacteriostatic antibiotics inhibit the activity of bactericidal antibiotics. Thus, in certain embodiments, bactericidal and bacteriostatic antibiotics are not combined.

[217] Antibiotics include, but are not limited to aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofurans, oxazolidonones, penicillins, polypeptide antibiotics, quinolones, fluoroquinolone, sulfonamides, tetracyclines, and anti-mycobacterial compounds, and combinations thereof.

[218] Aminoglycosides include, but are not limited to Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, and Spectinomycin. Aminoglycosides are effective, e.g., against 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 the bacterial 30S or 50S ribosomal subunit thereby inhibiting bacterial protein synthesis.

[219] Ansamycins include, but are not limited to, Geldanamycin, Herbimycin, Rifamycin, and Streptovaricin. Geldanamycin and Herbimycin are believed to inhibit or alter the function of Heat Shock Protein 90.

[220] Carbacephems include, but are not limited to, Loracarbef. Carbacephems are believed to inhibit bacterial cell wall synthesis.

[221] Carbapenems include, but are not limited to, Ertapenem, Doripenem, Imipenem/Cilastatin, and Meropenem. Carbapenems are bactericidal for both Gram-positive and Gram-negative bacteria as broad-spectrum antibiotics. Carbapenems are believed to inhibit bacterial cell wall synthesis.

[222] Cephalosporins include, but are not limited to, Cefadroxil, Cefazolin, Cefalotin, Cefalothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil, and Ceftobiprole. Selected Cephalosporins are effective, e.g, against Gram-negative bacteria and against Gram-positive bacteria, including Pseudomonas , certain Cephalosporins are effective against methicillin- resistant Staphylococcus aureus (MRSA). Cephalosporins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[223] Glycopeptides include, but are not limited to, Teicoplanin, Vancomycin, and Telavancin. Glycopeptides are effective, e.g., against aerobic and anaerobic Gram-positive bacteria including MRSA and Clostridium difficile. Glycopeptides are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[224] Lincosamides include, but are not limited to, Clindamycin and Lincomycin. Lincosamides are effective, e.g., against anaerobic bacteria, as well as Staphylococcus, and Streptococcus. Lincosamides are believed to bind to the bacterial 50S ribosomal subunit thereby inhibiting bacterial protein synthesis. [225] Lipopeptides include, but are not limited to, Daptomycin. Lipopeptides are effective, e.g., against Gram-positive bacteria. Lipopeptides are believed to bind to the bacterial membrane and cause rapid depolarization.

[226] Macrolides include, but are not limited to, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, and Spiramycin. Macrolides are effective, e.g., against Streptococcus and Mycoplasma. Macrolides are believed to bind to the bacterial or 50S ribosomal subunit, thereby inhibiting bacterial protein synthesis.

[227] Monobactams include, but are not limited to, Aztreonam. Monobactams are effective, e.g., against Gram-negative bacteria. Monobactams are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[228] Nitrofurans include, but are not limited to, Furazolidone and Nitrofurantoin.

[229] Oxazolidonones include, but are not limited to, Linezolid, Posizolid, Radezolid, and Torezolid. Oxazolidonones are believed to be protein synthesis inhibitors.

[230] Penicillins include, but are not limited to, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cioxacillin, Dicloxacillin, Flucioxacillin, Mezlocillin, Methicillin, Nafcillin, Oxacillin, Penicillin G, Penicillin V, Piperacillin, Temocillin and Ticarcillin. Penicillins are effective, e.g., against Gram-positive bacteria, facultative anaerobes, e.g., Streptococcus, Borrelia, and Treponema. Penicillins are believed to inhibit bacterial cell wall synthesis by disrupting synthesis of the peptidoglycan layer of bacterial cell walls.

[231] Penicillin combinations include, but are not limited to, Amoxicillin/clavulanate, Ampicillin/sulbactam, Piperacillin/tazobactam, and Ticarcillin/clavulanate.

[232] Polypeptide antibiotics include, but are not limited to, Bacitracin, Colistin, and Polymyxin B and E. Polypeptide Antibiotics are effective, e.g., against Gram-negative bacteria. Certain polypeptide antibiotics are believed to inhibit isoprenyl pyrophosphate involved in synthesis of the peptidoglycan layer of bacterial cell walls, while others destabilize the bacterial outer membrane by displacing bacterial counter-ions.

[233] Quinolones and Fluoroquinolone include, but are not limited to, Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidixic acid, Norfloxacin, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, and Temafloxacin. Quinolones/Fluoroquinolone are effective, e.g., against Streptococcus and Neisseria. Quinolones/Fluoroquinolone are believed to inhibit the bacterial DNA gyrase or topoisomerase IV, thereby inhibiting DNA replication and transcription. [234] Sulfonamides include, but are not limited to, Mafenide, Sulfacetamide, Sulfadiazine, Silver sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (Co-trimoxazole), and Sulfonamidochrysoidine. Sulfonamides are believed to inhibit folate synthesis by competitive inhibition of dihydropteroate synthetase, thereby inhibiting nucleic acid synthesis.

[235] Tetracyclines include, but are not limited to, Demeclocy cline, Doxycycline, Minocycline, Oxy tetracycline, and Tetracycline. Tetracyclines are effective, e.g, against Gram-negative bacteria. Tetracyclines are believed to bind to the bacterial 30S ribosomal subunit thereby inhibiting bacterial protein synthesis.

[236] Anti-mycobacterial compounds include, but are not limited to, Clofazimine, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Rifapentine, and Streptomycin.

[237] Suitable antibiotics also include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, tigecy cline, tinidazole, trimethoprim amoxicillin/clavulanate, ampicillin/sulbactam, amphomycin ristocetin, azithromycin, bacitracin, buforin II, carbomycin, cecropin Pl, clarithromycin, erythromycins, furazolidone, fusidic acid, Na fusidate, gramicidin, imipenem, indolicidin, josamycin, magainan II, metronidazole, nitroimidazoles, mikamycin, mutacin B-Ny266, mutacin B-JH1 140, mutacin J-T8, nisin, nisin A, novobiocin, oleandomycin, ostreogrycin, piperacillin/tazobactam, pristinamycin, ramoplanin, ranalexin, reuterin, rifaximin, rosamicin, rosaramicin, spectinomycin, spiramycin, staphylomycin, streptogramin, streptogramin A, synergistin, taurolidine, teicoplanin, telithromycin, ticarcillin/clavulanic acid, triacetyloleandomycin, tylosin, tyrocidin, tyrothricin, vancomycin, vemamycin, and virginiamycin.

[238] In some embodiments, the additional therapeutic is an immunosuppressive agent, a DMARD, a pain-control drug, a steroid, anon-steroidal anti-inflammatory drug (NSAID), or a cytokine antagonist, and combinations thereof. Representative agents include, but are not limited to, cyclosporin, retinoids, corticosteroids, propionic acid derivative, acetic acid derivative, enolic acid derivatives, fenamic acid derivatives, Cox-2 inhibitors, lumiracoxib, ibuprophen, cholin magnesium salicylate, fenoprofen, salsalate, difunisal, tolmetin, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, ketorolac, nabumetone, naproxen, valdecoxib, etoricoxib, MK0966; rofecoxib, acetominophen, Celecoxib, Diclofenac, tramadol, piroxicam, meloxicam, tenoxicam, droxicam, lomoxicam, isoxicam, mefanamic acid, meclofenamic acid, flufenamic acid, tolfenamic, valdecoxib, parecoxib, etodolac, indomethacin, aspirin, ibuprophen, firocoxib, methotrexate (MTX), antimalarial drugs (e.g, hydroxychloroquine and chloroquine), sulfasalazine, Leflunomide, azathioprine, cyclosporin, gold salts, minocycline, cyclophosphamide, D-penicillamine, minocycline, auranofin, tacrolimus, myocrisin, chlorambucil, TNF alpha antagonists (e.g, TNF alpha antagonists or TNF alpha receptor antagonists), e.g, ADALIMUMAB (Humira®), ETANERCEPT (Enbrel®), INFLIXIMAB (Remicade®; TA-650), CERTOLIZUMAB PEGOL (Cimzia®; CDP870), GOLIMUMAB (Simpom®; CNTO 148), ANAKINRA (Kineret®), RITUXIMAB (Rituxan®; MabThera®), ABAT ACEPT (Orencia®), TOCILIZUMAB (RoActemra /Actemra®), integrin antagonists (TYSABRI® (natalizumab)), IL-1 antagonists (ACZ885 (Haris)), Anakinra (Kineret®)), CD4 antagonists, IL-23 antagonists, IL-20 antagonists, IL-6 antagonists, BLyS antagonists (e.g, Atacicept, Benlysta®/ LymphoStat-B® (belimumab)), p38 Inhibitors, CD20 antagonists (Ocrelizumab, Ofatumumab (Arzerra®)), interferon gamma antagonists (Fontolizumab), prednisolone, Prednisone, dexamethasone, Cortisol, cortisone, hydrocortisone, methylprednisolone, betamethasone, triamcinolone, beclometasome, fludrocortisone, deoxycorticosterone, aldosterone, Doxycycline, vancomycin, pioglitazone, SBI-087, SCIO-469, Cura- 100, Oncoxin + Viusid, TwHF, Methoxsalen, Vitamin D - ergocalciferol, Milnacipran, Paclitaxel, rosig tazone, Tacrolimus (Prograf®), RADOO1, rapamune, rapamycin, fostamatinib, Fentanyl, XOMA 052, Fostamatinib disodium, rosightazone, Curcumin (Longvida™), Rosuvastatin, Maraviroc, ramipnl, Milnacipran, Cobiprostone, somatropin, tgAAC94 gene therapy vector, MK0359, GW856553, esomeprazole, everolimus, trastuzumab, JAK1 and JAK2 inhibitors, pan JAK inhibitors, e.g., tetracyclic pyridone 6 (P6), 325, PF-956980, denosumab, IL-6 antagonists, CD20 antagonists, CTLA4 antagonists, IL-8 antagonists, IL- 21 antagonists, IL-22 antagonist, integrin antagonists (Tysarbri® (natalizumab)), VGEF antagnosits, CXCL antagonists, MMP antagonists, defensin antagonists, IL-1 antagonists (including IL-1 beta antagonsits), and IL-23 antagonists (e.g, receptor decoys, antagonistic antibodies, etc.).

[239] In some embodiments, the additional therapeutic is an oral PDE4 inhibitor (such as apremilast). In some embodiments, the additional therapeutic is apremilast, etanercept, infliximab, adalimumab, ustekinumab, or secukinumab.

[240] In some embodiments, the agent is an immunosuppressive agent. Examples of immunosuppressive agents include, but are not limited to, corticosteroids, mesalazine, mesalamine, sulfasalazine, sulfasalazine derivatives, immunosuppressive drugs, cyclosporin A, mercaptopurine, azathiopurine, prednisone, methotrexate, antihistamines, glucocorticoids, epinephrine, theophylline, cromolyn sodium, anti-leukotrienes, anti-cholinergic drugs for rhinitis, TLR antagonists, inflammasome inhibitors, anti-cholinergic decongestants, mast-cell stabilizers, monoclonal anti-IgE antibodies, vaccines (e.g., vaccines used for vaccination where the amount of an allergen is gradually increased), cytokine inhibitors, such as anti-IL-6 antibodies, TNF inhibitors such as infliximab, adalimumab, certolizumab pegol, golimumab, or etanercept, and combinations thereof.

Administration

[241] In some embodiments, the bacterial composition is administered orally. In some embodiments, the administration to the subject once daily. In some embodiments, the bacterial composition is administered in 2 or more doses (e.g., 3 or more, 4 or more or 5 or more doses). In some embodiments, the administration to the subject of the two or more doses are separated by at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days or 21 days.

[242] In some embodiments, the bacterial composition is administered once daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.

[243] In some embodiments, the bacterial composition is administered twice daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.

[244] In some embodiments, the bacterial composition is administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered once daily for at least 8 weeks. In some embodiments, the bacterial composition is administered once daily for at least 16 weeks. [245] In some embodiments, the bacterial composition is administered twice daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered twice daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered twice daily for at least 8 weeks. In some embodiments, the bacterial composition is administered twice daily for at least 16 weeks.

[246] In some embodiments, the bacterial composition is formulated as a tablet. In some embodiments, the bacterial formulation comprises an enteric coating or micro encapsulation.

[247] In some embodiments, the bacterial composition is formulated as a capsule. In some embodiments, the bacterial formulation comprises an enteric coating or micro encapsulation.

[248] In some embodiments, the bacterial composition is formulated as a powder.

[249] In some embodiments, the subject is a mammal. In some embodiments, the subject is a human. In some embodiments, the subject is anon-human mammal (e.g, a dog, a cat, a cow, a horse, a pig, a donkey, a goat, a camel, a mouse, a rat, a guinea pig, a sheep, a llama, a monkey, a gorilla or a chimpanzee).

[250] In some embodiments of the methods provided herein, the bacterial composition is administered in conjunction with the administration of an additional therapeutic. In some embodiments, the bacterial composition comprises Prevotella histicola bacteria coformulated with the additional therapeutic. In some embodiments, the bacterial composition is co-administered with the additional therapeutic. In some embodiments, the additional therapeutic is administered to the subject before administration of the bacterial composition (e.g, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes before, 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 before, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days before). In some embodiments, the additional therapeutic is administered to the subject after administration of the bacterial composition (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50 or 55 minutes after, 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 after, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 days after). In some embodiments the same mode of delivery are used to deliver both the bacterial composition and the additional therapeutic. In some embodiments different modes of delivery are used to administer the bacterial composition and the additional therapeutic. For example, in some embodiments the bacterial composition is administered orally while the additional therapeutic is administered via injection (e.g, an intravenous, and/or intramuscular injection). [251] In certain embodiments, the bacterial compositions, dosage forms, and kits described herein can be administered in conjunction with any other conventional treatment. These treatments may be applied as necessary and/or as indicated and may occur before, concurrent with or after administration of the bacterial compositions, dosage forms, and kits described herein.

[252] The dosage regimen can be any of a variety of methods and amounts, and can be determined by one skilled in the art according to known clinical factors. As is known in the medical arts, dosages for any one patient can depend on many factors, including the subject's species, size, body surface area, age, sex, immunocompetence, and general health, the particular microorganism to be administered, duration and route of administration, the kind and stage of the disease, and other compounds such as drugs being administered concurrently. In addition to the above factors, such levels can be affected by the infectivity of the microorganism, and the nature of the microorganism, as can be determined by one skilled in the art. In the present methods, appropriate minimum dosage levels of microorganisms can be levels sufficient for the microorganism to survive, grow and replicate. The dose of the bacterial compositions described herein may be appropriately set or adjusted in accordance with the dosage form, the route of administration, the degree or stage of a target disease, and the like. For example, the general effective dose of the agents may range between 0.01 mg/kg body weight/day and 1000 mg/kg body weight/day, between 0.1 mg/kg body weight/day and 1000 mg/kg body weight/day, 0.5 mg/kg body weight/day and 500 mg/kg body weight/day, 1 mg/kg body weight/day and 100 mg/kg body weight/day, or between 5 mg/kg body weight/day and 50 mg/kg body weight/day. The effective dose 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/day or more, but the dose is not limited thereto.

[253] In some embodiments, the dose administered to a subject is sufficient to prevent disease (e.g., autoimmune disease, inflammatory disease, metabolic disease), or treat disease, e.g., delay its onset, ameliorate one or more symptom of the disease, lessen the severity of the disease (or a symptom thereof), or slow or stop its progression. One skilled in the art will recognize that dosage will depend upon a variety of factors including the strength of the particular compound employed, as well as the age, species, condition, and body 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 might accompany the administration of a particular compound and the desired physiological effect. [254] Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached. An effective dosage and treatment protocol can be determined by routine and conventional means, starting e.g., with a low dose in laboratory animals and then increasing the dosage while monitoring the effects, and systematically varying the dosage regimen as well. Animal studies are commonly used to determine the maximal tolerable dose ("MTD") of bioactive agent per kilogram weight. Those skilled in the art regularly extrapolate doses for efficacy, while avoiding toxicity, in other species, including humans.

[255] In accordance with the above, in therapeutic applications (e.g., for treatment and/or prevention), the dosages of the active agents used in accordance with the invention vary depending on the active agent, the age, weight, and clinical condition of the recipient patient, and the experience and judgment of the clinician or practitioner administering the therapy, among other factors affecting the selected dosage.

[256] Separate administrations 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 perform or the desirability of performing one or more additional administrations according to methods known in the art for monitoring therapeutic methods and other monitoring methods provided herein. Accordingly, the methods provided herein include methods of providing to the subject one or more administrations of a bacterial composition, where the number of administrations can be determined by monitoring the subject, and, based on the results of the monitoring, determining whether or not to provide one or more additional administrations. Deciding on whether or not to provide one or more additional administrations can be based on a variety of monitoring results.

[257] The time period between administrations can be any of a variety of time periods. The time period between administrations can be a function of any of a variety of factors, including monitoring steps, as described in relation to the number of administrations, the time period for a subject to mount an immune response and/or the time period for a subject to clear the bacteria from normal tissue. In one example, the time period can be a function of the time period for a subject to mount an immune response; for example, the time period can be more than the time period for a subject to mount an immune response, such as more than about one week, more than about ten days, more than about two weeks, or more than about a month; in another example, the time period can be less than the time period for a subject to mount an immune response, such as less than about one week, less than about ten days, less than about two weeks, or less than about a month. In another example, the time period can be a function of the time period for a subject to clear the bacteria from normal tissue; for example, the time period can be more than the time period for a subject to clear the bacteria from normal tissue, such as more than about a day, more than about two days, more than about three days, more than about five days, or more than about a week.

[258] In some embodiments, the delivery of an additional therapeutic in combination with the bacterial composition described herein reduces the adverse effects and/or improves the efficacy of the additional therapeutic.

[259] The effective dose of an additional therapeutic described herein is the amount of the therapeutic agent that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, with the least toxicity to the patient. The effective dosage level can be identified using the methods described herein and will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions administered, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts. In general, an effective dose of an additional therapy will be the amount of the therapeutic agent which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.

[260] The toxicity of an additional therapy is the level of adverse effects experienced by the subject during and following treatment. Adverse events associated with additional therapy toxicity include, but are not limited to, abdominal pain, acid indigestion, acid reflux, allergic reactions, alopecia, anaphylaxis, anemia, anxiety, lack of appetite, arthralgias, asthenia, ataxia, azotemia, loss of balance, bone pain, bleeding, blood clots, low blood pressure, elevated blood pressure, difficulty breathing, bronchitis, bruising, low white blood cell count, low red blood cell count, low platelet count, cardiotoxicity, cystitis, hemorrhagic cystitis, arrhythmias, heart valve disease, cardiomyopathy, coronary artery disease, cataracts, central neurotoxicity, cognitive impairment, confusion, conjunctivitis, constipation, coughing, cramping, cystitis, deep vein thrombosis, dehydration, depression, diarrhea, dizziness, dry mouth, dry skin, dyspepsia, dyspnea, edema, electrolyte imbalance, esophagitis, fatigue, loss of fertility, fever, flatulence, flushing, gastric reflux, gastroesophageal reflux disease, genital pain, granulocytopenia, gynecomastia, glaucoma, hair loss, hand-foot syndrome, headache, hearing loss, heart failure, heart palpitations, heartbum, hematoma, hemorrhagic cystitis, hepatotoxicity, hyperamylasemia, hypercalcemia, hyperchloremia, hyperglycemia, hyperkalemia, hyperlipasemia, hypermagnesemia, hypernatremia, hyperphosphatemia, hyperpigmentation, hypertriglyceridemia, hyperuricemia, hypoalbuminemia, hypocalcemia, hypochloremia, hypoglycemia, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia, impotence, infection, injection site reactions, insomnia, iron deficiency, itching, joint pain, kidney failure, leukopenia, liver dysfunction, memory loss, menopause, mouth sores, mucositis, muscle pain, myalgias, myelosuppression, myocarditis, neutropenic fever, nausea, nephrotoxicity, neutropenia, nosebleeds, numbness, ototoxicity, pain, palmar- plantar erythrodysesthesia, pancytopenia, pericarditis, peripheral neuropathy, pharyngitis, photophobia, photosensitivity, pneumonia, pneumonitis, proteinuria, pulmonary embolus, pulmonary fibrosis, pulmonary toxicity, rash, rapid heartbeat, rectal bleeding, restlessness, rhinitis, seizures, shortness of breath, sinusitis, thrombocytopenia, tinnitus, urinary tract infection, vaginal bleeding, vaginal dryness, vertigo, water retention, weakness, weight loss, weight gain, and xerostomia. In general, toxicity is acceptable if the benefits to the subject achieved through the therapy outweigh the adverse events experienced by the subject due to the therapy.

Immune disorders

[261] In some embodiments, the methods and compositions described herein relate to the treatment or prevention of a disease or disorder associated a pathological immune response, such as an autoimmune disease, an allergic reaction and/or an inflammatory disease. In some embodiments, the disease or disorder is an inflammatory bowel disease (e.g, Crohn’s disease or ulcerative colitis). In some embodiments, the disease or disorder is psoriasis (e.g., mild to moderate psoriasis). In some embodiments, the disease or disorder is atopic dermatitis (e.g, mild to moderate atopic dermatitis). In some embodiments, the disease or disorder is psoriatic arthritis.

[262] The methods described herein can be used to treat any subject in need thereof. As used herein, a “subject in need thereof’ includes any subject that has a disease or disorder associated with a pathological immune response (psoriasis (e.g., mild to moderate psoriasis) or atopic dermatitis (e.g., mild to moderate atopic dermatitis)) or psoriatic arthritis, as well as any subject with an increased likelihood of acquiring a such a disease or disorder. [263] The compositions described herein can be used, for example, as a bacterial composition for preventing or treating (reducing, partially or completely, the adverse effects of) an autoimmune disease, such as chronic inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, muckle-wells syndrome, rheumatoid arthritis, multiple sclerosis, or Hashimoto's disease; an allergic disease, such as a food allergy, pollenosis, or asthma; an infectious disease, such as an infection with Clostridium difficile; an inflammatory disease such as a TNF-mediated inflammatory disease (e.g, an inflammatory disease of the gastrointestinal tract, such as pouchitis, a cardiovascular inflammatory condition, such as atherosclerosis, or an inflammatory lung disease, such as chronic obstructive pulmonary disease); a bacterial composition for suppressing rejection in organ transplantation or other situations in which tissue rejection might occur; a supplement, food, or beverage for improving immune functions; or a reagent for suppressing the proliferation or function of immune cells.

[264] In some embodiments, the methods provided herein are useful for the treatment of inflammation. In certain embodiments, the inflammation of any tissue and organs of the body, including musculoskeletal inflammation, vascular inflammation, neural inflammation, digestive system inflammation, ocular inflammation, inflammation of the reproductive system, and other inflammation, as discussed below.

[265] Immune disorders of the musculoskeletal system include, but are not limited, to those conditions affecting skeletal joints, including joints of the hand, wrist, elbow, shoulder, jaw, spine, neck, hip, knew, ankle, and foot, and conditions affecting tissues connecting muscles to bones such as tendons. Examples of such immune disorders, which may 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, fibrositis (fibromyalgia), epicondylitis, myositis, and osteitis (including, for example, Paget's disease, osteitis pubis, and osteitis fibrosa cystic).

[266] Ocular immune disorders refers to an immune disorder that affects any structure of the eye, including the eye lids. Examples of ocular immune disorders which may be treated with the methods and compositions described herein include, but are not limited to, blepharitis, blepharochalasis, conjunctivitis, dacryoadenitis, keratitis, keratoconjunctivitis sicca (dry eye), scleritis, trichiasis, and uveitis. [267] Examples of nervous system immune disorders which may be treated with the methods and compositions 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 which may be treated with the methods and compositions described herein include, but are not limited to, arthrosclerosis, arthritis, phlebitis, vasculitis, and lymphangitis.

[268] Examples of digestive system immune disorders which may be treated with the methods and compositions described herein include, but are not limited to, cholangitis, cholecystitis, enteritis, enterocolitis, gastritis, gastroenteritis, inflammatory bowel disease, ileitis, and proctitis. Inflammatory bowel diseases include, for example, certain art- recognized forms of a group of related conditions. Several major forms of inflammatory bowel diseases are known, with Crohn's disease (regional bowel disease, e.g., inactive and active forms) and ulcerative colitis (e.g., inactive and active forms) the most common of these disorders. In addition, the inflammatory bowel disease encompasses irritable bowel syndrome, microscopic colitis, lymphocytic-plasmocytic enteritis, coeliac 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 masses or lesions, and primary sclerosing cholangitis.

[269] Examples of reproductive system immune disorders which may be treated with the methods and compositions described herein include, but are not limited to, cervicitis, chorioamnionitis, endometritis, epididymitis, omphalitis, oophoritis, orchitis, salpingitis, tubo-ovarian abscess, urethritis, vaginitis, vulvitis, and vulvodynia.

[270] The methods and compositions described herein may be used to treat autoimmune conditions having an inflammatory component. Such conditions include, but are not limited to, acute disseminated alopecia universalise, Behcet's disease, Chagas' disease, chronic fatigue syndrome, dysautonomia, encephalomyelitis, ankylosing spondylitis, aplastic anemia, hidradenitis suppurativa, autoimmune hepatitis, autoimmune oophoritis, celiac disease, Crohn's disease, diabetes mellitus type 1, giant cell arteritis, good pasture's syndrome, Grave's disease, Guillain-Barre 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, opsoclonus myoclonus syndrome, optic neuritis, Ord’s thyroiditis, pemphigus, polyarteritis nodosa, polymyalgia, rheumatoid arthritis, Reiter's syndrome, Sjogren's syndrome, temporal arteritis, Wegener's granulomatosis, warm autoimmune haemolytic anemia, interstitial cystitis, Lyme disease, morphea, psoriasis, psoriatic arthritis, sarcoidosis, scleroderma, ulcerative colitis, and vitiligo.

[271] The methods and compositions described herein may be used to treat T-cell mediated hypersensitivity diseases having an inflammatory component. Such conditions include, but are not limited to, contact hypersensitivity, contact dermatitis (including that due to poison ivy), uticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis, house dustmite allergy) and gluten-sensitive enteropathy (Celiac disease).

[272] Other immune disorders which may be treated with the methods and compositions include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, iritis, laryngitis, mastitis, myocarditis, nephritis, otitis, pancreatitis, parotitis, percarditis, peritonoitis, pharyngitis, pleuritis, pneumonitis, prostatistis, pyelonephritis, and stomatisi, transplant rejection (involving organs such as kidney, liver, heart, lung, pancreas (e.g, islet cells), bone marrow, cornea, small bowel, skin allografts, skin homografts, and heart valve xengrafts, sewrum sickness, and graft vs host disease), acute pancreatitis, chronic pancreatitis, acute respiratory distress syndrome, Sexary's syndrome, congenital adrenal hyperplasis, nonsuppurative thyroiditis, hypercalcemia associated with cancer, pemphigus, bullous dermatitis herpetiformis, severe erythema multiforme, exfoliative dermatitis, seborrheic dermatitis, seasonal or perennial allergic rhinitis, bronchial asthma, contact dermatitis, atopic dermatitis, drug hypersensistivity reactions, allergic conjunctivitis, keratitis, herpes zoster ophthalmicus, iritis and oiridocyclitis, chorioretinitis, optic neuritis, symptomatic sarcoidosis, fulminating or disseminated pulmonary tuberculosis chemotherapy, idiopathic thrombocytopenic purpura in adults, secondary thrombocytopenia in adults, acquired (autoimmune) haemolytic anemia, leukaemia and lymphomas in adults, acute leukaemia of childhood, regional enteritis, autoimmune vasculitis, multiple sclerosis, chronic obstructive pulmonary disease, solid organ transplant rejection, sepsis. Preferred treatments include treatment of transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosis, psoriasis, psoriatic arthritis, chronic obstructive pulmonary disease, and inflammation accompanying infectious conditions (e.g, sepsis).

[273] In some aspects, bacterial compositions for use of treating psoriasis are disclosed. In some aspects, a bacterial composition comprising Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) for use in treating psoriasis is described herein.

[274] In some aspects, uses of a bacterial composition for the preparation of a medicament for treating psoriasis (e.g., mild to moderate psoriasis) are disclosed. In some aspects, use of a bacterial composition for the preparation of a medicament for treating psoriasis wherein the bacterial composition comprises Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) is described herein.

[275] In some aspects, bacterial compositions for use of treating psoriatic arthritis are disclosed. In some aspects, a bacterial composition comprising Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) for use in treating psoriatic arthritis is described herein.

[276] In some aspects, uses of a bacterial composition for the preparation of a medicament for treating psoriatic arthritis are disclosed. In some aspects, use of a bacterial composition for the preparation of a medicament for treating psoriatic arthritis wherein the bacterial composition comprises Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) is described herein.

[277] In some aspects, bacterial compositions for use of treating atopic dermatitis are disclosed. In some aspects, a bacterial composition comprising Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) for use in treating atopic dermatitis is described herein.

[278] In some aspects, uses of a bacterial composition for the preparation of a medicament for treating atopic dermatitis (e.g., mild to moderate atopic dermatitis) are disclosed. In some aspects, use of a bacterial composition for the preparation of a medicament for treating atopic dermatitis wherein the bacterial composition comprises Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) is described herein.

[279] Numerous embodiments are further provided that can be applied to any aspect of the present invention described herein. For example, in some embodiments, the Prevotella histicola is a strain comprising at least 99.9% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329). In some embodiments, the Prevotella histicola is the Prevotella histicola Strain B 50329 (NRRL accession number B 50329). In some embodiments, the bacterial composition is administered orally. In some embodiments, the bacterial composition is formulated as a tablet.

[280] In some aspects, bacterial compositions for use of treating a Thl inflammatory disease are disclosed. In some aspects, a bacterial composition comprising Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) for use in treating atopic dermatitis is described herein.

[281] In some aspects, uses of a bacterial composition for the preparation of a medicament for treating a Thl inflammatory disease are disclosed. In some aspects, use of a bacterial composition for the preparation of a medicament for treating a Thl inflammatory disease wherein the bacterial composition comprises Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) is described herein.

[282] In some aspects, bacterial compositions for use of treating a Th2 inflammatory disease are disclosed. In some aspects, a bacterial composition comprising Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) for use in treating atopic dermatitis is described herein.

[283] In some aspects, uses of a bacterial composition for the preparation of a medicament for treating a Th2 inflammatory disease are disclosed. In some aspects, use of a bacterial composition for the preparation of a medicament for treating a Th2 inflammatory disease wherein the bacterial composition comprises Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) is described herein.

[284] In some aspects, bacterial compositions for use of treating a Thl7 inflammatory disease are disclosed. In some aspects, a bacterial composition comprising Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) for use in treating atopic dermatitis is described herein. [285] In some aspects, uses of a bacterial composition for the preparation of a medicament for treating a Thl7 inflammatory disease are disclosed. In some aspects, use of a bacterial composition for the preparation of a medicament for treating a Th 17 inflammatory disease wherein the bacterial composition comprises Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) is described herein.

[286] In some embodiments, the bacterial composition is administered once daily. In some embodiments, the bacterial composition is administered once daily for 15 continuous days. In some embodiments, the bacterial composition is administered once daily for 28 continuous days. In some embodiments, the bacterial composition is administered once daily for 29 continuous days. In some embodiments, the bacterial composition is administered to a subject with psoriasis. In some embodiments, the psoriasis is mild to moderate psoriasis. In some embodiments, the bacterial composition is administered to a subject with psoriatic arthritis.

In some embodiments, the bacterial composition is administered to a subject with atopic dermatitis. In some embodiments, the atopic dermatitis is mild to moderate atopic dermatitis.

EXAMPLES

Example 1: Prevotella histicola Strain B treatment for mild to moderate psoriasis

[287] Introduction: A therapeutic agent that offers the potential of systemic immune system modulation following oral administration, without systemic exposure, is being developed. Prevotella Strain B 50329 is a pharmaceutical preparation of a strain of Prevotella histicola isolated from a human duodenal biopsy: it has not been genetically modified. Strains of the Prevotella genus of microbes have been found in all human populations tested to date, at abundances ranging from less than 1% to nearly 50% of total fecal microbial load (Vandeputte 2017). Prevotella are gram-negative, obligate anaerobes that are natural human commensals in the oral cavity and GI tract. Prevotella Strain B 50329 is a gram-negative bacterium sensitive to the major classes of antibiotics, e.g., penicillins and cephalosporins. In non-clinical and clinical studies, its therapeutic effects have been dose-dependent.

[288] Several studies (de Groot et al 2017; Hindson et al 2017; Yan et al 2017; Felix et al 2018) suggest that host-microbe interactions in the gut, and particularly in the small intestine, can influence systemic inflammation. Preclinical data confirms that individual strains of microbes exhibit unique pharmacological profiles. This is thought to be based on multiple distinct microbial structural pattern motifs interacting with varying combinations of host pattern recognition receptors in small intestinal epithelium.

[289] Studies of Prevotella Strain B 50329 in vitro in a range of human and mouse assays and studies in vivo in model symptoms support the use of Prevotella Strain B 50329 in the treatment of inflammatory diseases including psoriasis. Prevotella Strain B 50329 increases secretion of anti-inflammatory cytokines such as IL-10, IL1RA, and IL-27 from human immune cells, while inducing minimal production of pro-inflammatory cytokines such as IL- 6, TNFa, and IFNy.

[290] Oral administration of Prevotella Strain B 50329 to mice results in striking pharmacodynamic effects on animal models of delay ed-type hypersensitivity, fluorescein isothiocyanate cutaneous hypersensitivity, collagen-induced arthritis (Marietta et al 2016) and experimental acute encephalomyelitis (Mangalam et al 2017). The high degree of consistency of both effect and dose suggests the potential for clinical benefit across multiple type 1, type 2, and type 3 inflammatory conditions. No potentially related adverse effects were seen in the animals used in these experiments with daily dosing for up to 3 weeks or with alternate day dosing for over 7 weeks. Immunophenotyping ex vivo in these models shows increased regulatory T cell numbers and regulatory dendritic cells in spleen and mesenteric lymph nodes, as well as decreases in pro-inflammatory cytokines such as IL-23p40, IL- 17, TNF, IL-6, and IL-13. Treatment also led to enhancement of gut intestinal barrier integrity, which is often disrupted in patients with inflammatory diseases. These effects on immune parameters have been observed both within and outside the GI tract, which demonstrates that host-microbe interactions in the gut can affect the immune response in peripheral tissues.

[291] Psoriasis is a chronic immune-mediated type 1/3 inflammatory skin disease in which hyperactive T cells trigger excessive keratinocyte proliferation. This results in the formation of raised erythematous plaques with scaling. Psoriatic lesions can appear anywhere on the body but are most often seen on the knees, elbows, scalp, and lumbar area. Critical events in the inflammatory process include activation of Langerhans cells and T cells, selective trafficking of activated T cells to the skin, and induction of an inflammatory cytokine and chemokine cascade in skin lesions. Clinical data have validated the role of anti-TNFa, anti-IL-17, and anti-IL-23 therapy in moderate to severe psoriasis. For patients with mild to moderate psoriasis, therapy usually involves topical agents (topical corticosteroids, vitamin D3 analogs), with topical corticosteroids providing the greatest range of efficacy and a wide range of formulations. More recently, physicians are prescribing apremilast, a first-in-class oral PDE4 inhibitor, ahead of biological therapy, which includes etanercept, infliximab, adalimumab, ustekinumab, and secukinumab.

Dose:

[292] Cohort: 12.8 x 10¹¹ cells of Prevotella Strain B 50329 or matching placebo administered as 4 tablets, once daily to subjects with psoriasis for 4, 6, 8, 12, and/or 16 weeks.

Efficacy Assessments:

[293] The following endpoints can be evaluated prior to first administration of a bacterial composition described herein, and/or at intervals during administration (e.g., 4, 6, 8, 12, and/or 16 weeks) of a bacterial composition described herein and/or after administration has terminated (e.g., 2 and/or 4 weeks after termination):

Psoriasis Area and Severity Index Score

[294] The PASI score will be assessed as described by Langley and Ellis (2004). The PASI is a physician assessment that combines the assessment of the severity of and area affected by psoriasis into a single score in the range 0 (no disease) to 72 (maximal disease). The absolute PASI score in this study is used as part of inclusion criterion #4. The PASI percentage response rates are efficacy endpoints (i.e., PASI-50, PASI-75, PASI-90, and PASI-100). For example, the percentage of participants who achieve a 75% or greater reduction in PASI score from baseline is represented by the PASI-75 value. Details of the PASI assessment will be provided in the study manual.

Lesion Severity Score

[295] The LSS is used to score the severity of psoriasis plaques (Patel and Tsui 2011). The dimensions of scaling, erythema, and plaque elevation are each scored on a scale from 0 to 4, and the total LSS is the numerical sum of the 3-dimensional scores observed at a single study visit.

Physician’s Global Assessment

[296] The National Psoriasis Foundation Psoriasis Score version of a static PGA is calculated by averaging the total body erythema, induration, and desquamation scores (Feldman and Krueger 2005). Erythema, induration, and desquamation will be scored on a 6- point scale, ranging from 0 (clear) to 5 (severe): the total PGA score is defined as the average of the erythema, induration, and desquamation scores. Details of the PGA assessment will be provided in the study manual.

Percent of Body Surface Area Involvement

[297] The percent of BSA involvement will be estimated for each participant, where 1% is approximately the area of the participant’s handprint (Walsh et al 2013). Details of the BSA assessment will be provided in the study manual.

[298] Walsh and colleagues proposed the product of the PGA and the BSA involvement as a simple and effective alternative for measuring severity of psoriasis in clinical trials (Walsh et al 2013).

Modified Nail Psoriasis Severity Index

[299] The mNAPSI is a numeric, reproducible, objective, and simple tool for physicians to evaluate the severity of nail bed psoriasis and nail matrix psoriasis by area of involvement in the nail unit (Cassell et al 2007). Details of conducting the mNAPSI will be provided in the study manual.

Dermatology Life Quality Index

[300] The DLQI is a patient reported outcomes instrument for assessing the impact of dermatologic conditions on patients’ quality of life (Finlay and Khan 1994). Details of administering the DLQI will be provided in the study manual.

Psoriasis Symptom Inventory

[301] The PSI is a patient reported outcomes instrument that is used to assess the severity of plaque psoriasis symptoms (Bushnell et al 2013). All symptoms (itch, redness, scaling, burning, cracking, stinging, flaking, and pain) are rated on a 5-point severity scale. The PSI demonstrated good construct validity and was sensitive to within-subject change (p<0.0001). Details of administering the PSI will be provided in the study manual.

Pain

[302] Pain will be assessed by the SF-36 Bodily Pain Scale (SF-36 BPS) and the VAS Pain (Hawker et al 2011). Details of administering the pain assessments will be provided in the study manual.

Fatigue

[303] Consistent with a recent study of fatigue in psoriasis (Skoie et al 2017), fatigue will be assessed by the vitality subscale of the SF-36 (van der Heijden et al 2003) and a fatigue VAS (Wolfe 2004). Details of administering the fatigue assessments will be provided in the study manual.

Histologic Assessment

[304] Standard histology will be performed on skin plaque biopsies (including epidermal thickness, basal mitotic counts and immune cell infiltrates, immunohistochemistry). mRNA Transcription Analysis

[305] An mRNA transcription analysis will be performed on the skin plaque biopsies.

Blood Cytokine and Chemokine Analysis

[306] Blood samples will be stimulated ex vivo and analyzed for levels of cytokines and chemokines, including IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-17A, TNFa, and IFNy.

References

Blake MR, Raker JM, Whelan K. Validity and reliability of the Bristol Stool Form Scale in healthy adults and patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2016;44:693-703.

Bomkamp B. Practical considerations for using functional uniform prior distributions for dose-response estimation in clinical trials. Biom J. 2014;56(6):947-62.

Bushnell DM, Martin ML, McCarrier K, et al. Validation of the Psoriasis Symptom Inventory (PSI), a patient-reported outcome measure to assess psoriasis symptom severity.

J Dermatolog Treat. 2013;24(5):356-60.

Cassell SE, Bieber JD, Rich P, et al. The modified Nail Psoriasis Severity Index: validation of an instrument to assess psoriatic nail involvement in patients with psoriatic arthritis.

J Rheumatol. 2007 Jan;34(l): 123-9. de Groot PF, Belzer C, Ay din O, et al. Distinct fecal and oral microbiota composition in human type 1 diabetes, an observational study. PLoS One. 2017;12(12):e0188475.

Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis. 2005;64(Suppl 2):ii65-8; discussion ii69-73.

Felix KM, Tahsin S, Wu HJ. Host-microbiota interplay in mediating immune disorders. Ann N Y Acad Sci. 2018;1417(l):57-70. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19:210-6.

Hawker GA, Mian S, Kendzerska T, et al. Measures of adult pain: Visual Analog Scale for Pain (VAS Pain), Numeric Rating Scale for Pain (NRS Pain), McGill Pain Questionnaire (MPQ), Short-Form McGill Pain Questionnaire (SF-MPQ), Chronic Pain Grade Scale (CPGS), Short Form-36 Bodily Pain Scale (SF-36 BPS), and Measure of Intermittent and Constant Osteoarthritis Pain (ICOAP). Arthritis Care Res (Hoboken). 2011;63 Suppl 1LS240-52.

Hindson J. Multiple sclerosis: A possible link between multiple sclerosis and gut microbiota. Nat Rev Neurol. 2017;13(12):705.

Human Microbiome Project Consortium. A framework for human microbiome research. Nature. 2012;486:215-21.

Langley RG, Ellis CN. Evaluating psoriasis with Psoriasis Area and Severity Index, Psoriasis Global Assessment, and Lattice System Physician's Global Assessment. J Am Acad Dermatol. 2004;51(4):563-9.

Mangalam A, Shahi SK, Luckey D, et al. Human gut-derived commensal bacteria suppress CNS inflammatory and demyelinating disease. Cell Rep. 2017;20(6): 1269-77.

Marietta EV, Murray JA, Luckey DH, et al. Human gut-derived Prevotella histicola suppresses inflammatory arthritis in humanized mice. Arthritis Rheumatol. 2016;68(12):2878-88.

O’Donnell LJD, Viijee J, Heaton KW. Detection of pseudodiarrhoea by simple clinical assessment of intestinal transit rate. BMJ. 1990;300:439-40.

Patel RV, Tsui CL. Evaluating psoriasis: a review of the assessments most commonly used in clinical trials. Psoriasis Forum. 2011;17(4):259-66. doi: 10.1177/247553031117a00403.

Skoie IM, Dalen I, Temowitz T, et al. Fatigue in psoriasis: a controlled study. Br J Dermatol. 2017;177(2):505-12.

Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian approaches to clinical trials and healthcare evaluation. Chichester: John Wiley and Sons Ltd; 2004. 408 p. van der Heijden PG, van Buuren S, Fekkes M, et al. Uni dimensionality and reliability under Mokken scaling of the Dutch language version of the SF-36. Qual Life Res. 2003;12:189-98. Vandeputte D, Falony G, Vieira-Silva S, et al. Stool consistency is strongly associated with gut microbiota richness and composition, enterotypes and bacterial growth rates. Gut. 2016;65:57-62.

Vandeputte D, Kathagen G, D’hoe K, et al. Quantitative microbiome profiling links gut community variation to microbial load. Nature. 2017;551:507-11.

Walsh JA, McFadden M, Woodcock J, et al. Product of the Physician Global Assessment and body surface area: a simple static measure of psoriasis severity in a longitudinal cohort. J Am Acad Dermatol. 2013;69(6):931-7.

Wolfe F. Fatigue assessments in rheumatoid arthritis: comparative performance of visual analog scales and longer fatigue questionnaires in 7760 patients. J Rheumatol.

2004;31(10): 1896-902.

Yan D, IssaN, Afifi L, et al. The role of the skin and gut microbiome in psoriatic disease. Curr Dermatol Rep. 2017;6:94-103.

Example 2: Prevotella histicola Strain B treatment for mild to moderate psoriasis

Dose:

[307] 12.8 x io¹¹ cells of Prevotella Strain B 50329 or matching placebo administered as 4 tablets, once daily to subjects with psoriasis for 4, 6, 8, 12, and/or 16 weeks.

Endpoints:

[308] The following endpoints can be evaluated at intervals prior to first administration of a bacterial composition described herein, and/or during administration (e.g., 4, 6, 8, 12, and/or 16 weeks) of a bacterial composition described herein and/or after administration has terminated (e.g., 2 and/or 4 weeks after termination):

PASI score

[309] The Psoriasis Area and Severity Index (PASI) score will be assessed as described by Langley and Ellis (Langley, 2004). The PASI is a physician assessment that combines the assessment of the severity of and area affected by psoriasis into a single score. The PASI score ranges from 0 (no disease) to 72 (maximal disease). PASI-50 and PASI-75 responses are defined as at least 50% and 75% decrease from baseline PASI score respectively.

LSS

[310] The LSS is used to score the severity of psoriasis plaques (Patel, 2011). The dimensions of scaling, erythema, and plaque elevation are each scored on a scale from 0 to 4, and the total LSS is the numerical sum of the 3-dimensional scores observed at a single study visit. The LSS score therefore ranges from 0 to 12. A measure of the size of the target lesion will also be included.

BSA

[3H] The Body Surface Area (BSA) is a measure of the extent of psoriasis at a given time. It is calculated by estimating the number of participant’s handprints of psoriasis are present; where one handprint (including digits) represents 1% body surface area.

PGA

[312] The static PGA is calculated by averaging the total body erythema, induration, and desquamation scores (Feldman , 2005). Erythema, induration, and desquamation will be scored on a 6-point scale, ranging from 0 (clear) to 5 (severe): the total PGA score is defined as the average of the erythema, induration, and desquamation scores.

PGA x BSA

[313] The product of the PGA and BSA provides a simple but useful measure of the extent and severity of eczema that is commonly used in the clinical trial setting (Walsh, 2013).

DLQI questionnaire

[314] This is a validated patient reported outcomes instrument which asks 10 questions to assess how a participant’s skin disease has affected their quality of life over the past week (Finlay, 1994). The DLQI score ranges from 0 to 30.

Example 3: Additional psoriasis read-outs

Dose:

[315] 12.8 x io¹¹ cells of Prevotella Strain B 50329 or matching placebo administered as 4 tablets, once daily to subjects with psoriasis for 4, 6, 8, 12, and/or 16 weeks.

Endpoints:

[316] The effects of Prevotella histicola Strain B on psoriasis can be optionally evaluated by one or more of the following criteria:

• Mean percentage change from baseline in the product of sPGA and BSA (total psoriasis severity index), e.g., at week 8 or 16

• Mean absolute and percentage change from baseline in the product of sPGA and BSA (e.g., at weeks 4, 8, 12 and/or 16)

• Mean absolute and percentage change from baseline in PASI (e.g., at weeks 4, 8, 12 and/or 16) • Percentage of patients achieving at least a 50% improvement in PASI from baseline (PASI50) (e.g., at weeks 4, 8, 12 and 16)

• Time to achieve PASI50

• Percentage of patients achieving at least a 75% improvement in PASI from baseline (PASI75) (e.g., at weeks 4, 8, 12 and/or 16)

• Time to achieve PASI75

• Percentage of patients with a sPGA of clear (0) or very mild (1) (e.g., at weeks 4, 8, 12 and/or 16)

• Time to achieve sPGA of 0 or 1

• Percentage of patients with a sPGA of clear (0) or very mild (1) with a >2 point improvement from baseline (e.g., at weeks 4, 8, 12 and 16)

• Absolute and Percentage change from baseline in total BSA affected by psoriasis (e.g., at weeks 4, 8, 12 and/or 16)

• Absolute and Percentage change from baseline in total PSI score: (e.g., at weeks 4, 8, 12 and/or 16)

• Absolute and Percentage change from baseline in total DLQI (subjects aged >1_8_)_ or cDLQI (subjects aged <18) score: (e.g., at weeks 4, 8, 12 and/or 16)

• Percentage of subjects achieving an improvement from baseline of 4 or more in the DLQI (weeks 4, 8, 12 and 16)

• Absolute and Percentage change from baseline in Pruritus-NRS (e.g., at weeks 4, 8, 12 and/or 16)

• Change from baseline in mNAPSI score

• Change from baseline in Psoriasis scalp severity index (PSSI) score

• EQ-5D (version 3L for subjects aged >18; and version Y for subjects aged 12 to <18)

• Treatment Satisfaction Questionnaire for Medication (TSQM)

• Hospital Anxiety and Depression Scale (HADS) (subjects aged >18), or the Paediatric Index of Emotional Distress (PI-ED) (subjects aged 12 to < 18)

• Decrease in pain, e.g., as assessed by the SF-36 Bodily Pain Scale and/or the VAS Pain assessment

• Decrease in fatigue, e.g., as assessed by the vitality subscale of SF-36 and/or a fatigue VAS [317] Efficacy assessments can include one or more of: the PASI score, the LSS, the National Psoriasis Foundation Psoriasis Score version of a static PGA, the percent of BSA involvement, the mNAPSI, the DLQI, the PSI (Psoriasis Symptom Inventory).

[318] Psoriasis Area and Severity Index Score: The PASI score can be assessed as described by Langley and Ellis (2004). The PASI is a physician assessment that combines the assessment of the severity of and area affected by psoriasis into a single score in the range 0 (no disease) to 72 (maximal disease). The PASI percentage response rates are efficacy endpoints (i.e., PASI-50, PASI-75, PASI-90, and PASI- 100). For example, the percentage of participants who achieve a 75% or greater reduction in PASI score from baseline is represented by the PASI-75 value.

[319] Lesion Severity Score: The LSS is used to score the severity of psoriasis plaques (Patel and Tsui 2011). The dimensions of scaling, erythema, and plaque elevation are each scored on a scale from 0 to 4, and the total LSS is the numerical sum of the 3-dimensional scores observed at a single study visit.

[320] Physician ’s Global Assessment: The National Psoriasis Foundation Psoriasis Score version of a static PGA is calculated by averaging the total body erythema, induration, and desquamation scores (Feldman and Krueger 2005). Erythema, induration, and desquamation will be scored on a 6-point scale, ranging from 0 (clear) to 5 (severe): the total PGA score is defined as the average of the erythema, induration, and desquamation scores.

[321] Percent of Body Surface Area Involvement: The percent of BSA involvement can be estimated for each participant, where 1% is approximately the area of the participant’s handprint (Walsh et al 2013).

[322] Walsh and colleagues proposed the product of the PGA and the BSA involvement as a simple and effective alternative for measuring severity of psoriasis in clinical trials (Walsh et al 2013).

[323] Modified Nail Psoriasis Severity Index: The mNAPSI is a numeric, reproducible, objective, and simple tool for physicians to evaluate the severity of nail bed psoriasis and nail matrix psoriasis by area of involvement in the nail unit (Cassell et al 2007).

[324] Dermatology Life Quality Index: The DLQI is a patient reported outcomes instrument for assessing the impact of dermatologic conditions on patients’ quality of life (Finlay and Khan 1994).

[325] Psoriasis Symptom Inventory: The PSI is a patient reported outcomes instrument that is used to assess the severity of plaque psoriasis symptoms (Bushnell et al 2013). All symptoms (itch, redness, scaling, burning, cracking, stinging, flaking, and pain) are rated on a 5-point severity scale. The PSI demonstrated good construct validity and was sensitive to wi thin-subject change (p<0.0001).

[326] Pain: Pain can be assessed by the SF-36 Bodily Pain Scale (SF-36 BPS) and the VAS Pain (Hawker et al 2011).

[327] Fatigue: Consistent with a recent study of fatigue in psoriasis (Skoie et al 2017), fatigue can be assessed by the vitality subscale of the SF-36 (van der Heijden et al 2003) and a fatigue VAS (Wolfe 2004).

[328] In embodiments, provided herein is a method of treating psoriasis comprising administering (e.g., orally administering) to a human subject aPrevotella histicola strain and/or a composition (e.g., a bacterial composition and/or a solid dosage form) comprising a strain of aPrevotella histicola provided herein. In some embodiments, the human subject has a confirmed diagnosis of mild to moderate plaque-type psoriasis for at least 6 months involving no more than 10% of body surface area (BSA) (excluding the scalp). In some embodiments, the human subject has a minimum of 2 psoriatic lesions. In some embodiments, the subject has not received systemic non-biologic psoriasis therapy (methotrexate [MTX], steroids, cyclophosphamide) or psoralen plus ultraviolet A (PUVA)/ultraviolet A (UVA) phototherapy within 4 weeks prior to dosing. In some embodiments, subject has not received treatment with biologic agents within 12 months prior to first dose. In some embodiments, the subject is not continuing use of topical or oral pharmacologically active agents 2 weeks prior to the start of dosing. In some embodiments, the human subject has a documented diagnosis of plaque psoriasis for >6 months.

[329] In some embodiments, the human subject has had mild to moderate plaque psoriasis with plaque covering BSA of >3% and <10% and meet both of the following additional criteria: (i) PASI score of >6 and <15, and (ii) PGA score of 2 or 3.

[330] In some embodiments, the method decreases the PASI (Psoriasis Area and Severity Index) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s PASI score prior to the commencement of treatment).

[331] In some embodiments, the method increases a PASI percentage response rate (e.g., PASI-50, PASI-75, PASI-90, or PASI-100), e.g., as described herein. For example, the percentage of subjects who achieve a 75% or greater reduction in PASI score from baseline is represented by the PASI-75 value, e.g., after 16 weeks of treatment.

[332] In some embodiments, the method decreases the LSS (Lesion Severity Score) in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s LSS prior to the commencement of treatment), e.g., as described herein. [333] In some embodiments, the method decreases the PGA (Physician’s Global Assessment) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s PGA score prior to the commencement of treatment), e.g., as described herein.

[334] In some embodiments, the method decreases the percent of BSA (Body Surface Area) involvement in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s percent involvement prior to the commencement of treatment), e.g., as described herein.

[335] In some embodiments, the method decreases the mNAPSI (Modified Nail Psoriasis Severity Index) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s mNAPSI score prior to the commencement of treatment), e.g., as described herein.

[336] In some embodiments, the method improves the DLQI (Dermatology Life Quality Index) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s DLQI score prior to the commencement of treatment), e.g., as described herein.

[337] In some embodiments, the method improves the PSI (Psoriasis Symptom Inventory) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s PSI score prior to the commencement of treatment), e.g., as described herein.

[338] In some embodiments, the method decreases pain in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s pain prior to the commencement of treatment), e.g., as described herein. For example, pain can be assessed by the SF-36 Bodily Pain Scale (SF-36 BPS) or the VAS Pain.

[339] In some embodiments, the method decreases fatigue in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s fatigue prior to the commencement of treatment), e.g., as described herein.

References:

J Dermatolog Treat. 2013;24(5):356-60.

J Rheumatol. 2007 Jan;34(l): 123-9.

Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis. 2005;64(Suppl 2):ii65-8; discussion ii69-73. Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19:210-6.

Skoie IM, Dalen I, Temowitz T, et al. Fatigue in psoriasis: a controlled study. Br J Dermatol. 2017;177(2):505-12. van der Heijden PG, van Buuren S, Fekkes M, et al. Uni dimensionality and reliability under Mokken scaling of the Dutch language version of the SF-36. Qual Life Res. 2003;12:189-98.

Wolfe F. Fatigue assessments in rheumatoid arthritis: comparative performance of visual analog scales and longer fatigue questionnaires in 7760 patients. J Rheumatol. 2004;31(10): 1896-902.

Example 4: Prevotella histicola Strain B treatment for mild to moderate atopic dermatitis

Dose:

[340] Cohort: 12.8 x 10¹¹ cells of Prevotella Strain B 50329 or matching placebo administered as 4 tablets, once daily to subjects with atopic dermatitis for 4, 6, 8, 12, and/or 16 weeks. Efficacy Assessments:

[341] The following endpoints can be evaluated at intervals prior to first administration of a bacterial composition described herein, and/or during administration (e.g., 4, 6, 8, 12, and/or 16 weeks) of a bacterial composition described herein and/or after administration has terminated (e.g., 2 and/or 4 weeks after termination):

EASI

[342] The Eczema Area and Severity Index (EASI) is a validated measure of eczema severity, which takes into account a combination of the body surface area affected, and the severity of erythema, oedema, excoriation and lichenification. The EASI score ranges from 0 - 72. (EASI, 2017) EASI-50 and EASI-75 responses are defined as at least 50% and 75% decrease from baseline EASI score respectively.

SCORAD

[343] The SCORing Atopic Dermatitis (SCORAD) is a clinical tool which is also used to assess the extent and severity of eczema, to assess treatment effects (ETFAD, 1993). As well as an investigator-rated area and disease intensity score, there is a subjective symptoms component which takes into account itch and sleeplessness using a visual analogue scale. The SCORAD score ranges from 0 - 103.

BSA

[344] The Body Surface Area (BSA) is a measure of the extent of atopic dermatitis at a given time. It is calculated by estimating the number of participant’s handprints of active atopic dermatitis are present; where one handprint (including digits) represents 1% body surface area.

IGA

[345] The Validated Investigator Global Assessment scale for Atopic Dermatitis (vIGA- AD) will be used to describe the overall appearance of lesions, at a given time-point (Simpson, 2020). There is a standardised grading system. In indeterminate cases, extent will be used to differentiate between scores - but otherwise extent is not used in the scoring system. The IGA score ranges from 0 (Clear) to 4 (Severe).

IGA x BSA

[346] The product of the IGA and BSA provides a simple but useful measure of the extent and severity of eczema that is commonly used in the clinical trial setting. DLQI questionnaire

[347] This is a validated patient reported outcomes instrument which asks 10 questions to assess how a participant’s skin disease has affected their quality of life over the past week (Finlay, 1994). The DLQI score ranges from 0 to 30.

POEM questionnaire

[348] The Patient-Orientated Eczema Measure (POEM) includes 7 questions about the participant’s atopic dermatitis. Each of the 7 questions is scored from 0 to 4, giving a POEM score range from 0 to 28.

Pruritus NRS questionnaire

[349] The Pruritus Numerical Rating Scale (Pruritus-NRS) is a 10-point scale for participants to rate both their average and worst itch that they have experienced over the previous 24 hours.

Example 5: Prevotella histicola Strain B for the treatment of psoriatic arthritis

[350] Prevotella histicola Strain B can be used for the treatment of psoriatic arthritis (PsA), e.g., at the doses and dosing regimens provided herein.

Dose:

[351] 12.8 x io¹¹ cells of Prevotella Strain B 50329 or matching placebo administered as 4 tablets, once daily to subjects with psoriasis for 4, 6, 8, 12, and/or 16 weeks.

Endpoints:

[352] The effects of Prevotella histicola Strain B on psoriatic arthritis can be evaluated by one or more of the following criteria:

[353] Percentage of patients with an ACR20, ACR50, and/or ACR70 response: The ACR (American College of Rheumatology) is a standard criteria originally developed to measure the effectiveness of various arthritis medications or treatments in clinical trials for rheumatoid arthritis, but is also widely used in PsA. The ACR measures improvement in tender joint count (TJC) or swollen joint count (SJC), and improvement in at least 3 of the following 5 parameters: Patient Global Assessment (PtGA), Physician's Global Assessment of Disease Activity (PhGA), physical function (using HAQ-DI), visual analog pain scale, and acute phase reactant (using ESR or CRP). ACR 20/50/70 response is achieved if > 20%/> 50%/> 70% improvement in tender joint count (TJC) or swollen joint count (SJC) as well as a > 20%/> 50%/> 70% improvement in > 3 of the other 5 parameters. [354] Change in Modified Psoriatic Arthritis Response Criteria (PsARC) score: Response is defined by improvement in at least 2 of the 4 following measures, one of which must be joint swelling or tenderness, and no worsening in any of the 4 measures: PtGA (patient global assessment) of articular disease (1-5) and PhGA (physician global assessment) of articular disease (1-5): improvement= decrease by at least one point on the 5 point scale, worsening=increase by at least one point on the 5 point scale. Joint pain/tendemess score and joint swelling score: improv ement= decrease by 30%, worsening= increase by 30%.

[355] Dactylitis severity score: Changes from baseline in Dactylitis Severity Score at 4, 8, 12, and/or 16 weeks. Each digit with dactylitis is evaluated in a severity scale from 0 to 3 (0 = no dactylitis; 1 = mild dactylitis, 2 = moderate dactylitis, 3 = severe dactylitis). The total score is calculated as the sum of the individual digits dactylitis scores, ranging from a minimum 0 to a maximum of 60, with higher scores corresponding to worse severities.

[356] Clinical Disease Activity Index (CDAI): The Clinical Disease Activity Index (CD Al) is a composite index that is calculated as the sum of the: • 28 tender joint count (TJC), • 28 swollen joint count (SJC), • Patient's Global Assessment of Disease Activity measured on a 10 cm visual analog scale (VAS), where 0 cm = lowest disease activity and 10 cm = highest;

• Physician's Global Assessment of Disease Activity -measured on a 10 cm VAS, where 0 cm = lowest disease activity and 10 cm = highest. The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI: Remission: < 2.8 Low Disease Activity: > 2.8 and < 10 Moderate Disease Activity: > 10 and < 22 High Disease Activity: > 22.

[357] DAS28: Disease Activity Score (DAS): Changes in DAS28 (utilizing hsCRP) from baseline. The DAS28 is a measure of disease activity in PsA based on Swollen and Tender Joint Counts (out of a total of 28), hsCRP and the Patient's Global Assessment of Disease Activity. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score of 3.2 to 5.1 indicates moderate disease activity, a DAS28 score of 2.6 to 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission.

[358] Maastricht Ankylosing Spondylitis Enthesis Score (MASES) : The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. See also L Heuft- Dorenbosch et al., Ann. Rheum. Dis. 62: 127-132 (2003).

[359] The effects of Prevotella histicola Strain B on psoriatic arthritis can be evaluated by one or more of the following criteria:

Tender and Swollen Joint Assessment, Psoriasis Area and Severity Index (PASI), Nail Psoriasis Severity Index (NAPSI), Modified Nail Psoriasis Severity Index (mNAPSI), Mander/Newcastle Enthesitis Index (MEI), Leeds Enthesitis Index (LEI), Spondyloarthritis Research Consortium of Canada (SPARCC), Maastricht Ankylosing Spondylitis Enthesis Score (MASES), Leeds Dactylitis Index (LDI), Patient Global for Psoriatic Arthritis, Dermatology Life Quality Index (DLQI), Psoriatic Arthritis Quality of Life (PsAQOL), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), Psoriatic Arthritis Response Criteria (PsARC), Psoriatic Arthritis Joint Activity Index (PsAJAI), Disease Activity in Psoriatic Arthritis (DAPSA), and Composite Psoriatic Disease Activity Index (CPDAI). See Mease, Arthritis Care & Research 63:S64-S85 (2011).

See also Gladman et al., J Rheumatology 34: 1159-1166 (2007).

Example 6: Tablet Comprising Prevotella histicola

[360] A tablet with the following recipe in Table i was prepared.

Table i: Prevotella histicola Tablet Composition

[361] The tablet was prepared as a 17.4mm x 7.1 mm tablet.

[362] The tablet was enteric coated.

[363] The tablet contained 3.2 x 10¹¹ TCC of Prevotella histicola Strain B (NRRL accession number B 50329). [364] The Prevotella histicola strain referred to above has been deposited as Prevotella histicola Strain B (NRRL accession number B 50329).

Example 7: Capsule Comprising revote/fa histicola

[365] Capsules according to the following recipe in Table ii were prepared:

Table ii: Prevotella histicola Capsule Composition

a Swedish orange Vcap capsules

[366] The Prevotella histicola strain referred to above has been deposited as Prevotella histicola Strain B (NRRL accession number B 50329).

[367] The capsule was banded with an HPMC-based banding solution.

[368] The banded capsule was enteric coated with Eudragit L30-D55, a poly(methacrylic acid-co-ethyl acrylate) copolymer.

Incorporation by Reference

[369] 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.

Equivalents

[370] 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 encompassed by the following claims.

Claims

What is claimed is:

1. A method of treating psoriasis in a human subject comprising orally administering to the human subject a bacterial composition comprising a dose of about 9.6 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more solid dosage forms.

2. A method of decreasing Lesion Severity Score (LSS) (e.g, mean LSS) (e.g, as compared to baseline or placebo control) in a human subject (e.g, a subject with psoriasis) comprising orally administering to the human subject a bacterial composition comprising a dose of about 9.6 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more solid dosage forms.

3. The method of claim 2, wherein the mean LSS is decreased in the subject.

4. The method of claim 2 or claim 3, wherein the LSS is reduced as compared to baseline or placebo control.

5. A method of decreasing Psoriasis Area and Severity Index (PASI) score (e.g, mean PASI score) (e.g, as compared to baseline or placebo control) in a human subject (e.g, a subject with psoriasis) comprising orally administering to the human subject a bacterial composition comprising a dose of about 9.6 x 10" to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more solid dosage forms.

6. The method of claim 5, wherein the mean PASI score is decreased in the subject.

7. The method of claim 5 or claim 6, wherein the PASI score is reduced as compared to baseline or placebo control.

8. The method of any one of claims 1-7, wherein the solid dosage form comprises a tablet or capsule.

9. The method of any one of claims 1-8, wherein the solid dosage form is enteric coated.

10. The method of any one of claims 1-9, wherein the bacterial composition comprises about 9.6 x 10¹¹ total cells of Prevotella histicola.

11. The method of any one of claims 1-9, wherein the bacterial composition comprises about 12.8 x 10¹¹ total cells of Prevotella histicola.

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12. The method of any one of claims 1-9, wherein the bacterial composition comprises about 16 x 10¹¹ total cells of Prevotella histicola.

13. The method of any one of claims 1-12, wherein the bacterial composition is administered at least once daily.

14. The method of any one of claims 1-13, wherein the bacterial composition is administered once daily.

15. The method of any one of claims 1-14, wherein the bacterial composition is administered once daily for 15 continuous days.

16. The method of any one of claims 1-14, wherein the bacterial composition is administered once daily for 28 continuous days.

17. The method of any one of claims 1-14, wherein the bacterial composition is administered once daily for 16 weeks.

18. The method of any one of claims 1-17, wherein the psoriasis is mild to moderate psoriasis.

19. A method of treating atopic dermatitis in a human subject comprising orally administering to the human subject a dose of about 9.6 x IO^{1 1} to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more solid dosage forms.

20. A method of decreasing Eczema Area and Severity Index (EASI) score (e.g., mean EASI score) (e.g, as compared to baseline or placebo control) in a human subject (e.g, a subject with atopic dermatitis) comprising orally administering to the human subject a bacterial composition comprising a dose of about 9.6 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more solid dosage forms.

21. The method of claim 20, wherein the mean EASI score is decreased in the subject.

22. The method of claim 20 or claim 21, wherein the EASI score is reduced as compared to baseline or placebo control.

23. A method of decreasing IGA (Investigator’s Global Assessment) score (e.g., mean IGA score) (e.g., as compared to baseline or placebo control) in a human subject (e.g., a subject with atopic dermatitis) comprising orally administering to the human subject a

77 bacterial composition comprising a dose of about 9.6 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more solid dosage forms.

24. The method of claim 23, wherein the mean IGA score is decreased in the subject.

25. The method of claim 23 or claim 24, wherein the IGA score is reduced as compared to baseline or placebo control.

26. A method of decreasing SCORAD (SCORing Atopic Dermatitis) score (e.g, mean SCORAD score) (e.g, as compared to baseline or placebo control) in ahuman subject (e.g, a subject with atopic dermatitis) comprising orally administering to the human subject a bacterial composition comprising a dose of about 9.6 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more solid dosage forms.

27. The method of claim 26, wherein the mean SCORAD score is decreased in the subject.

28. The method of claim 26 or claim 27, wherein the SCORAD score is reduced as compared to baseline or placebo control.

29. The method of any one of claims 19-28, wherein the solid dosage form comprises a tablet or capsule.

30. The method of any one of claims 19-29, wherein the solid dosage form is enteric coated.

31. The method of any one of claims 19-30, wherein the bacterial composition comprises about 9.6 x 10¹¹ total cells of Prevotella histicola.

32. The method of any one of claims 19-30, wherein the bacterial composition comprises about 12.8 x 10¹¹ total cells of Prevotella histicola.

33. The method of any one of claims 19-30, wherein the bacterial composition comprises about 16 x 10¹¹ total cells of Prevotella histicola.

34. The method of any one of claims 19-33, wherein the bacterial composition is administered at least once daily.

35. The method of any one of claims 19-33, wherein the bacterial composition is administered once daily.

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36. The method of any one of claims 19-33, wherein the bacterial composition is administered once daily for 15 continuous days.

37. The method of any one of claims 19-33, wherein the bacterial composition is administered once daily for 28 continuous days.

38. The method of any one of claims 19-33, wherein the bacterial composition is administered once daily for 16 weeks.

39. The method of any one of claims 19-38, wherein the atopic dermatitis is mild to moderate atopic dermatitis.

40. A method of treating psoriatic arthritis in a human subject comprising orally administering to the human subject a dose of about 9.6 x IO^{1 1} to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more solid dosage forms.

41. A method of improving the percentage of human subjects (e.g., subjects with psoriatic arthritis) with an ACR20 or ACR50 or ACR70 response (e.g., as compared to baseline or placebo control) comprising orally administering to the human subjects a bacterial composition comprising a dose of about 9.6 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more solid dosage forms.

42. The method of claim 41, wherein the ACR20 or ACR50 or ACR70 response is improved in the subjects.

43. The method of claim 41 or claim 42, wherein ACR20 or ACR50 or ACR70 response is improved as compared to baseline or placebo control.

44. A method of improving Modified Psoriatic Arthritis Response Criteria (PsARC) score (e.g., as compared to baseline or placebo control) in a human subject (e.g., a subject with psoriatic arthritis) comprising orally administering to the human subject a bacterial composition comprising a dose of about 9.6 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more tablets or capsules.

45. The method of claim 44, wherein the PsARC score is decreased in the subject.

46. The method of claim 44 or claim 45, wherein PsARC score is reduced as compared to baseline or placebo control.

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47. A method of decreasing dactylitis severity score in a human subject (e.g., as compared to baseline or placebo control) (e.g, a subject with psoriatic arthritis) comprising orally administering to the human subject a bacterial composition comprising a dose of about 9.6 x 10ⁿ to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more solid dosage forms.

48. The method of claim 47, wherein the dactylitis severity score is decreased in the subject.

49. The method of claim 47 or claim 48, wherein the dactylitis severity score is reduced as compared to baseline or placebo control.

50. A method of decreasing Clinical Disease Activity Index (CDAI) score e.g., as compared to baseline or placebo control) in a human subject (e.g., a subject with psoriatic arthritis) comprising orally administering to the human subject a bacterial composition comprising a dose of about 9.6 x 10¹¹ to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more solid dosage forms.

51. The method of claim 50, wherein the CDAI score is decreased in the subject.

52. The method of claim 50 or claim 51, wherein the CDAI is reduced as compared to baseline or placebo control.

53. A method of decreasing DAS28 score (e.g., as compared to baseline or placebo control) in a human subject (e.g., a subject with psoriatic arthritis) comprising orally administering to the human subject a bacterial composition comprising a dose of about 9.6 x 10ⁿ to about 16 x 10¹¹ total cells of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more solid dosage forms.

54. The method of claim 53, wherein the DAS28 score is decreased in the subject.

55. The method of claim 53 or claim 54, wherein DAS28 score is reduced as compared to baseline or placebo control.

56. A method of decreasing Maastricht Ankylosing Spondylitis Enthesis Score (MASES) (e.g., as compared to baseline or placebo control) in ahuman subject (e.g., a subject with psoriatic arthritis) comprising orally administering to the human subject a bacterial composition comprising a dose of about 9.6 x 10" to about 16 x 10¹¹ total cells of Prevotella

80 histicola Strain B 50329 (NRRL accession number B 50329) formulated in one or more tablets or capsules.

57. The method of claim 55, wherein the MASES is decreased in the subject.

58. The method of claim 55 or claim 57, wherein MASES is reduced as compared to baseline or placebo control.

59. The method of any one of claims 40-58, wherein the solid dosage form comprises a tablet or capsule.

60. The method of any one of claims 40-59, wherein the solid dosage form is enteric coated.

61. The method of any one of claims 40-60, wherein the bacterial composition comprises about 9.6 x 10¹¹ total cells of Prevotella histicola.

62. The method of any one of claims 40-60, wherein the bacterial composition comprises about 12.8 x 10¹¹ total cells of Prevotella histicola.

63. The method of any one of claims 40-60, wherein the bacterial composition comprises about 16 x 10¹¹ total cells of Prevotella histicola.

64. The method of any one of claims 40-63, wherein the bacterial composition is administered at least once daily.

65. The method of any one of claims 40-63, wherein the bacterial composition is administered once daily.

66. The method of any one of claims 40-63, wherein the bacterial composition is administered once daily for 15 continuous days.

67. The method of any one of claims 40-63, wherein the bacterial composition is administered once daily for 28 continuous days.

68. The method of any one of claims 40-63, wherein the bacterial composition is administered once daily for 16 weeks.

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