WO2021142279A1

WO2021142279A1 - Compositions and methods of treatment using veillonella parvula

Info

Publication number: WO2021142279A1
Application number: PCT/US2021/012724
Authority: WO
Inventors: Mark BODMER; Andrea Itano; Duncan MCHALE
Original assignee: Evelo Biosciences, Inc.
Priority date: 2020-01-10
Filing date: 2021-01-08
Publication date: 2021-07-15
Also published as: TW202140050A

Abstract

Provided herein are methods and compositions related to Veillonella parvula bacteria useful as therapeutic agents, e.g, for the treatment of atopic dermatitis, psoriasis, psoriatic arthritis, and/or asthma.

Description

COMPOSITIONS AND METHODS OF TREATMENT USING VEILLONELLA PARVULA

RELATED APPLICATIONS

This application claims the benefit of priority to U.S. Provisional Patent Applications having serial numbers 62/959,454, filed January 10, 2020; 63/021,892, filed May 8, 2020; 63/071,688, filed August 28, 2020; 63/110,603, filed November 6, 2020; and 63/112,310, filed November 11, 2020, the entire contents of each of which are hereby incorporated by reference in their entirety.

SUMMARY

In certain aspects, provided herein are bacterial compositions ( e.g ., pharmaceutical compositions) comprising Veillonella parvula 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 Veillonella parvula useful for the treatment and/or prevention of an immune disorder.

In certain aspects, provided herein are bacterial compositions (e.g, pharmaceutical compositions) comprising Veillonella parvula useful for the treatment and/or prevention of psoriasis (e.g, moderate psoriasis), psoriatic arthritis, and/or atopic dermatitis (e.g, moderate atopic dermatitis) and/or asthma (e.g., mild asthma) (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 treatment of psoriatic arthritis, for the treatment of atopic dermatitis, and/or for the treatment of asthma). In some embodiments, the bacterial compositions comprise whole Veillonella parvula bacteria. In some embodiments, the Veillonella parvula bacteria are gamma irradiated.

In some embodiments, the Veillonella parvula is Veillonella parvula strain A (ATCC Deposit Number PTA-125691). In some embodiments, the Veillonella parvula strain is a strain comprising 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 Veillonella parvula strain A.

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 Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises one strain of bacteria, wherein the one strain of bacteria is the Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 3 x 10¹⁰ total cells of Veillonella parvula , e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 4.5 x 10¹⁰ total cells of Veillonella parvula , e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 1.5 x 10¹¹ total cells of Veillonella parvula , e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 7.5 x 10¹¹ total cells of Veillonella parvula , e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 1.5 x 10¹² total cells of Veillonella parvula , e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 3 x 10¹⁰to about 1.5 x 10¹² total cells of Veillonella parvula , e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 4.5 x 10¹⁰to about 1.5 x 10¹² total cells of Veillonella parvula , e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 3 x 10¹⁰to about 1.5 x 10¹¹ total cells of Veillonella parvula , e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA-125691). In some embodiments, the bacterial composition comprises about 4.5 x 10¹⁰to about 1.5 x 10¹¹ total cells of Veillonella parvula , e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 1.5 x 10^uto about 1.5 x 10¹² total cells of Veillonella parvula , e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 1.5 x 10^uto about 7.5 x 10¹¹ total cells of Veillonella parvula , e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 7.5 x 10^uto about 1.5 x 10¹² total cells of Veillonella parvula, e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In certain embodiments, the bacterial composition (e.g, pharmaceutical composition) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x 10¹⁰ total cells, about 2 x 10¹⁰ total cells, about 3 x 10¹⁰ total cells, about 4 x 10¹⁰ total cells, about 4.5 x 10¹⁰ total cells, about 5 x 10¹⁰ total cells, about 6 x 10¹⁰ total cells, about 7 x 10¹⁰ total cells, about 8 x 10¹⁰ total cells, about 9 x 10¹⁰ total cells, about 1 x 10¹¹ total cells, about 1.5 x 10¹¹ total cells, about 2 x 10¹¹ total cells, about 3 x 10¹¹ total cells, about 4 x 10¹¹ total cells, about 5 x 10¹¹ total cells, about 6 x 10¹¹ total cells, about 7 x 10¹¹ total cells, about 7.5 x 10¹¹ total cells, about 8 x 10¹¹ total cells, about 9 x 10¹¹ total cells, about 1 x 10¹² total cells, about 1.5 x 10¹² total cells, about 2 x 10¹² total cells of the Veillonella parvula bacteria. In certain embodiments, the bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises at least 1 x 10¹⁰ total cells (e.g, at least 1 x 10¹⁰ total cells, at least 2 x 10¹⁰ total cells, at least 3 x 10¹⁰ total cells, at least 4 x 10¹⁰ total cells, at least 4.5 x 10¹⁰ total cells, at least 5 x 10¹⁰ total cells, at least 6 x 10¹⁰ total cells, at least 7 x 10¹⁰ total cells, at least 8 x 10¹⁰ total cells, at least 9 x 10¹⁰ total cells, at least 1 x 10¹¹ total cells, at least 1.5 x 10¹¹ total cells, at least 2 x 10¹¹ total cells, at least 3 x 10¹¹ total cells, at least 4 x 10¹¹ total cells, at least 5 x 10¹¹ total cells, at least 6 x 10¹¹ total cells, at least 7 x 10¹¹ total cells, at least 7.5 x 10¹¹ total cells, at least 8 x 10¹¹ total cells, at least 9 x 10¹¹ total cells, at least 1 x 10¹² total cells, at least 1.5 x 10¹² total cells, at least 2 x 10¹² total cells) of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 7.5 x 10¹¹ total cells the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 1.5 x 10¹² total cells the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 3 x 10¹⁰to about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 4.5 x 10¹⁰to about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 3 x 10¹⁰to about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 4.5 x 10¹⁰to about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 1.5 x 10^uto about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 1.5 x 10^uto about 7.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 7.5 x 10^uto about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the Veillonella parvula bacteria are gamma irradiated.

In certain embodiments, provided herein are solid dosage forms comprising the Veillonella parvula bacteria. In some embodiments, the solid dosage form comprises an enteric coating. In some embodiments, the solid dosage form is a capsule, e.g., an enteric coated capsule. In some embodiments, each capsule comprises about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria. In some embodiments, each capsule comprises about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria. In some embodiments, each capsule comprises about 1.5 x 10¹¹ total cells of the Veillonella parvula 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 x 10¹⁰ total cells) is administered, e.g., once or twice daily to a subject. In some embodiments, 2 capsules (e.g., each comprising about 3 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 4 capsules (e.g., each comprising about 3 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 10 capsules (e.g., each comprising about 3 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 1 capsule (e.g., comprising about 4.5 x 10¹⁰ total cells) is administered, e.g., once or twice daily to a subject. In some embodiments, 2 capsules (e.g., each comprising about 4.5 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 4 capsules (e.g., each comprising about 4.5 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 10 capsules (e.g., each comprising about 4.5 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 1 capsule (e.g., comprising about 1.5 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 1.5 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 1.5 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 1.5 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, the Veillonella parvula bacteria in the capsule are lyophilized (e.g., in a powder). In some embodiments, the Veillonella parvula bacteria in the capsule are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide. In some embodiments, the capsule comprises excipients and the excipients include mannitol, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose, methacrylic acid ethyl acrylate copolymer, triethyl citrate, and/or talc. In some embodiments, the Veillonella parvula bacteria of the capsule are gamma irradiated.

In some embodiments, the solid dosage form comprises a capsule. In some embodiments, the capsule is an enteric coated capsule. In some embodiments, the capsule comprises about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria (e.g., total dose of a capsule or plurality of capsules). In some embodiments, the capsule comprises about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria (e.g., total dose of a capsule or plurality of capsules). In some embodiments, the capsule comprises about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria (e.g., total dose of a capsule or plurality of capsules). In some embodiments, the Veillonella parvula bacteria in the capsule are lyophilized (e.g., in a powder). In some embodiments, the Veillonella parvula bacteria in the capsule are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide. In some embodiments, the capsule comprises excipients and the excipients include mannitol, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose, methacrylic acid ethyl acrylate copolymer, triethyl citrate, and/or talc. In some embodiments, the Veillonella parvula bacteria of the capsule are gamma irradiated.

In some embodiments, the solid dosage form comprises 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 enteric coated tablet is 5.5mm in diameter. In some embodiments, the enteric coated tablet is 18mm in diameter. In some embodiments, the tablet comprises about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria (e.g., total dose of a tablet or plurality of tablets). In some embodiments, the tablet comprises about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria (e.g., total dose of a tablet or plurality of tablets). In some embodiments, the tablet comprises about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria (e.g., total dose of a tablet or plurality of tablets). In some embodiments, the Veillonella parvula bacteria in the tablet are lyophilized. In some embodiments, the Veillonella parvula bacteria of the tablet are gamma irradiated.

In certain embodiments, provided herein are solid dosage forms comprising the Veillonella parvula bacteria. In some embodiments, the solid dosage form is a tablet, e.g., an enteric coated tablet. 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). In some embodiments, each tablet comprises about 3 x 10¹⁰ total cells, about 4.5 x 10¹⁰ total cells or about 1.5 x 10¹¹ total cells of the Veillonella parvula 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 x 10¹⁰ total cells) is administered, e.g., once or twice daily to a subject. In some embodiments, 2 tablets (e.g., each comprising about 3 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 5 tablets (e.g., each comprising about 3 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 10 tablets (e.g., each comprising about 3 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments,

1 tablet (e.g., comprising about 4.5 x 10¹⁰ total cells) is administered, e.g., once or twice daily to a subject. In some embodiments, 2 tablets (e.g., each comprising about 4.5 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 5 tablets (e.g., each comprising about 4.5 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 10 tablets (e.g., each comprising about 4.5 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, each tablet comprises about 1.5 x 10¹¹ total cells of the Veillonella parvula 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 1.5 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 1.5 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 1.5 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 1.5 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, the Veillonella parvula bacteria in the tablet are lyophilized (e.g., in a powder). In some embodiments, the Veillonella parvula bacteria in the tablet are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide. In some embodiments, the Veillonella parvula bacteria of the tablet are gamma irradiated.

In some embodiments, the solid dosage form comprises a mini-tablet. In some embodiments, the mini-tablet is enteric coated. In some embodiments, the mini-tablet is from 1mm to 4mm in diameter. In some embodiments, the mini -tablet (e.g., enteric coated mini-tablet) is a 1mm mini-tablet, 1.5 mm mini-tablet, 2mm mini-tablet, 3mm mini-tablet, or 4mm mini-tablet. In some embodiments, the solid dosage form comprises mini-tablets that comprise about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria (e.g., total dose of a plurality of mini-tablets). In some embodiments, the solid dosage form comprises mini -tablets that comprise about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria (e.g., total dose of a plurality of mini -tablets). In some embodiments, the solid dosage form comprises mini-tablets that comprise about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria (e.g., total dose of a plurality of mini -tablets). In some embodiments, the Veillonella parvula bacteria in the mini-tablets are lyophilized. In some embodiments, the Veillonella parvula bacteria of the mini-tablet are gamma irradiated.

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 a non-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 mini -tablets (e.g, enteric coated mini -tablets) that comprise about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria are contained in a capsule(s), wherein optionally the capsule comprises gelatin or HPMC. In some embodiments, the mini-tablets (e.g, enteric coated mini-tablets) that comprise about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria are contained in a capsule(s), wherein optionally the capsule comprises gelatin or HPMC. In some embodiments, the mini-tablets (e.g, enteric coated mini-tablets) that comprise about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria are contained in a capsule(s), wherein optionally the capsule comprises gelatin or HPMC. In some embodiments, the Veillonella parvula bacteria of the mini-tablet are gamma irradiated.

In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprising Veillonella parvula 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, a pill, 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 Veillonella parvula bacteria are gamma irradiated.

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.

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, 42 days, 45 days, 48 days, 52 days, or 56 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 8 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.

In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises lyophilized Veillonella parvula bacteria. In certain embodiments, the lyophilized Veillonella parvula bacteria is formulated into a solid dose form, such as a tablet, a mini-tablet, a capsule, a pill, or a powder. In some embodiments, the lyophilized Veillonella parvula bacteria is contained in a capsule. In some embodiments, the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide. In some embodiments, the lyophilized Veillonella parvula bacteria is resuspended in a solution.

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 enteric coating allows the bacterial composition to be released in the upper small intestine, e.g, duodenum.

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).

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.

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 Veillonella parvula and/or a composition (e.g, a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Veillonella parvula provided herein.

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.

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 Veillonella parvula and/or a composition (e.g., abacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Veillonella parvula provided herein.

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 abacterial composition described herein.

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 Veillonella parvula and/or a composition (e.g, a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Veillonella parvula provided herein.

In certain embodiments, provided herein are methods of treating a subject who has psoriasis (e.g, moderate psoriasis) comprising administering to the subject a bacterial composition described herein.

In embodiments, provided herein is a method of treating psoriasis comprising administering (e.g, orally administering) to a human subject (e.g., a subject with psoriasis) a strain of a Veillonella parvula and/or a composition (e.g, a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Veillonella parvula provided herein.

In some embodiments, the human subject meets one or more of the inclusion criteria for a psoriasis (e.g., moderate psoriasis) cohort participant (or for all participants) described herein. In some embodiments, the human subject has moderate plaque psoriasis with plaque covering BSA of >3% and <10%, and meets both of the following additional criteria: (a) PASI score of >6 and <15, and (b) PGA score of 2 or 3.

In some embodiments, the human subject does not meet one or more of the exclusion criteria for a psoriasis (e.g., moderate psoriasis) cohort participant (or for all participants) described herein.

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).

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.

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.

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.

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.

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 DLQI score prior to the commencement of treatment), e.g., as described herein.

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.

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 Veillonella parvula and/or a composition (e.g., a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Veillonella parvula provided herein. In some embodiments, the method improves (e.g., increases) the percentage of patients 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.

In some embodiments, the method improves (e.g., increases) the percentage of patients 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.

In some embodiments, the method improves (e.g., increases) the percentage of patients 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.

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.

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.

In some embodiments, the method decreases the Clinical Disease Activity Index (CDAI) scorein the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s CDAI prior to the commencement of treatment), e.g., as described herein.

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.

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.

In certain embodiments, provided herein are methods of treating a subject who has atopic dermatitis (e.g., moderate atopic dermatitis) comprising administering to the subject a bacterial composition described herein. In embodiments, provided herein is a method of treating atopic dermatitis comprising administering ( e.g ., orally administering) to a human subject (e.g., a subject with atopic dermatitis) a strain of a Veillonella parvula and/or a composition (e.g., a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Veillonella parvula.

In some embodiments, the human subject meets one or more of the inclusion criteria for an atopic dermatitis (e.g., moderate atopic dermatitis) cohort participant (or for all participants) described herein. 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 human subject does not meet one or more of the exclusion criteria for an atopic dermatitis (e.g., moderate atopic dermatitis) cohort participant (or for all participants) described herein.

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.

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.

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.

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.

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. 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.

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.

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.

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.

In certain embodiments, provided herein are methods of treating a subject who has asthma (e.g., mild asthma) comprising administering to the subject a bacterial composition described herein.

In embodiments, provided herein is a method of treating asthma comprising administering (e.g, orally administering) to a human subject (e.g., a subject with asthma) a strain of a Veillonella parvula and/or a composition (e.g, a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Veillonella parvula.

In some embodiments, the human subject meets one or more of the inclusion criteria for an asthma (e.g., mild asthma) cohort participant (or for all participants) described herein. In some embodiments, the human subject has FeNO of >40ppb and/or FEV1 >70% of predicted normal.

In some embodiments, the human subject does not meet one or more of the exclusion criteria for an asthma (e.g., mild asthma) cohort participant (or for all participants) described herein.

In some embodiments, the method improves the Fraction of Exhaled Nitric Oxide (FeNO) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s FeNO score prior to the commencement of treatment), e.g., as described herein. In some embodiments, the method improves the number of exacerbations in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s number of exacerbations prior to the commencement of treatment), e.g., as described herein.

In some embodiments, the method improves the use of short-acting beta-agonists (SABA) in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s use of short-acting beta-agonists (SABA) prior to the commencement of treatment), e.g., as described herein.

In some embodiments, the method improves the Forced Expiratory Volume in 1 second (FEV1) in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s Forced Expiratory Volume in 1 second (FEV1) prior to the commencement of treatment), e.g., as described herein.

In some embodiments, the method improves the Forced Vital Capacity (FVC) in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s Forced Vital Capacity (FVC) score prior to the commencement of treatment), e.g., as described herein.

In some embodiments, the method improves the Peak Expiratory Flow (PEF) in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s Peak Expiratory Flow (PEF) prior to the commencement of treatment), e.g., as described herein.

In some embodiments, the method improves the IgE levels in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s IgE levels prior to the commencement of treatment), e.g., as described herein.

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, moderate psoriasis) and/or psoriatic arthritis and/or atopic dermatitis (e.g, moderate atopic dermatitis) and/or asthma (e.g, mild asthma).

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, moderate psoriasis) and/or psoriatic arthritis and/or atopic dermatitis (e.g, moderate atopic dermatitis) and/or asthma (e.g, mild asthma). 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.

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.

DETAILED DESCRIPTION

Veillonella parvula strain A- G.I. is a pharmaceutical preparation of a single strain of Veillonella parvula , originally isolated from a fresh ileostomy sample of an IBD patient in remission, which has been gamma-irradiated. Preclinical studies using Veillonella parvula strain A- G.I. have been carried out across a range of human and mouse in vitro assays as well as key in vivo models of human disease, including delayed type hypersensitivity [DTH], imiquimod-induced skin inflammation, fluorescein isothiocyanate (FITC) cutaneous hypersensitivity, MC903-induced dermatitis, and experimental acute encephalomyelitis (EAE) in-vivo models. It has dose dependent therapeutic effects. Data from the in-vivo models support the use of Veillonella parvula strain A- G.I. in the treatment of Th2-mediated (e.g. atopic dermatitis, asthma) and Thl7- mediated (e.g. psoriasis) immunoinflammatory diseases.

As predicted based on the mechanism of action, no potentially related adverse effects were seen in the animals used in these experiments with daily dosing up to 6 weeks. In addition, while ex vivo immunophenotyping in these models shows decreases in pro-inflammatory cytokines such as IL-6, IL-13, TNFa, 11-17, TSLP and KC (murine IL- 8), Veillonella parvula strain A- G.I. does not suppress the expression of interferon gamma (IFNy) in these experiments, suggesting that the broad spectrum of anti inflammatory effects is achieved without damaging mechanisms of immune surveillance critical for the prevention of malignancy and response to pathogens such as viral or bacterial infections. Definitions

“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.

“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.

As used herein, the term “antibody” may refer to both an intact antibody and an antigen binding fragment thereof. Intact antibodies are glycoproteins that include at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds. Each heavy chain includes a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. Each light chain includes a light chain variable region (abbreviated herein as VL) and a light chain constant region. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR). Each VH and VL is composed of three CDRs and four FRs, arranged from amino-terminus to carboxy -terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. The term “antibody” includes, for example, monoclonal antibodies, polyclonal antibodies, chimeric antibodies, humanized antibodies, human antibodies, multispecific antibodies ( e.g ., bispecific antibodies), single chain antibodies and antigen-binding antibody fragments.

The terms “antigen binding fragment” and “antigen-binding portion” of an antibody, as used herein, refers to one or more fragments of an antibody that retain the ability to bind to an antigen. Examples of binding fragments encompassed within the term "antigen-binding fragment" of an antibody include Fab, Fab', F(ab')2, Fv, scFv, disulfide linked Fv, Fd, diabodies, single-chain antibodies, NANOBODIES®, isolated CDRH3, and other antibody fragments that retain at least a portion of the variable region of an intact antibody. These antibody fragments can be obtained using conventional recombinant and/or enzymatic techniques and can be screened for antigen binding in the same manner as intact antibodies.

“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.

“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 ³97% 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 Lond B Biol Sci 361 : 1929- 1940.). In embodiments involving the complete genome, MLSTs, specific genes, or sets of genes OTUs that share ³95% 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 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. Such characterization employs, e.g, WGS data or a whole genome sequence.

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 co-localization of the monoclonal microbial strains.

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)).

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. 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.

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.

“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, T, et al., Nucleic Acids Research 12(I):387 (1984)), BLASTP, BLASTN, FASTA Atschul, S. F., etal. , 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.)).

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).

“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. 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^L3 fold, 10^L4 fold, 10^L5 fold, 10^L6 fold, and/or 10^L7 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).

“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, TLRIO 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).

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.

“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.

“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.

“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.

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.

“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.

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 wild-type 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.

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.

“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.

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.

“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.

As used herein, “specific binding” refers to the ability of an antibody to bind to a predetermined antigen or the ability of a polypeptide to bind to its predetermined binding partner. Typically, an antibody or polypeptide specifically binds to its predetermined antigen or binding partner with an affinity corresponding to a KD of about 10⁷ M or less, and binds to the predetermined antigen/binding partner with an affinity (as expressed by KD) that is at least 10 fold less, at least 100 fold less or at least 1000 fold less than its affinity for binding to a non-specific and unrelated antigen/binding partner (e.g, BSA, casein). Alternatively, specific binding applies more broadly to a two component system where one component is a protein, lipid, or carbohydrate or combination thereof and engages with the second component which is a protein, lipid, carbohydrate or combination thereof in a specific way.

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. The subject or patient may be healthy, or may be suffering from an immune disorder at any developmental stage.

“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.

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 alia 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

In certain aspects, provided herein are bacterial compositions (e.g, pharmaceutical compositions) comprising Veillonella parvula useful for the treatment and/or prevention of psoriasis (e.g, moderate psoriasis) and/or psoriatic arthritis, and/or atopic dermatitis (e.g, moderate atopic dermatitis) and/or asthma (e.g., mild asthma) and methods of using such bacterial compositions (e.g, for the treatment of psoriasis, for the treatment of psoriatic arthritis, for the treatment of atopic dermatitis, for the treatment of asthma), e.g., in a subject, e.g., in a human subject. In some embodiments, the bacterial compositions comprise whole Veillonella parvula bacteria (e.g, live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the Veillonella parvula bacteria are gamma irradiated. In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises only one strain of bacteria, e.g., Veillonella parvula.

In some embodiments, the bacteria is a strain comprising 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, 16S or CRISPR nucleotide sequence) of Veillonella parvula bacteria strain A (ATCC Deposit Number PTA-125691).

Under the terms of the Budapest Treaty on the International Recognition of the Deposit of Microorganisms for the Purpose of Patent Procedure, the Veillonella parvula strain A was deposited on January 25, 2019, with the American Type Culture Collection (ATCC) of 10801 University Boulevard, Manassas, Va. 20110-2209 USA and was assigned ATCC Accession Number PTA-125691.

Applicant represents that the ATCC is a depository affording permanence of the deposit and ready accessibility thereto by the public if a patent is granted. All restrictions on the availability to the public of the material so deposited will be irrevocably removed upon the granting of a patent. The material will be available during the pendency of the patent application to one determined by the Commissioner to be entitled thereto under 37 CFR 1.14 and 35 U.S.C. 122. The deposited material will be maintained with all the care necessary to keep it viable and uncontaminated for a period of at least five years after the most recent request for the furnishing of a sample of the deposited plasmid, and in any case, for a period of at least thirty (30) years after the date of deposit or for the enforceable life of the patent, whichever period is longer. Applicant acknowledges its duty to replace the deposit should the depository be unable to furnish a sample when requested due to the condition of the deposit.

In some embodiments, the Veillonella parvula is Veillonella parvula strain A (ATCC Deposit Number PTA-125691) (also referred to as “ Veillonella parvula strain A”). In some embodiments, the Veillonella parvula strain is a strain comprising 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 Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacteria described herein are modified to improve colonization and/or engraftment in the mammalian gastrointestinal tract (e.g, modified metabolism, such as improved mucin degradation, enhanced competition profile, increased motility, increased adhesion to gut epithelial cells, modified chemotaxis). In some embodiments, the bacteria described herein are modified to enhance their immunomodulatory and/or therapeutic effect ( e.g ., either alone or in combination with another therapeutic agent). In some embodiments, the bacteria described herein are modified to enhance immune activation (e.g., through modified production of polysaccharides, pili, fimbriae, adhesins, vesicles). In some embodiments, the bacteria described herein are modified to improve bacterial manufacturing (e.g, higher oxygen tolerance, improved freeze-thaw tolerance, shorter generation times).

Veillonella parvula strain A can be cultured according to methods known in the art. For example, Veillonella parvula strain A can be grown under anaerobic conditions in PM1 l+5g/L Na-L-lactate liquid medium supplemented with 0.05g/L FeSCri, and 0.5 g/L L-cysteine-HCL as reducing agent at 37 degrees C.

In some embodiments, the bacterial compositions comprise whole Veillonella parvula bacteria (e.g, live bacteria, killed bacteria, attenuated bacteria).

In some embodiments, the bacterial compositions comprise gamma irradiated Veillonella parvula bacteria.

In certain embodiments, the bacterial composition (e.g, pharmaceutical composition) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x 10¹⁰ total cells, about 2 x 10¹⁰ total cells, about 3 x 10¹⁰ total cells, about 4 x 10¹⁰ total cells, about 4.5 x 10¹⁰ total cells, about 5 x 10¹⁰ total cells, about 6 x 10¹⁰ total cells, about 7 x 10¹⁰ total cells, about 8 x 10¹⁰ total cells, about 9 x 10¹⁰ total cells, about 1 x 10¹¹ total cells, about 1.5 x 10¹¹ total cells, about 2 x 10¹¹ total cells, about 3 x 10¹¹ total cells, about 4 x 10¹¹ total cells, about 5 x 10¹¹ total cells, about 6 x 10¹¹ total cells, about 7 x 10¹¹ total cells, about 7.5 x 10¹¹ total cells, about 8 x 10¹¹ total cells, about 9 x 10¹¹ total cells, about 1 x 10¹² total cells, about 1.5 x 10¹² total cells, about 2 x 10¹² total cells of the Veillonella parvula bacteria.

In certain embodiments, the bacterial composition (e.g, pharmaceutical composition) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises at least 1 x 10¹⁰ total cells (e.g, at least 1 x 10¹⁰ total cells, at least 2 x 10¹⁰ total cells, at least 3 x 10¹⁰ total cells, at least 4 x 10¹⁰ total cells, at least 4.5 x 10¹⁰ total cells, at least 5 x 10¹⁰ total cells, at least 6 x 10¹⁰ total cells, at least 7 x 10¹⁰ total cells, at least 8 x 10¹⁰ total cells, at least 9 x 10¹⁰ total cells, at least 1 x 10¹¹ total cells, at least 1.5 x 10¹¹ total cells, at least 2 x 10¹¹ total cells, at least 3 x 10¹¹ total cells, at least 4 x 10¹¹ total cells, at least 5 x 10¹¹ total cells, at least 6 x 10¹¹ total cells, at least 7 x 10¹¹ total cells, at least 7.5 x 10¹¹ total cells, at least 8 x 10¹¹ total cells, at least 9 x 10¹¹ total cells, at least 1 x 10¹² total cells, at least 1.5 x 10¹² total cells, at least 2 x 10¹² total cells) of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 7.5 x 10¹¹ total cells the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 1.5 x 10¹² total cells the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 3 x 10¹⁰to about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 4.5 x 10¹⁰to about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 3 x 10¹⁰to about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 4.5 x 10¹⁰to about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 1.5 x 10^uto about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 1.5 x 10^uto about 7.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition comprises about 7.5 x 10¹¹ to about 1.5 x 10¹² total cells of the Veillonella parvula bacteria.

In some embodiments, the bacterial composition comprises about 3 x 10¹⁰ total cells of Veillonella parvula , e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 1.5 x 10¹¹ total cells of Veillonella parvula , e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA-125691). In some embodiments, the bacterial composition comprises about 7.5 x 10¹¹ total cells of Veillonella parvula , e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 3 x 10¹⁰to about 1.5 x 10¹¹ total cells of Veillonella parvula , e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 4.5 x 10¹⁰to about 1.5 x 10¹¹ total cells of Veillonella parvula , e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 1.5 x 10^uto about 1.5 x 10¹² total cells of Veillonella parvula, e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial composition comprises about 1.5 x 10^uto about 7.5 x 10¹¹ total cells of Veillonella parvula, e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the Veillonella parvula bacteria may be quantified based on total cells, e.g., total cell count (TCC) (e.g., determined by Coulter counter).

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, 42 days, 45 days, 48 days, 52 days, or 56 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 8 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.

In some embodiments, the bacterial composition is formulated as a capsule or a tablet or mini-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 mini-tablet is an enteric coated mini-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.

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

In certain embodiments, the methods provided herein comprise use of bacterial compositions ( e.g ., pharmaceutical compositions) comprising Veil lone Ha par vi_lla bacteria provided herein.

In some embodiments, the bacterial compositions (e.g., pharmaceutical compositions) comprise whole Veillonella parvula bacteria (e.g, live bacteria, killed bacteria, attenuated bacteria). In some embodiments, the Veillonella parvula bacteria is non-viable. In some embodiments, the Veillonella parvula bacteria have been gamma irradiated (e.g, according to a method described herein). In some embodiments, the Veillonella parvula bacteria are live.

In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises only one strain of bacteria, e.g., Veillonella parvula.

In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises more than one strain of bacteria, e.g., Veillonella parvula, and the therapeutic effect caused by the bacterial composition is due to the the presence of the Veillonella parvula bacterial present in the composition.

In some embodiments, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the bacteria in the composition are of the Veillonella parvula strain. 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the bacteria in the composition are of the Veillonella parvula strain. In some embodiments, at least 99% of the bacteria in the bacterial composition are of the Veillonella parvula strain. In some embodiments, the bacteria in the composition are essentially (e.g., about 100%) of the Veillonella parvula strain.

In some embodiments, about 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%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%,

42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,

57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%,

72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,

87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the protein in the bacterial composition is Veillonella parvula strain bacteria protein. In some embodiments, the Veillonella parvula is Veillonella parvula strain A (ATCC Deposit Number PTA-125691). In some embodiments, the Veillonella parvula strain is a strain comprising 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 Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

In some embodiments, the bacterial compositions (e.g, pharmaceutical compositions) comprise whole Veillonella parvula bacteria (e.g, live bacteria, killed bacteria, attenuated bacteria).

In some embodiments, the bacterial compositions (e.g, pharmaceutical compositions) comprise gamma irradiated Veillonella parvula bacteria.

In certain embodiments, the bacterial compositions (e.g, pharmaceutical compositions) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x 10¹⁰ total cells, about 2 x 10¹⁰ total cells, about 3 x 10¹⁰ total cells, about 4 x 10¹⁰ total cells, about 4.5 x 10¹⁰ total cells, about 5 x 10¹⁰ total cells, about 6 x 10¹⁰ total cells, about 7 x 10¹⁰ total cells, about 8 x 10¹⁰ total cells, about 9 x 10¹⁰ total cells, about 1 x 10¹¹ total cells, about 1.5 x 10¹¹ total cells, about 2 x 10¹¹ total cells, about 3 x 10¹¹ total cells, about 4 x 10¹¹ total cells, about 5 x 10¹¹ total cells, about 6 x 10¹¹ total cells, about 7 x 10¹¹ total cells, about 7.5 x 10¹¹ total cells, about 8 x 10¹¹ total cells, about 9 x 10¹¹ total cells, about 1 x 10¹² total cells, about 1.5 x 10¹² total cells, about 2 x 10¹² total cells of the Veillonella parvula bacteria.

In certain embodiments, the bacterial composition (e.g, pharmaceutical composition) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises at least 1 x 10¹⁰ total cells (e.g, at least 1 x 10¹⁰ total cells, at least 2 x 10¹⁰ total cells, at least 3 x 10¹⁰ total cells, at least 4 x 10¹⁰ total cells, at least 4.5 x 10¹⁰ total cells, at least 5 x 10¹⁰ total cells, at least 6 x 10¹⁰ total cells, at least 7 x 10¹⁰ total cells, at least 8 x 10¹⁰ total cells, at least 9 x 10¹⁰ total cells, at least 1 x 10¹¹ total cells, at least 1.5 x 10¹¹ total cells, at least 2 x 10¹¹ total cells, at least 3 x 10¹¹ total cells, at least 4 x 10¹¹ total cells, at least 5 x 10¹¹ total cells, at least 6 x 10¹¹ total cells, at least 7 x 10¹¹ total cells, at least 7.5 x 10¹¹ total cells, at least 8 x 10¹¹ total cells, at least 9 x 10¹¹ total cells, at least 1 x 10¹² total cells, at least 1.5 x 10¹² total cells, at least 2 x 10¹² total cells) of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises about 7.5 x 10¹¹ total cells the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises about 1.5 x 10¹² total cells the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises about 3 x 10¹⁰to about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 4.5 x 10¹⁰to about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises about 3 x 10¹⁰to about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises about 4.5 x 10¹⁰to about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises about 1.5 x 10^uto about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises about 1.5 x 10^uto about 7.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g, pharmaceutical composition) comprises about 7.5 x 10^uto about 1.5 x 10¹² total cells of the Veillonella parvula bacteria.

In some embodiments, the Veillonella parvula bacteria are quantified based on total cells, e.g., total cell count (TCC) (e.g., determined by Coulter counter).

In some embodiments, the bacterial composition (e.g, pharmaceutical 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.

In some embodiments, the bacterial composition ( e.g ., pharmaceutical 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, 42 days, 45 days, 48 days, 52 days, or 56 days.

In some embodiments, the bacterial composition (e.g., pharmaceutical 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 (e.g, pharmaceutical composition) is administered once daily for 8 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.

In some embodiments, the bacterial composition (e.g, pharmaceutical composition) is formulated as a capsule or a tablet or mini-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 enteric coating allows release of the bacterial composition in the small intestine, e.g, in the upper small intestine, e.g, in the duodenum.

In certain embodiments, at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the bacteria in the bacterial composition are Veillonella bacteria (e.g, Veillonella parvula bacteria strain A (ATCC Deposit Number PTA-125691)). In certain embodiments, substantially all of the bacteria in the bacterial composition are Veillonella bacteria (e.g., Veillonella parvula bacteria strain A (ATCC Deposit Number PTA-125691)). In certain embodiments, the bacterial composition comprises at least 1 x 10³ colony forming units (CFUs), 1 x 10⁴ colony forming units (CFUs), 1 x 10⁵ colony forming units (CFUs), 5 x 10⁵ colony forming units (CFUs), 1 x 10⁶ colony forming units (CFUs), 2 x 10⁶ colony forming units (CFUs), 3 x

10⁶ colony forming units (CFUs), 4 x 10⁶ colony forming units (CFUs), 5 x 10⁶ colony forming units (CFUs), 6 x 10⁶ colony forming units (CFUs), 7 x 10⁶ colony forming units (CFUs), 8 x 10⁶ colony forming units (CFUs), 9 x 10⁶ colony forming units (CFUs), 1 x

10⁷ colony forming units (CFUs), 2 x 10⁷ colony forming units (CFUs), 3 x 10⁷ colony forming units (CFUs), 4 x 10⁷ colony forming units (CFUs), 5 x 10⁷ colony forming units (CFUs), 6 x 10⁷ colony forming units (CFUs), 7 x 10⁷ colony forming units (CFUs), 8 x

10⁷ colony forming units (CFUs), 9 x 10⁷ colony forming units (CFUs), 1 x 10⁸ colony forming units (CFUs), 2 x 10⁸ colony forming units (CFUs), 3 x 10⁸ colony forming units (CFUs), 4 x 10⁸ colony forming units (CFUs), 5 x 10⁸ colony forming units (CFUs), 6 x

10⁸ colony forming units (CFUs), 7 x 10⁸ colony forming units (CFUs), 8 x 10⁸ colony forming units (CFUs), 9 x 10⁸ colony forming units (CFUs), 1 x 10⁹ colony forming units (CFUs), 5 x 10⁹ colony forming units (CFUs), 1 x 10¹⁰ colony forming units (CFUs) 5 x 10¹⁰ colony forming units (CFUs), 1 x 10¹¹ colony forming units (CFUs) 5 x 10¹¹ colony forming units (CFUs), 1 x 10¹² colony forming units (CFUs) 5 x 10¹² colony forming units (CFUs), 1 x 10¹³ colony forming units (CFUs) of Veillonella bacteria (e.g, Veillonella parvula bacteria strain A (ATCC Deposit Number PTA-125691)).

In some embodiments, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the bacteria in the composition are selected from among the bacterial species described herein. 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the bacteria in the composition are selected from among the bacterial strains described herein.

In some embodiments, the bacterial composition comprises a killed bacterium, a live bacterium and/or an attenuated bacterium. Bacteria may be heat-killed by pasteurization, sterilization, high temperature treatment, spray cooking and/or spray drying (heat treatments can be performed at 50°C, 65°C, 85°C or a variety of other temperatures and/or a varied amount of time). Bacteria may also be killed or inactivated using g-irradiation (gamma irradiation), exposure to UV light, formalin-inactivation, and/or freezing methods, or a combination thereof. For example, the bacteria may be exposed to 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 35, 40, or 50kGy of radiation prior to administration. In some embodiments, bacteria (e.g., Veillonella parvula bacteria strain A (ATCC Deposit Number PTA-125691)) are killed using gamma irradiation. In some embodiments, the bacteria are killed or inactivated using electron irradiation (e.g., beta radiation) or x-ray irradiation.

Bacteria may be grown to various growth phases and tested for efficacy at different dilutions and at different points during the growth phase. For example, bacteria may be tested for efficacy following administration at stationary phase (including early or late stationary phase), or at various timepoints during exponential phase. In addition to inactivation by various methods, bacteria may be tested for efficacy using different ratios of live versus inactivated cells, or different ratios of cells at various growth phases.

In some embodiments, to quantify the numbers of Veillonella parvula bacteria present in a bacterial sample, electron microscopy (e.g, EM of ultrathin frozen sections) can be used to visualize the bacteria and count their relative numbers. Alternatively, combinations of nanoparticle tracking analysis (NT A), Coulter counting, and dynamic light scattering (DLS) or a combination of these techniques can be used. NTA and the Coulter counter count particles and show their sizes. DLS gives the size distribution of particles, but not the concentration. Bacteria frequently have diameters of 1-2 um. The full range is 0.2-20 um. Combined results from Coulter counting and NTA can reveal the numbers of bacteria in a given sample. Coulter counting reveals the numbers of particles with diameters of 0.7-10 um. NTA reveals the numbers of particles with diameters of 50- 1400 nm. For most bacterial samples, the Coulter counter alone can reveal the number of bacteria in a sample.

In some embodiments, the bacterial composition (e.g, pharmaceutical 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 (e.g, pharmaceutical 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. In some embodiments, 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%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the particles in the pharmaceutical composition are Veillonella bacteria.

In some embodiments, no more than 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%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the particles in the pharmaceutical composition are Veillonella bacteria.

In some embodiments, about 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%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the particles in the pharmaceutical composition are Veillonella bacteria.

In some embodiments, 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%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the protein in the pharmaceutical composition is Veillonella bacteria protein. In some embodiments, no more than 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%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the protein in the pharmaceutical composition is Veillonella bacteria protein.

In some embodiments, about 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%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the protein in the pharmaceutical composition is Veillonella bacteria protein.

In some embodiments, 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%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the lipids in the pharmaceutical composition are Veillonella bacteria lipids.

In some embodiments, no more than 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%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the lipids in the pharmaceutical composition are Veillonella bacteria lipids. In some embodiments, about 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%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%,

42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%,

57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%,

72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%,

87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% of the lipids in the pharmaceutical composition are Veillonella bacteria lipids.

As described in detail below, the pharmaceutical compositions disclosed herein may be specially formulated for administration in solid or liquid form, including those adapted for oral or rectal administration.

In some embodiments, the composition described herein may be a pharmaceutical composition, a dietary supplement, or a food product ( e.g ., a food or beverage). In some embodiments, the food product is an animal feed.

In certain embodiments, the pharmaceutical composition for oral administration described herein comprises an additional component that enables efficient delivery of the bacteria to the colon. In some embodiments, pharmaceutical preparation that enables the delivery of the bacteria to the colon can be used. Examples of such formulations include pH sensitive compositions, such as buffered sachet formulations or enteric polymers that release their contents when the pH becomes alkaline after the enteric polymers pass through the stomach. When a pH sensitive composition is used for formulating the pharmaceutical preparation, the pH sensitive composition can be a polymer whose pH threshold of the decomposition of the composition is between about 6.8 and about 7.5.

Another embodiment of a pharmaceutical composition useful for delivery of the bacteria to the colon is one that ensures the delivery to the colon by delaying the release of the bacteria by approximately 3 to 5 hours, which corresponds to the small intestinal transit time. In some embodiments, the pharmaceutical composition for delayed release includes a hydrogel shell. The hydrogel is hydrated and swells upon contact with gastrointestinal fluid, with the result that the contents are effectively released (released predominantly in the colon). Delayed release dosage units include bacteria-containing compositions having a material which coats or selectively coats the bacteria. Examples of such a selective coating material include in vivo degradable polymers, gradually hydrolyzable polymers, gradually water-soluble polymers, and/or enzyme degradable polymers. A wide variety of coating materials for efficiently delaying the release is available and includes, for example, cellulose-based polymers such as hydroxypropyl cellulose, acrylic acid polymers and copolymers such as methacrylic acid polymers and copolymers, and vinyl polymers and copolymers such as polyvinylpyrrolidone.

Examples of composition enabling the delivery to the colon further include bioadhesive compositions which specifically adhere to the colonic mucosal membrane (for example, a polymer described in the specification of U.S. Pat. No. 6,368,586, hereby incorporated by reference) and compositions into which a protease inhibitor is incorporated for protecting particularly a biopharmaceutical preparation in the gastrointestinal tracts from decomposition due to an activity of a protease.

An example of a system enabling the delivery to the colon is a system of delivering a composition to the colon by pressure change in such a way that the contents are released by utilizing pressure change caused by generation of gas in bacterial fermentation at a distal portion of the stomach. Such a system is not particularly limited, and a more specific example thereof is a capsule which has contents dispersed in a suppository base and which is coated with a hydrophobic polymer (for example, ethyl cellulose).

Another example of the system enabling the delivery to the colon is a system of delivering a composition to the colon, the system being specifically decomposed by an enzyme (for example, a carbohydrate hydrolase or a carbohydrate reductase) present in the colon. Such a system is not particularly limited, and more specific examples thereof include systems which use food components such as non-starch polysaccharides, amylose, xanthan gum, and azopolymers.

In some embodiments, probiotic formulations containing abacterial strain ( e.g ., Veillonella parvula bacteria strain A (ATCC Deposit Number PTA-125691)) are provided as encapsulated, enteric coated, or powder forms, with doses ranging up to 10¹¹ cfu (e.g., up to 10¹⁰ cfu). In some embodiments, the composition comprises 5 x 10¹¹ cfu of a bacterial strain (e.g, Veillonella parvula bacteria strain A (ATCC Deposit Number PTA-125691)) and 10% (w/w) corn starch in a capsule. The capsule is enteric coated for duodenal release at pH 5.5 In some embodiments, the capsule is enteric coated for duodenal release at pH 5.5. In some embodiments, the composition comprises a powder of freeze-dried bacteria of a bacterial strain (e.g, Veillonella parvula bacteria strain A (ATCC Deposit Number PTA-125691)) which is deemed “Qualified Presumption of Safety” (QPS) status. In some embodiments, the composition is stable at frozen or refrigerated temperature.

Methods for producing microbial compositions may include three main processing steps. The steps are: organism banking, organism production, and preservation. In certain embodiments, a sample that contains an abundance of the bacterial strain (e.g., (e.g, Veillonella parvula bacteria strain A (ATCC Deposit Number PTA-125691)) may be cultured by avoiding an isolation step.

For banking, the strains included in the microbial composition may be (1) isolated directly from a specimen or taken from a banked stock, (2) optionally cultured on a nutrient agar or broth that supports growth to generate viable biomass, and (3) the biomass optionally preserved in multiple aliquots in long-term storage.

In embodiments using a culturing step, the agar or broth may contain nutrients that provide essential elements and specific factors that enable growth. An example would be a medium composed of 20 g/L glucose, 10 g/L yeast extract, 10 g/L soy peptone, 2 g/L citric acid, 1.5 g/L sodium phosphate monobasic, 100 mg/L ferric ammonium citrate, 80 mg/L magnesium sulfate, 10 mg/L hemin chloride, 2 mg/L calcium chloride, 1 mg/L menadione. Another example would be a medium composed of 10 g/L beef extract, 10 g/L peptone, 5 g/L sodium chloride, 5 g/L dextrose, 3 g/L yeast extract, 3 g/L sodium acetate, 1 g/L soluble starch, and 0.5 g/L L-cysteine HC1, at pH 6.8. A variety of microbiological media and variations are well known in the art (e.g, R.M. Atlas, Handbook of Microbiological Media (2010) CRC Press). Culture media can be added to the culture at the start, may be added during the culture, or may be intermittently/continuously flowed through the culture. The strains in the bacterial composition may be cultivated alone, as a subset of the microbial composition, or as an entire collection comprising the microbial composition. As an example, a first strain may be cultivated together with a second strain in a mixed continuous culture, at a dilution rate lower than the maximum growth rate of either cell to prevent the culture from washing out of the cultivation.

The inoculated culture is incubated under favorable conditions for a time sufficient to build biomass. For microbial compositions for human use this is often at 37°C temperature, pH, and other parameter with values similar to the normal human niche. The environment may be actively controlled, passively controlled (e.g, via buffers), or allowed to drift. For example, for anaerobic bacterial compositions, an anoxic/reducing environment may be employed. This can be accomplished by addition of reducing agents such as cysteine to the broth, and/or stripping it of oxygen. As an example, a culture of a bacterial composition may be grown at 37°C, pH 7, in the medium above, pre-reduced with 1 g/L cysteine-HCl.

When the culture has generated sufficient biomass, it may be preserved for banking. The organisms may be placed into a chemical milieu that protects from freezing (adding ‘cryoprotectants’), drying (Tyoprotectants’), and/or osmotic shock (‘osmoprotectants’), dispensing into multiple (optionally identical) containers to create a uniform bank, and then treating the culture for preservation. Containers are generally impermeable and have closures that assure isolation from the environment. Cryopreservation treatment is accomplished by freezing a liquid at ultra-low temperatures ( e.g ., at or below -80°C). Dried preservation removes water from the culture by evaporation (in the case of spray drying or ‘cool drying’) or by sublimation (e.g., for freeze drying, spray freeze drying). Removal of water improves long-term microbial composition storage stability at temperatures elevated above cryogenic conditions. If the microbial composition comprises, for example, spore forming species and results in the production of spores, the final composition may be purified by additional means such as density gradient centrifugation. Microbial composition banking may be done by culturing and preserving the strains individually, or by mixing the strains together to create a combined bank. As an example of cryopreservation, a microbial composition culture may be harvested by centrifugation to pellet the cells from the culture medium, the supernatant decanted and replaced with fresh culture broth containing 15% glycerol. The culture can then be aliquoted into 1 mL cryotubes, sealed, and placed at -80°C for long-term viability retention. This procedure achieves acceptable viability upon recovery from frozen storage.

Microbial production may be conducted using similar culture steps to banking, including medium composition and culture conditions described above. It may be conducted at larger scales of operation, especially for clinical development or commercial production. At larger scales, there may be several subcultivations of the microbial composition prior to the final cultivation. At the end of cultivation, the culture is harvested to enable further formulation into a dosage form for administration. This can involve concentration, removal of undesirable medium components, and/or introduction into a chemical milieu that preserves the microbial composition and renders it acceptable for administration via the chosen route. For example, a microbial composition may be cultivated to a concentration of 10¹⁰ CFU/mL, then concentrated 20-fold by tangential flow microfiltration; the spent medium may be exchanged by diafiltering with a preservative medium consisting of 2% gelatin, 100 mM trehalose, and 10 mM sodium phosphate buffer. The suspension can then be freeze-dried to a powder and titrated.

After drying, the powder may be blended to an appropriate potency, and mixed with other cultures and/or a filler such as microcrystalline cellulose for consistency and ease of handling, and the bacterial composition formulated as provided herein.

In certain aspects, provided are bacterial compositions ( e.g ., pharmaceutical 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 are combined with an adjuvant such as an immuno-adjuvant (e.g., STING agonists, TLR agonists, NOD agonists).

In some embodiments, the bacterial composition (e.g, pharmaceutical 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 CnFhnOn. 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, raffmose, 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. In some embodiments, the bacterial composition ( e.g ., pharmaceutical 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) (EPA), 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 bacterial composition (e.g., pharmaceutical composition) comprises at least one modified lipid, for example a lipid that has been modified by cooking.

In some embodiments, the bacterial composition (e.g, pharmaceutical 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.

In some embodiments, the bacterial composition (e.g, pharmaceutical 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.

In some embodiments, the bacterial composition (e.g, pharmaceutical 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.

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.

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.

In some embodiments, the bacterial composition ( e.g ., pharmaceutical composition) comprises a binder as an excipient. Non-limiting 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.

In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises a lubricant as an excipient. Non-limiting 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.

In some embodiments, the bacterial composition (e.g, pharmaceutical 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.

In some embodiments, the bacterial composition (e.g, pharmaceutical 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, micro crystalline 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.

In some embodiments, the bacteraial 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.

In some embodiments, the bacterial 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.

In certain embodiments, the bacteria disclosed herein are administered in conjunction with a prebiotic to the subject. Prebiotics are carbohydrates which are generally indigestible by a host animal and are selectively fermented or metabolized by bacteria. Prebiotics may be short-chain carbohydrates (e.g., oligosaccharides) and/or simple sugars (e.g, mono- and di-saccharides) and/or mucins (heavily glycosylated proteins) that alter the composition or metabolism of a microbiome in the host. The short chain carbohydrates are also referred to as oligosaccharides, and usually contain from 2 or 3 and up to 8, 9, 10, 15 or more sugar moieties. When prebiotics are introduced to a host, the prebiotics affect the bacteria within the host and do not directly affect the host. In certain aspects, a prebiotic composition can selectively stimulate the growth and/or activity of one of a limited number of bacteria in a host. Prebiotics include oligosaccharides such as fructooligosaccharides (FOS) (including inulin), galactooligosaccharides (GOS), trans-galactooligosaccharides, xylooligosaccharides (XOS), chitooligosaccharides (COS), soy oligosaccharides (e.g, stachyose and raffmose) gentiooligosaccharides, isomaltooligosaccharides, mannooligosaccharides, maltooligosaccharides and mannanoligosaccharides. Oligosaccharides are not necessarily single components, and can be mixtures containing oligosaccharides with different degrees of oligomerization, sometimes including the parent disaccharide and the monomeric sugars. Various types of oligosaccharides are found as natural components in many common foods, including fruits, vegetables, milk, and honey. Specific examples of oligosaccharides are lactulose, lactosucrose, palatinose, glycosyl sucrose, guar gum, gum Arabic, tagalose, amylose, amylopectin, pectin, xylan, and cyclodextrins. Prebiotics may also be purified or chemically or enzymatically synthesized.

Dose Forms

Dose forms comprising Veillonella parvula bacteria are also provided herein, e.g., for use in methods to treat or prevent inflammation (such as inflammation associated with atopic dermatitis and/or psoriasis and/or psoriatic arthritis and/or asthma) in a subject (e.g., a human subject). Abacterial composition (e.g., pharmaceutical composition) comprising Veillonella parvula bacteria can be formulated as a solid dose form, e.g. , for oral administration. The solid dose form can comprise one or more excipients, e.g. , pharmaceutically acceptable excipients. The Veillonella parvula bacteria in the solid dose form can be isolated Veillonella parvula bacteria. Optionally, the Veillonella parvula bacteria in the solid dose form can be lyophilized. Optionally, the Veillonella parvula bacteria in the solid dose form are live. Optionally, the Veillonella parvula bacteria in the solid dose form are gamma irradiated. The solid dose 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).

The Veillonella parvula bacteria in the solid dose form can be in a powder (e.g., the powder comprises lyophilized Veillonella parvula 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.

In some embodiments, the lyophilized Veillonella parvula bacteria is resuspended in a solution.

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

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. The capsule can comprise Veillonella parvula bacteria powder (e.g., lyophilized Veillonella parvula 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. In some embodiments, the capsule comprises excipients and the excipients include mannitol, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose, methacrylic acid ethyl acrylate copolymer, triethyl citrate, and/or talc.

In some embodiments, the solid dosage form described herein can be, e.g., a tablet or a mini -tablet. In some embodiments, a plurality of mini -tablets can be in (e.g, loaded into) a capsule.

In some embodiments, the solid dosage form comprises a tablet (> 4mm) (e.g, 5mm- 17mm). For example, the tablet is a 5mm, 5.5mm, 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. As used herein, the size of the tablet refers to the size of the tablet prior to application of an enteric coating.

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.

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, a non-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.

The solid dosage form (e.g, tablet or 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).

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 methacrylic/acrylic 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.

The solid dose form (e.g, a capsule) can comprise HPMC or gelatin.

A bacterial composition (e.g., pharmaceutical composition) comprising Veillonella parvula bacteria can be formulated as a suspension, e.g, for oral administration or for injection. Administration by injection includes intravenous (IV), intramuscular (IM), and subcutaneous (SC) administration. For a suspension, Veillonella parvula bacteria can be in a buffer, e.g, a pharmaceutically acceptable buffer, e.g, saline or PBS. The suspension can comprise one or more excipients, e.g, pharmaceutically acceptable excipients. The suspension can comprise, e.g, sucrose or glucose. The Veillonella parvula bacteria in the suspension can be isolated Veillonella parvula bacteria. Optionally, the Veillonella parvula bacteria in the suspension can be lyophilized. Optionally, the Veillonella parvula bacteria in the solid dose form are live. Optionally, the Veillonella parvula bacteria in the suspension can be gamma irradiated.

Dosage

For oral administration to a human subject, the dose of Veillonella parvula bacteria can be, e.g ., about 3 x 10¹⁰to about 1.5 x 10¹² particles, about 4.5 x 10¹⁰to about

1.5 x 10¹² particles, about 3 x 10¹⁰to about 1.5 x 10¹¹ particles, about 4.5 x 10¹⁰to about

1.5 x 10¹¹ particles, about 1.5 x 10^uto about 1.5 x 10¹² particles, 1.5 x 10^uto about 7.5 x 10¹¹ particles, about 7.5 x 10^uto about 1.5 x 10¹² particles. The dose can be, e.g. , about 1 x 10¹⁰ particles, about 2 x 10¹⁰ particles, about 3 x 10¹⁰ particles, about 4 x 10¹⁰ particles, about 4.5 x 10¹⁰ particles, about 5 x 10¹⁰ particles, about 6 x 10¹⁰ particles, about 7 x 10¹⁰ particles, about 8 x 10¹⁰ particles, about 9 x 10¹⁰ particles, about 1 x 10¹¹ particles, about

1.5 x 10¹¹ particles, about 2 x 10¹¹ particles, about 3 x 10¹¹ particles, about 4 x 10¹¹ particles, about 5 x 10¹¹ particles, about 6 x 10¹¹ particles, about 7 x 10¹¹ particles, about

7.5 x 10¹¹ particles, about 8 x 10¹¹ particles, about 9 x 10¹¹ particles, about 1 x 10¹² particles, about 1.5 x 10¹² particles, about 2 x 10¹² particles. The dose can be, e.g. , about 3xl0¹⁰ particles. The dose can be, e.g. , about 4.5xl0¹⁰ particles. The dose can be, e.g. , about 1.5xl0^u particles. The dose can be, e.g. , about 7.5xl0^u particles. The dose can be, e.g. , about 1.5xl0¹² particles. Particle count can be determined, e.g. , by NTA.

For oral administration to a human subject, the dose of Veillonella parvula bacteria can be, e.g. , about 3 x 10¹⁰to about 1.5 x 10¹² total cells, about 4.5 x 10¹⁰to about

1.5 x 10¹² total cells, about 3 x 10¹⁰to about 1.5 x 10¹¹ total cells, about 4.5 x 10¹⁰to about

1.5 x 10¹¹ total cells, about 1.5 x 10^uto about 1.5 x 10¹² total cells, 1.5 x 10^uto about 7.5 x 10¹¹ total cells, about 7.5 x 10^uto about 1.5 x 10¹² total cells. The dose can be, e.g. , about 1 x 10¹⁰ total cells, about 2 x 10¹⁰ total cells, about 3 x 10¹⁰ total cells, about 4 x 10¹⁰ total cells, about 4.5 x 10¹⁰ total cells, about 5 x 10¹⁰ total cells, about 6 x 10¹⁰ total cells, about 7 x 10¹⁰ total cells, about 8 x 10¹⁰ total cells, about 9 x 10¹⁰ total cells, about 1 x 10¹¹ total cells, about 1.5 x 10¹¹ total cells, about 2 x 10¹¹ total cells, about 3 x 10¹¹ total cells, about 4 x 10¹¹ total cells, about 5 x 10¹¹ total cells, about 6 x 10¹¹ total cells, about 7 x 10¹¹ total cells, about 7.5 x 10¹¹ total cells, about 8 x 10¹¹ total cells, about 9 x 10¹¹ total cells, about 1 x 10¹² total cells, about 1.5 x 10¹² total cells, about 2 x 10¹² total cells of the Veillonella parvula bacteria.

In certain embodiments, the bacterial composition (e.g., pharmaceutical composition) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x 10¹⁰ total cells, about 2 x 10¹⁰ total cells, about 3 x 10¹⁰ total cells, about 4 x 10¹⁰ total cells, about 4.5 x 10¹⁰ total cells, about 5 x 10¹⁰ total cells, about 6 x 10¹⁰ total cells, about 7 x 10¹⁰ total cells, about 8 x 10¹⁰ total cells, about 9 x 10¹⁰ total cells, about 1 x 10¹¹ total cells, about 1.5 x 10¹¹ total cells, about 2 x 10¹¹ total cells, about 3 x 10¹¹ total cells, about 4 x 10¹¹ total cells, about 5 x 10¹¹ total cells, about 6 x 10¹¹ total cells, about 7 x 10¹¹ total cells, about 7.5 x 10¹¹ total cells, about 8 x 10¹¹ total cells, about 9 x 10¹¹ total cells, about 1 x 10¹² total cells, about 1.5 x 10¹² total cells, about 2 x 10¹² total cells of the Veillonella parvula bacteria.

In certain embodiments, the bacterial composition (e.g., pharmaceutical composition) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises at least 1 x 10¹⁰ total cells (e.g., at least 1 x 10¹⁰ total cells, at least 2 x 10¹⁰ total cells, at least 3 x 10¹⁰ total cells, at least 4 x 10¹⁰ total cells, at least 4.5 x 10¹⁰ total cells, at least 5 x 10¹⁰ total cells, at least 6 x 10¹⁰ total cells, at least 7 x 10¹⁰ total cells, at least 8 x 10¹⁰ total cells, at least 9 x 10¹⁰ total cells, at least 1 x 10¹¹ total cells, at least 1.5 x 10¹¹ total cells, at least 2 x 10¹¹ total cells, at least 3 x 10¹¹ total cells, at least 4 x 10¹¹ total cells, at least 5 x 10¹¹ total cells, at least 6 x 10¹¹ total cells, at least 7 x 10¹¹ total cells, at least 7.5 x 10¹¹ total cells, at least 8 x 10¹¹ total cells, at least 9 x 10¹¹ total cells, at least 1 x 10¹² total cells, at least 1.5 x 10¹² total cells, at least 2 x 10¹² total cells) of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 7.5 x 10¹¹ total cells the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 1.5 x 10¹² total cells the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 3 x 10¹⁰to about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 4.5 x 10¹⁰to about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 3 x 10¹⁰to about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 4.5 x 10¹⁰to about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 1.5 x 10^uto about 1.5 x 10¹² total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 1.5 x 10^uto about 7.5 x 10¹¹ total cells of the Veillonella parvula bacteria. In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprises about 7.5 x 10^uto about 1.5 x 10¹² total cells of the Veillonella parvula bacteria.

In certain embodiments, provided herein are solid dosage forms comprising the Veillonella parvula bacteria. In some embodiments, the solid dosage form comprises an enteric coating. In some embodiments, the solid dosage form is a capsule, e.g., an enteric coated capsule. In some embodiments, each capsule comprises about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria. In some embodiments, each capsule comprises about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria. In some embodiments, each capsule comprises about 1.5 x 10¹¹ total cells of the Veillonella parvula 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 x 10¹⁰ total cells) is administered, e.g., once or twice daily to a subject. In some embodiments, 2 capsules (e.g., each comprising about 3 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 4 capsules (e.g., each comprising about 3 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 10 capsules (e.g., each comprising about 3 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 1 capsule (e.g., comprising about 4.5 x 10¹⁰ total cells) is administered, e.g., once or twice daily to a subject. In some embodiments, 2 capsules (e.g., each comprising about 4.5 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 4 capsules (e.g., each comprising about 4.5 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 10 capsules (e.g., each comprising about 4.5 x 10¹⁰ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, 1 capsule (e.g., comprising about 1.5 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 1.5 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 1.5 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 1.5 x 10¹¹ total cells) are administered, e.g., once or twice daily to a subject. In some embodiments, the Veillonella parvula bacteria in the capsule are lyophilized (e.g., in a powder). In some embodiments, the Veillonella parvula bacteria in the capsule are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide. In some embodiments, the Veillonella parvula bacteria of the capsule are gamma irradiated.

In some embodiments, the solid dosage form comprises a capsule. In some embodiments, the capsule is an enteric coated capsule. In some embodiments, the capsule comprises about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria (e.g., total dose of a capsule or plurality of capsules). In some embodiments, the capsule comprises about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria (e.g., total dose of a capsule or plurality of capsules). In some embodiments, the capsule comprises about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria (e.g., total dose of a capsule or plurality of capsules). In some embodiments, the Veillonella parvula bacteria in the capsule are lyophilized (e.g., in a powder). In some embodiments, the Veillonella parvula bacteria in the capsule are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide. In some embodiments, the Veillonella parvula bacteria of the capsule are gamma irradiated.

In some embodiments, the solid dosage form comprises 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 x 10¹⁰ total cells of the Veillonella parvula bacteria (e.g., total dose of a tablet or plurality of tablets). In some embodiments, the tablet comprises about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria (e.g., total dose of a tablet or plurality of tablets). In some embodiments, the tablet comprises about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria (e.g., total dose of a tablet or plurality of tablets). In some embodiments, the Veillonella parvula bacteria in the tablet are lyophilized. In some embodiments, the Veillonella parvula bacteria of the tablet are gamma irradiated.

In some embodiments, the solid dosage form comprises a mini-tablet. In some embodiments, the mini-tablet is enteric coated. In some embodiments, the mini-tablet is from 1mm to 4mm in diameter. In some embodiments, the mini -tablet (e.g., enteric coated mini-tablet) is a 1mm mini-tablet, 1.5 mm mini-tablet, 2mm mini-tablet, 3mm mini-tablet, or 4mm mini-tablet. In some embodiments, the solid dosage form comprises mini-tablets that comprise about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria (e.g., total dose of a plurality of mini-tablets). In some embodiments, the solid dosage form comprises mini -tablets that comprise about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria (e.g., total dose of a plurality of mini -tablets). In some embodiments, the solid dosage form comprises mini-tablets that comprise about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria (e.g., total dose of a plurality of mini -tablets). In some embodiments, the Veillonella parvula bacteria in the mini-tablets are lyophilized. In some embodiments, the Veillonella parvula bacteria in the mini-tablet are gamma irradiated.

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 a non 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 mini -tablets (e.g, enteric coated mini -tablets) that comprise about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria are contained in a capsule(s), wherein optionally the capsule comprises gelatin or HPMC. In some embodiments, the mini tablets (e.g, enteric coated mini -tablets) that comprise about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria are contained in a capsule(s), wherein optionally the capsule comprises gelatin or HPMC. In some embodiments, the mini -tablets (e.g, enteric coated mini-tablets) that comprise about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria are contained in a capsule(s), wherein optionally the capsule comprises gelatin or HPMC. In some embodiments, the Veillonella parvula bacteria of the mini-tablet are gamma irradiated. 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 a non 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 or HPMC. In some embodiments, the mini-tablets (e.g., enteric coated mini -tablets) that comprise about 3 x 10¹⁰ total cells of the Veillonella parvula bacteria are contained in a capsule(s), wherein optionally the capsule comprises gelatin or HPMC. In some embodiments, the mini-tablets (e.g., enteric coated mini-tablets) that comprise about 4.5 x 10¹⁰ total cells of the Veillonella parvula bacteria are contained in a capsule(s), wherein optionally the capsule comprises gelatin or HPMC. In some embodiments, the mini-tablets (e.g., enteric coated mini-tablets) that comprise about 1.5 x 10¹¹ total cells of the Veillonella parvula bacteria are contained in a capsule(s), wherein optionally the capsule comprises gelatin or HPMC.

In some embodiments, the bacterial composition (e.g., pharmaceutical composition) comprising Veillonella parvula 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, a pill, 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 Veillonella parvula bacteria are gamma irradiated.

Gamma-irradiation

Powders (e.g, of Veillonella parvula bacteria) can be gamma-irradiated at 17.5 kGy radiation unit at ambient temperature.

Frozen biomasses (e.g, of Veillonella parvula bacteria) can be gamma-irradiated at 25 kGy radiation unit in the presence of dry ice.

Therapeutic Agents

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. In some embodiments the Veillonella parvula 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 Veillonella parvula 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 Veillonella parvula 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 Veillonella parvula 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 Veillonella parvula 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 Veillonella parvula bacteria and the antibiotic are administered to the subject simultaneously or nearly simultaneously (e.g, administrations occur within an hour of each other).

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, b-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. 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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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

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

Penicillins include, but are not limited to, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, 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.

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

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.

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.

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.

Tetracyclines include, but are not limited to, Demeclocy cline, Doxy cy cline, Minocycline, Oxytetracy cline, 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.

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

Suitable antibiotics also include arsphenamine, chloramphenicol, fosfomycin, fusidic acid, metronidazole, mupirocin, platensimycin, quinupristin/dalfopristin, tigecycline, tinidazole, trimethoprim amoxicillin/clavulanate, ampicillin/sulbactam, amphomycin ristocetin, azithromycin, bacitracin, buforin II, carbomycin, cecropin PI, 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. In some embodiments, the additional therapeutic is an immunosuppressive agent, a DMARD, a pain-control drug, a steroid, a non-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, lornoxicam, 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, auranofm, 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), CERT OLIZUM AB PEGOL (Cimzia®; CDP870), GOLIMUMAB (Simpom®; CNTO 148), ANAKINRA (Kineret®), RITUXIMAB (Rituxan®; MabThera®), ABATACEPT (Orencia®), TOCILIZUMAB (RoActemra /Actemra®), integrin antagonists (TYSABRI® (natalizumab)), IL-1 antagonists (ACZ885 (Ilaris)), 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, Doxy cy cline, vancomycin, pioglitazone, SBI-087, SCIO-469, Cura- 100, Oncoxin + Viusid, TwHF, Methoxsalen, Vitamin D - ergocalciferol, Milnacipran, Paclitaxel, rosig tazone, Tacrolimus (Prograf®), RADOOl, rapamune, rapamycin, fostamatinib, Fentanyl, XOMA 052, Fostamatinib di sodium, rosightazone, Curcumin (Longvida™), Rosuvastatin, Maraviroc, ramipnl, Milnacipran, Cobiprostone, somatropin, tgAAC94 gene therapy vector, MK0359, GW856553, esomeprazole, everolimus, trastuzumab, JAKl and JAK2 inhibitors, pan JAK inhibitors, e.g, tetracyclic pyridone 6 (P6), 325, PF-956980, denosumab, IL-6 antagonists, CD20 antagonistis, 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.).

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.

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, iand combinations thereof.

In some embodiments, the additional therapeutic is cyclosporine.

In some embodiments, the additional therapeutic is dupilumab.

In some embodiments, the additional therapeutic is apremilast.

In some embodiments, the additional therapeutic is etanercept, infliximab, adalimumab, ustekinumab, or secukinumab.

In some embodiments, the additional therapeutic is an inhaled corticosteroid.

In some embodiments, the additional therapeutic is a systemic corticosteroid.

In some embodiments, the additional therapeutic is a monoclonal antibody targeting IL-4, IL4R or IL-5.

Administration

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

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).

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 Veillonella parvula bacteria co formulated 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).

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.

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.

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.

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.

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.

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. 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.

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.

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. 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, heartburn, 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 heart beat, 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

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, moderate psoriasis). In some embodiments, the disease or disorder is psoriatic arthritis. In some embodiments, the disease or disorder is atopic dermatitis (e.g, moderate atopic dermatitis). In some embodiments, the disease or disorder is asthma (e.g, mild asthma).

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, moderate psoriasis) or psoriatic arthritis or atopic dermatitis (e.g, moderate atopic dermatitis) or asthma (e.g, mild asthma)), as well as any subject with an increased likelihood of acquiring a such a disease or disorder.

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); abacterial 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.

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.

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).

Ocular immune disorders refers to a 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.

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.

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.

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.

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.

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).

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 (autroimmine) 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).

In some aspects, bacterial compositions for use in treating psoriasis and/or psoriatic arthritis and/or atopic dermatitis and/or asthma are disclosed. In some aspects, a bacterial composition comprising Veillonella parvula, wherein the Veillonella parvula is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Veillonella parvula strain A (ATCC Deposit Number PTA-125691) for use in treating psoriasis is described herein. In other aspects, a bacterial composition comprising Veillonella parvula, wherein the Veillonella parvula is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Veillonella parvula strain A (ATCC Deposit Number PTA-125691) for use in treating psoriatic arthritis is described herein. In other aspects, a bacterial composition comprising Veillonella parvula, wherein the Veillonella parvula is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Veillonella parvula strain A (ATCC Deposit Number PTA-125691) for use in treating atopic dermatitis is described herein. In other aspects, a bacterial composition comprising Veillonella parvula, wherein the Veillonella parvula is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Veillonella parvula strain A (ATCC Deposit Number PTA-125691) for use in treating asthma is described herein.

In some aspects, uses of a bacterial composition for the preparation of a medicament for treating psoriasis ( e.g ., moderate psoriasis) and/or psoriatic arthritis and/or atopic dermatitis (e.g., moderate atopic dermatitits) and/or asthma are disclosed. In some aspects, use of a bacterial composition for the preparation of a medicament for treating psoriasis wherein the bacterial composition comprises Veillonella parvula , wherein the Veillonella parvula is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Veillonella parvula strain A (ATCC Deposit Number PTA-125691) is described herein. In some aspects, use of a bacterial composition for the preparation of a medicament for treating psoriatic arthritis wherein the bacterial composition comprises Veillonella parvula , wherein the Veillonella parvula is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Veillonella parvula strain A (ATCC Deposit Number PTA-125691) is described herein. In other aspects, use of a bacterial composition for the preparation of a medicament for treating atopic dermatitis wherein the bacterial composition comprises Veillonella parvula , wherein the Veillonella parvula is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Veillonella parvula strain A (ATCC Deposit Number PTA-125691) is described herein. In other aspects, use of a bacterial composition for the preparation of a medicament for treating asthma wherein the bacterial composition comprises Veillonella parvula , wherein the Veillonella parvula is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Veillonella parvula strain A (ATCC Deposit Number PTA-125691) is described herein.

Numerous embodiments are further provided that can be applied to any aspect of the present invention described herein. For example, in some embodiments, the Veillonella parvula is a strain comprising at least 99.9% sequence identity to the nucleotide sequence of the Veillonella parvula strain A (ATCC Deposit Number PTA- 125691). In some embodiments, the Veillonella parvula is the Veillonella parvula strain A (ATCC Deposit Number PTA-125691). In some embodiments, the bacterial composition is administered orally. In some embodiments, the bacterial composition is formulated as a capsule or a tablet. In some embodiments, the capsule is an enteric coated capsule. In some embodiments, the bacterial composition comprises about 3 x 10¹⁰ total cells of Veillonella parvula. In some embodiments, the bacterial composition comprises about 4.5 x 10¹⁰ total cells of Veillonella parvula. In some embodiments, the bacterial composition comprises about 1.5 x 10¹¹ total cells of Veillonella parvula. In some embodiments, the bacterial composition comprises about 7.5 x 10¹¹ total cells of Veillonella parvula. In some embodiments, the bacterial composition comprises about 1.5 x 10¹² total cells of Veillonella parvula. In some embodiments, the bacterial composition comprises from about 3 x 10¹⁰ to about 1.5 x 10¹² total cells of Veillonella parvula. In some embodiments, the bacterial composition comprises from about 4.5 x 10¹⁰ to about 1.5 x 10¹² total cells of Veillonella parvula. In some embodiments, the bacterial composition is administered at least once daily. In some embodiments, the bacterial composition is administered once daily. In some embodiments, the bacterial composition is administered once daily for at least 15 continuous days. In some embodiments, the bacterial composition is administered once daily for at least 28 continuous days. In some embodiments, the bacterial composition is administered once daily for at least 56 continuous days. In some embodiments, the psoriasis is moderate psoriasis. In some embodiments, the atopic dermatitis is moderate atopic dermatitis. In some embodiments, the asthma is mild asthma.

Atopic Dermatitis

In certain embodiments, provided herein are methods of treating a subject who has atopic dermatitis. Atopic dermatitis occurs when the skin is inflamed. It can occur along with allergic rhinitis and asthma. Its symptoms can include, individually or in combination, dry skin, redness, itching, rashes, and sores.

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 atopic dermatitis, is suspected of having atopic dermatitis, or has an increased risk of atopic dermatitis.

Psoriasis

In certain embodiments, provided herein are methods of treating a subject who has psoriasis. 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 psoriasis, is suspected of having psoriasis, or has an increased risk of atopic dermatitispsoriasis. 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).

In some embodiments, the method increases a PASI percentage response rate (e.g., PASI-50, PASI-75, PASI-90, or PASI-100). 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.

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.

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).

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).

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).

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).

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).

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). For example, pain can be assessed by the SF-36 Bodily Pain Scale (SF-36 BPS) or the VAS Pain.

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). EXAMPLES

Example 1: Powder preparation sample protocol

After desired level of bacterial culture growth is achieved, centrifuge cultures, discard the supernatant, leaving the pellet as dry as possible. Resuspend pellet in desired cryoprotectant solution to create a formulated cell paste. The cryoprotectant may contain, e.g., maltodextrin, sodium ascorbate, sodium glutamate, and/or calcium chloride. Load the formulated cell paste onto stainless steel trays and load into a freeze drier, e.g., operating in automated mode with defined cycle parameters. The freeze dried product is fed into a milling machine and the resulting powder is collected. Powders are stored (e.g., in vacuum sealed bags) at 2-8 degrees C (e.g., at 4 degrees C), e.g., in a desiccator.

Example 2: Gamma-irradiation: sample protocol:

Powders are gamma-irradiated at 17.5 kGy radiation unit at ambient temperature. Frozen biomasses are gamma-irradiated at 25 kGy radiation unit in the presence of dry ice.

Example 3: Veillonella yarvula strain A- G.I. Phase la/lb study in healthy participants and participants with moderate atopic dermatitis and optionally moderate psoriasis and/or mild asthma

A Phase la/lb, first in human, participant and investigator-blind sponsor-unblinded randomized placebo-controlled multiple dose study of Veillonella parvula strain A- G.I. in healthy volunteers and participants with moderate atopic dermatitis and, optionally, moderate psoriasis, and/or mild asthma.

ABBREVIATIONS

Abbreviation Definition

AE adverse event

ALT alanine aminotransferase

AST aspartate aminotransferase

BSA body surface area

BMI body mass index Abbreviation Definition

BUN blood urea nitrogen

CFR Code of Federal Regulations

CNS central nervous system

CIOMS council for international organizations of medical sciences

COPD chronic obstructive pulmonary disease

CONSORT consolidated standards of reporting trials

CRP C-reactive protein

CSR clinical study report

CTCAE Common Terminology Criteria for Adverse Events

DLQI Dermatology Life Quality Index

EASI Eczema Area and Severity Index

ECG electrocardiogram eCRF electronic case report form

EDC electronic data capture

Veillonella investigational study drug parvula strain A- G.I.

EOS end of study

FDA US Food and Drug Administration

FSH follicle-stimulating hormone

FVC forced vital capacity

GCP good clinical practice

GI gastrointestinal

GINA Global Initiative for Asthma

HbsAg hepatitis B surface antigen Abbreviation Definition

HBV hepatitis B virus

HCG human chorionic gonadotropin

HCV hepatitis C virus

HIV human immunodeficiency virus

HLA human leukocyte antigen

HRT hormone replacement therapy

IB investigator’ s brochure

IBS Irritable bowel syndrome

ICF informed consent form

ICH International Council for Harmonisation

IEC independent ethics committee

IGA Investigator’s Global Assessment for Atopic Dermatitis

IgE Immunoglobulin E

IL interleukin

IFNy interferon gamma

IRB institutional review board

IUD Intrauterine device

IUS Intrauterine hormone-releasing system

LSS lesion severity score

MCV mean cell volume

MCH mean corpuscular hemoglobin

MedDRA Medical Dictionary for Regulatory Activities

MTX methotrexate

NRS numerical rating scale Abbreviation Definition

OTC over-the-counter

PASI Psoriasis Area and Severity Index

PCR polymerase chain reaction

PGA Physician’s Global Assessment

POEM Patient-Oriented Eczema Measure

PUVB psoralen plus ultraviolet B

QTcF QT interval corrected using Fridericia’s formula

SABA short-acting-beta-agonists

RBC red blood cell

RNA ribonucleic acid

SAE serious adverse event

SAP statistical analysis plan

SCORAD SCORing Atopic Dermatitis

SGOT serum glutamic-oxaloacetic transaminase

SGPT serum glutamic-pyruvic transaminase

SINTAX™ Small intestinal axis

SoA schedule of activities

SRC safety review committee

SUSAR suspected unexpected serious adverse reaction

TEAE treatment-emergent adverse event

TNFa tumor necrosis factor alpha

ULN upper limit of normal

USA United States of America

UVA ultraviolet A Abbreviation Definition

UVB ultraviolet B

VAS visual analog scale

WBC white blood cell

WHO World Health Organization

WOCBP woman/women of child-bearing potential

1. Protocol Summary

1.1. Synopsis

Rationale:

Veillonella parvula strain A- G.I. is a pharmaceutical preparation of a single strain of Veillonella parvula ( Veillonella parvula strain A), originally isolated from a fresh ileostomy sample of an IBD patient in remission, which has been gamma-irradiated (G.I.). This study will investigate the safety and tolerability of Veillonella parvula strain A- G.I., a strain of the species Veillonella parvula , in healthy volunteers, participants with atopic dermatitis, and, optionally, in participants with psoriasis and/or asthma. Furthermore, the potential of Veillonella parvula strain A- G.I. to modify the immune system to provide benefit to these patient populations will also be assessed. Therefore, this study has been designed to obtain the maximum information and understanding about the potential benefit of Veillonella parvula strain A- G.I. by investigating its safety and pharmacodynamic effects in healthy volunteers and in patient cohorts.

Veillonella are gram-negative, obligate anaerobes that are natural human commensals found in the oral cavity and GI tract, and are therefore a normal component of a healthy human microbiome. Preclinical studies using Veillonella parvula strain A- G.I. have been carried out across a range of human and mouse primary cell in vitro assays, as well as in disease relevant in vivo models, which all support the use of this agent in the treatment of immunoinflammatory diseases.

In vitro studies of Veillonella parvula strain A- G.I. in human and mouse cellular assays and in vivo models support its use in the treatment of immunoinflammatory diseases, including atopic dermatitis, psoriasis, and asthma. Veillonella parvula strain A- G.I. increases secretion of anti-inflammatory cytokines from human immune cells, such as interleukin (IL)-10, while inducing minimal production of pro-inflammatory cytokines.

Oral administration of Veillonella parvula strain A- G.I. to mice led to striking therapeutic effects on delayed-type hypersensitivity (DTH), imiquimod-induced skin inflammation, fluorescein isothiocyanate (FITC) cutaneous hypersensitivity, MC903- induced dermatitis, and experimental acute encephalomyelitis (EAE) in-vivo models. This consistency of effect and dose shows that Veillonella parvula strain A- G.I. is co-ordinately resolving systemic inflammation across TH1, TH2 and TH17 pathways. This suggests the potential for clinical benefit across multiple conditions and populations. Table 1: Clinical Trial Objectives and Endpoints

Overall Design:

This is a Phase la/lb, first in human, participant and investigator-blind sponsor- unblinded randomized placebo-controlled multiple dose study of Veillonella parvula strain A- G.I. in healthy volunteers and participants with moderate atopic dermatitis and, optionally, in moderate psoriasis and/or mild asthma. The investigators and participants will be blinded to study drug allocation.

The primary objective is to assess the safety and tolerability of Veillonella parvula strain A- G.I. The secondary objectives are to assess the clinical and pharmacodynamic improvements in atopic dermatitis, and, optionally, in psoriasis and/or asthma. Exploratory objectives include further analysis of pharmacodynamic response and impact on the systemic immune system.

Two cohorts of healthy volunteers, each dosed at two dose levels, will be studied to provide evidence of safety and tolerability of the product, at dose levels ranging from 0.3 times (referred to throughout as 0.3x) to 10 times (lOx) the human equivalent dose (HED), based on allometric scaling. At each dose level, a sentinel pair will first be dosed and remain in-house for at least 48 hours, with a review of safety data before dosing the remaining participants. Following these first 4 dosing periods, participants with moderate atopic dermatitis will be studied to assess the safety and tolerability of Veillonella parvula strain A- G.I. in these patients, in addition to investigating the evidence of potential beneficial changes in the systemic immune environment and in clinical outcomes. A sentinel pair will initially be dosed and remain in-house for at least 48 hours with review of safety data before dosing further participants. Furthermore, 2 optional cohorts, 1 in moderate psoriasis and 1 in mild asthma, may be studied to assess the safety and tolerability of Veillonella parvula strain A- G.I. in these conditions, in addition to assessing clinical outcomes. These cohorts will all evaluate doses of 5 times the HED (5x) based on allometric scaling, with once daily dosing. All patient cohorts (3 - 5) may run concurrently or sequentially.

Up to 5 cohorts will be studied:

• Cohorts 1 and 2: 7-day daily dosing of Veillonella parvula strain A- G.I. or placebo in 12 healthy volunteers. Each cohort contains 2 periods of dosing with a minimum interval of 14 days between dosing periods 1 and 2. There is a 14-day follow-up at the end of the dosing periods. Sentinel dosing of the first pair (1 active and 1 placebo) will be used at the start of each period (i.e. at each dose level), with the sentinel pair remaining in-house for 3 days. Day 3 dosing in the sentinel pair will proceed following review of day 2 laboratory data. The remainder of the cohort may then be dosed following review of day 3 safety data from the sentinel pair in each cohort. All healthy volunteer participants will return to the clinical facility daily for each dosing and will be observed for at least 30 minutes after each outpatient dosing. The dosing schedule will proceed in the following order

(Table 2), with a Safety Review Committee (SRC) review required before moving to the next dose level:

Table 2: Design and Order of Healthy Volunteer Cohorts

review for first 2 participants who will receive > 3 daily doses before randomization is opened to the remaining participants in the cohort. These sentinel participants will be in-house for 3 days as per the SoA.

**SRC review and written outcome is required after completion of 7-day dosing in at least 8 participants, before dosing can begin at the next dose level. A review of safety data after at least 8 participants have completed the 7-day dosing in cohort 2, period 2 will occur prior to progressing to cohort 3, 4 and/or 5.

• Cohort 3: 56-day dosing of Veillonella parvula strain A- G.I. in subjects with moderate atopic dermatitis. Dose level 7.5xlO^u cells (5x the HED). 24 participants, 16 active and 8 placebo. Sentinel dosing of the first pair (1 active and 1 placebo) will be performed, with the sentinel pair in-house for 3 days. Cohorts 4 and 5 are both optional. Each may run concurrently or sequentially in either order.

• Optional Cohort 4: 56-day dosing of Veillonella parvula strain A- G.I. in subjects with moderate psoriasis. Dose level 7.5xlO^u cells (5x the HED). 24 participants, 16 active and 8 placebo. Sentinel dosing of the first pair (1 active and 1 placebo) will be performed, with the sentinel pair in-house for 3 days.

• Optional Cohort 5: 56-day dosing of Veillonella parvula strain A- G.I. in subjects with mild asthma and high baseline FeNO levels. Dose level 7.5xlO^u cells (5x the HED). 24 participants, 16 active and 8 placebo. Sentinel dosing of the first pair (1 active and 1 placebo) will be performed, with the sentinel pair in-house for 3 days.

The dose-range to be tested is therefore 4.5xl0¹⁰ total cells (0.3x the HED) to 1 5xl0¹² total cells (lOx the HED), (Table 3).

Table 3: Summary of Dose Levels

*These participants are the same as those dosed in period 1 unless subject replacement is required.

Safety Review Committee (SRC):

Each safety review will be based on the following data. Table 4: Summary of Safety Reviews

*Cohorts 4 and 5 may be run in non-numerical order, concurrently, or not at all.

Number of Participants:

A maximum of 120 participants will be randomized (Cohorts 1 to 5). Additional replacements participants may be randomized if necessary. · Cohorts 1 and 2: a total of 12 healthy volunteers will be randomized in each cohort (2:1 randomization ratio; 8 active, 4 placebo).

• Cohort 3: a total of 24 participants will be randomized (2: 1 randomization ratio;

16 active, 8 placebo).

• Cohorts 4 and 5 (optional); 24 participants will be randomized in each cohort (2:1 randomization ratio; 16 active, 8 placebo).

Participant Trial Duration:

The duration of the study for each participant is defined as the date signed written informed consent is provided through the last follow-up visit. Participants will be considered to have completed the study with the completion of all periods of their respective cohort, culminating with their End of Study follow-up visit.

Cohorts 1 and 2 have two treatment periods, separated by at least 14 days, while awaiting confirmation of the next dose level by the safety review committee. The first period consists of a 28-day screening period, seven days of treatment, and, and at minimum, a 14-day follow-up visit (up to 49 days). The second period consists of a 1-day baseline visit, seven days of treatment, and a 14-day follow-up period (up to 22 days).

The planned duration for each participant in cohorts 3 - 5 is approximately 14 weeks (including a 28-day screening period and 11 total scheduled study visits). In each of cohorts 3-5, there is a 56-day dosing-period with a 14-day follow-up period after completion of dosing.

Schedule of Activities (SoA) Cohorts 1 and 2 (healthy volunteers)

Abbreviations: AE = adverse event; CRP = C-reactive protein; ECG = electrocardiogram;

HBsAg = surface antigen of hepatitis B; HCG = human chorionic gonadotrophin; HCV = hepatitis C; HIV = human immunodeficiency virus; SAE = serious adverse event a. Dosing period 2 to start once SRC have given approval on the previous dose level b. Inpatient stay only required for sentinel participants. Inpatient requirement from Day -

1 (at least 24 hours prior to the first dose) to 48 hours post first dose. Sentinel pairs will be used at each dose level. c. Recheck inclusion/exclusion criteria before first dose of study intervention in Period

1. Recheck inclusion/exclusion criteria at baseline visit of period 2. d. Height at Screening only. e. Substances: urine drugs of abuse test and alcohol breath test, (urine alcohol testing may be performed in place of breath test). f. Women of child-bearing potential only. Serum HCG will be performed. If a scheduled test is not possible due to non-attendance it should be performed at the next clinic visit. Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is otherwise suspected (such ad hoc testing can be performed locally by urine testing if needed for faster reporting). Details of all pregnancies in female participants will be collected until 28 days after the last dose. g. Laboratory samples taken at the specified visit and reviewed at the next visit prior to dosing (i.e. at each visit the laboratory results from the previous visit are reviewed). Fasting glucose at baseline and end of dosing only. The day 2 safety laboratory samples of the sentinel pair must be reviewed prior to dosing on day 3. h. All ECGs to be measured in triplicate. All ECGs on dosing days to be conducted post dosing and within 2 hours after the dose. i. Blood pressure, pulse, respiratory rate and temperature - check prior to dosing and/or any procedures. j . Daily dosing to occur at approximately the same time ±2 hours. Refrain from consuming acidic drinks 1 hour either side of dosing and from eating 2 hours before dosing and 1 hour after dosing. All healthy volunteer participants will return to the clinical facility daily for each dosing and will be observed for at least 30 minutes after each outpatient dosing. k. Predose sample need only be taken once at any time before Day 1. Samples after Day 1 should be taken on the specified day where possible and if this is not possible, then a sample should be collected as close to the planned timepoint as possible. l. Take predose. Samples should be taken on the specified day where possible and if this is not possible, then a sample should be collected as close to the planned timepoint as possible. m. Daily review of AE, SAE, and concomitant medications will be required from screening (period 1) or baseline (period 2), up to the respective period follow-up visit. n. Baseline measurements should be taken on Day -1 if possible but may also be taken pre-dose on Day 1 for logistical reasons. The baseline measurements on Day -1 can be performed over more than 1 day within the visit window period of Day -3 to Day -1. o. Participants who withdraw from the study early should complete the final set of follow-up assessments wherever possible. p. Subjects will be re-randomised for the second treatment period (the assigned to active or placebo group in each treatment period is random and independent of the previous assignment. Both randomisation outcomes can be made during the initial randomisation). q. Participants who are unable to attend 2 or more visits will be automatically withdrawn from the study. These participants may be replaced.

Cohort 3 (atopic dermatitis participants)

Abbreviations: AE = adverse event; BSA = body surface area; CRP = C-reactive protein; DLQI = Dermatology Life Questionnaire Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; HBsAg = surface antigen of hepatitis B; HCG = human chorionic gonadotrophin; HCV = hepatitis C; HIV = human immunodeficiency virus; IGA = Investigator's Global Assessment; POEM = Patient-Oriented Eczema Measure; Pruritis NRS = Pruritis Numerical Rating Scale; SAE = serious adverse event; SCORAD = SCORing Atopic Dermatitis.

^L Inpatient stay only required for sentinel participants. Inpatient requirement from Day -1 (at least 24 hours prior to the first dose) to 48 hours post first dose. The day 2 visit and assessments are for the sentinel pair subjects only, who are in- house at this time. a. Recheck clinical status before first dose of study intervention. b. Height at Screening only. c. Substances: urine drugs of abuse test and alcohol breath test, (urine alcohol testing may be performed in place of breath test). d. Women of child-bearing potential only. Serum HCG will be performed. If a scheduled test is not possible due to non-attendance it should be performed at the next clinic visit. Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is otherwise suspected (such ad hoc testing can be performed locally by urine testing if needed for faster reporting). Details of all pregnancies in female participants will be collected until 28 days after the last dose. e. Laboratory samples should be taken on the specified day where possible and if this is not possible, then a sample should be collected as close to the planned timepoint as possible (i.e. within 48 hours). Laboratory samples will then be reviewed at the next visit prior to dosing (i.e. at each visit the laboratory results from the previous visit are reviewed). Fasting glucose at baseline and end of dosing (Visit 11) only. f. All ECGs on dosing days to be conducted post-dosing and within 2 hours after the dose. g. Blood pressure, pulse, respiratory rate and oral/tympanic temperature - check prior to dosing and/or any procedures. h. Randomisation can occur on either Day -1 or Day 1 after the participant has been confirmed as eligible for the study. i. Cohorts will use once daily dosing to occur at approximately the same time ±2 hours. Refrain from consuming acidic drinks 1 hour either side of dosing and from eating 2 hours before dosing and 1 hour after dosing. Note: If utilising visit window flexibility ensure patients still receive maximum of 56 daily doses. j . Take pre-dose. Samples should be taken on the specified day where possible and if this is not possible, then a sample should be collected as close to the planned timepoint as possible (i.e. within 48 hours). k. Predose sample need only be taken once at any time before Day 1. Samples after Day 1 should be taken on the specified day where possible and if this is not possible, then a sample should be collected as close to the planned timepoint as possible. l. Photos should be taken of up to 6 lesion sites. m. Baseline measurements should be taken on Day -1 if possible, but may also be taken pre-dose on Day 1 for logistical reasons. The baseline measurements on Day -1 can be performed over more than 1 day within the visit window period of Day -3 to Day -1. n. Participants who withdraw from the study early should complete these assessments on the same day as the last dose, or as soon as possible afterwards. o. Study staff will review the participant diaries with participants at each visit when diaries are collected. Diaries will be reviewed for completeness and accuracy, and participants will be coached as needed on compliance with the protocol. p. In exceptional circumstances, study assessments may be conducted remotely (i.e., via telephone), except for baseline, Visit 9, and Visit 11. Two consecutive visits should not be remote without consultation with the Sponsor’s medical monitor. Optional Cohort 4 (psoriasis participants)

^L Inpatient stay only required for sentinel participants. Inpatient requirement from Day -1 (at least 24 hours prior to the first dose) to 48 hours post first dose.

The day 2 visit and assessments are for the sentinel pair subjects only, who are in- house at this time. a. Recheck clinical status before first dose of study intervention. b. Height at Screening only. c. Substances: drugs urine test and alcohol breath test, (urine alcohol testing may be performed in place of breath test). d. Women of child-bearing potential only. Serum HCG will be performed. If a scheduled test is not possible due to non-attendance it should be performed at the next clinic visit. Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is otherwise suspected (such ad hoc testing can be performed locally by urine testing if needed for faster reporting). Details of all pregnancies in female participants will be collected until 28 days after the last dose. e. Laboratory samples should be taken on the specified day where possible and if this is not possible, then a sample should be collected as close to the planned timepoint as possible (i.e. within 48 hours). Laboratory samples will then be reviewed at the next visit prior to dosing (i.e. at each visit the laboratory results from the previous visit are reviewed). Fasting glucose at baseline and end of dosing (Visit 11) only. f. All ECGs on dosing days to be conducted post-dosing and within 2 hours after the dose. g. Blood pressure, pulse, respiratory rate and oral/tympanic temperature - check prior to dosing and/or any procedures. h. Randomisation can occur on either Day -1 or Day 1 after the participant has been confirmed as eligible for the study. i. Cohorts will use once daily dosing to occur at approximately the same time ±2 hours. Refrain from consuming acidic drinks 1 hour either side of dosing and from eating 2 hours before dosing and 1 hour after dosing. Note: If utilising visit window flexibility ensure patients still receive maximum of 56 daily doses. j . Take pre-dose. Samples should be taken on the specified day where possible and if this is not possible, then a sample should be collected as close to the planned timepoint as possible (i.e. within 48 hours). k. Predose sample need only be taken once at any time before Day 1. Samples after Day 1 should be taken on the specified day where possible and if this is not possible, then a sample should be collected as close to the planned timepoint as possible. l. Photos should be taken of up to 6 lesion sites. m. Baseline measurements should be taken on Day -1 if possible, but may also be taken pre-dose on Day 1 for logistical reasons. The baseline measurements on Day -1 can be performed over more than 1 day within the visit window period of Day -3 to Day -1. n. Participants who withdraw from the study early should complete these assessments on the same day as the last dose, or as soon as possible afterwards. o. Study staff will review the participant diaries with participants at each visit when diaries are collected. Diaries will be reviewed for completeness and accuracy, and participants will be coached as needed on compliance with the protocol. p. In exceptional circumstances, study assessments may be conducted remotely (ie, via telephone), except for baseline, Visit 9, and Visit 11. Two consecutive visits should not be remote without consultation with the Sponsor’s medical monitor.

Optional Cohort 5 (Asthma participants)

Abbreviations: AE = adverse event; BSA = body surface area; CRP = C-reactive protein; DLQI = Dermatology Life Questionnaire Index; EASI = Eczema Area and Severity Index; ECG = electrocardiogram; HBsAg = surface antigen of hepatitis B; HCG = human chorionic gonadotrophin; HCV = hepatitis C; HIV = human immunodeficiency virus; IGA = Investigator's Global Assessment; POEM = Patient-Oriented Eczema Measure; Pruritis NRS = Pruritis Numerical Rating Scale; SAE = serious adverse event; SCORAD = SCORing Atopic Dermatitis. ^L Inpatient stay only required for sentinel participants. Inpatient requirement from Day

-1 (at least 24 hours prior to the first dose) to 48 hours post first dose.

The day 2 visit and assessments are for the sentinel pair subjects only, who are in- house at this time. a. Recheck clinical status before first dose of study intervention. b. Height at Screening only. c. Substances: drugs urine test and alcohol breath test, (urine alcohol testing may be performed in place of breath test). d. Women of child-bearing potential only. Serum HCG will be performed. If a scheduled test is not possible due to non-attendance it should be performed at the next clinic visit. Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is otherwise suspected (such ad hoc testing can be performed locally by urine testing if needed for faster reporting). Details of all pregnancies in female participants will be collected until 28 days after the last dose. e. Laboratory samples should be taken on the specified day where possible and if this is not possible, then a sample should be collected as close to the planned timepoint as possible (i.e. within 48 hours). Laboratory samples will then be reviewed at the next visit prior to dosing (i.e. at each visit the laboratory results from the previous visit are reviewed). Fasting glucose at baseline and end of dosing (Visit 11) only. f. All ECGs on dosing days to be conducted post-dosing and within 2 hours after the dose. g. Blood pressure, pulse, respiratory rate and oral/tympanic temperature - check prior to dosing and/or any procedures. h. Randomisation can occur on either Day -1 or Day 1 after the participant has been confirmed as eligible for the study. i. Cohorts will use once daily dosing to occur at approximately the same time ±2 hours. Refrain from consuming acidic drinks 1 hour either side of dosing and from eating 2 hours before dosing and 1 hour after dosing. Note: If utilising visit window flexibility ensure patients still receive maximum of 56 daily doses. j . Take pre-dose. Samples should be taken on the specified day where possible and if this is not possible, then a sample should be collected as close to the planned timepoint as possible (i.e. within 48 hours). k. Predose sample need only be taken once at any time before Day 1. Samples after Day 1 should be taken on the specified day where possible and if this is not possible, then a sample should be collected as close to the planned timepoint as possible. l. Baseline measurements should be taken on Day -1 if possible, but may also be taken pre-dose on Day 1 for logistical reasons. The baseline measurements on Day -1 can be performed over more than 1 day within the visit window period of Day -3 to Day -1. m. Participants who withdraw from the study early should complete these assessments on the same day as the last dose, or as soon as possible afterwards. n. FeNO measurements will be performed in accordance with site SOPs and the ATS/ERS 2005 guidelines. At least 2 measurements that agree within 10% of each other will be recorded at each designated visit/time-point, with the average of the 2 chosen values reported. Where more than 2 measurements were performed, the two closest values that meet the reproducibility criteria will be used (not necessarily the highest two values). o. Study staff will review the dosing diaries with participants at each visit when diaries are collected. Diaries will be reviewed for completeness and accuracy, and participants will be coached as needed on compliance with the protocol. p. In exceptional circumstances, study assessments may be conducted remotely (i.e, via telephone), except for baseline, Visit 9, and Visit 11. Two consecutive visits should not be remote without consultation with the Sponsor’s medical monitor.

Introduction

1.2. Background

Orally administered biologic medicines are being developed based on an entirely new understanding of how immunity and inflammation are controlled. Results demonstrate a newly emerging, potent pathway of systemic inflammatory control centred in the small intestine. This newly defined inflammatory control pathway enables a new class of oral products which are effective, safe, and can be manufactured affordably at large scale.

Veillonella parvula strain A- G.I. is a pharmaceutical preparation of a single strain of Veillonella parvula , originally isolated from a fresh ileostomy sample of an IBD patient in remission, which has been gamma-irradiated to render it essentially non-replicating and non-viable. It has not been genetically modified. Veillonella are gram-negative, obligate anaerobes that are natural human commensals found in the oral cavity and GI tract.

Preclinical studies using Veillonella parvula strain A- G.I. have been carried out across a range of human and mouse in vitro assays as well as key in vivo models of human disease, including delayed type hypersensitivity (DTH), imiquimod-induced skin inflammation, fluorescein isothiocyanate (FITC) cutaneous hypersensitivity, MC903- induced dermatitis, and experimental acute encephalomyelitis (EAE) in-vivo models. It has dose dependent therapeutic effects. Data from the in-vivo models support the use of Veillonella parvula strain A- G.I. in the treatment of Th2-mediated (e.g. atopic dermatitis, asthma) and Thl7-mediated (e.g. psoriasis) immunoinflammatory diseases.

As predicted based on the mechanism of action, no potentially related adverse effects were seen in the animals used in these experiments with daily dosing up to 6 weeks. In addition, while ex vivo immunophenotyping in these models shows decreases in pro- inflammatory cytokines such as IL-6, IL-13, TNFa, 11-17, TSLP and KC (murine IL-8), Veillonella parvula strain A- G.I. does not suppress the expression of interferon gamma (IFNy) in these experiments, suggesting that the broad spectrum of anti-inflammatory effects is achieved without damaging mechanisms of immune surveillance critical for the prevention of malignancy and response to pathogens such as viral or bacterial infections. 1.3. Study Rationale

The study is a first in human (FIH) study for Veillonella parvula strain A- G.I. The study has been designed to confirm the safety and tolerability of Veillonella parvula strain A- G.I. in both healthy participants and participants with atopic dermatitis and, optionally, psoriasis, and/or asthma.

The healthy volunteer cohorts (cohorts 1 - 2) will establish safety and tolerability of escalating doses 0.3 times the human equivalent dose (HED) to up to 10 times the HED of Veillonella parvula strain A- G.I. for a dosing period of 7 days.

The potential of the product to modulate the systemic immune response in an immunoinflammatory condition will be established in the patient cohorts (cohorts 3 - 5). The dose level in these cohorts is 5x HED (1/2 the maximum dose level in the healthy volunteer cohorts). Due to the lack of systemic absorption of Veillonella parvula strain A- G.I., patient cohorts are required to provide evidence of pharmacodynamic effect. These 3 particular conditions have been chosen as pre-clinical data suggests Veillonella parvula strain A- G.I. will drive good clinical effects in both Th2- and Thl7- driven inflammatory diseases. In addition, these conditions often do not themselves significantly impact the overall health of the patient, so otherwise healthy patients will be recruited. Dosing is for 56 days due to expected ongoing pharmacodynamic and clinical effects from pre-clinical models and data from comparable IMPs. The data from this study will allow Sponsor to efficiently establish the safety and tolerability of Veillonella parvula strain A- G.I. while informing the potential indications of patient populations that could benefit from this product.

1.4. Benefit/Risk Assessment

Veillonella parvula strain A- G.I. is a pharmaceutical preparation of a single strain of Veillonella parvula , originally isolated from a fresh ileal pouch sample of an IBD patient in remission, which has been gamma-irradiated to render it essentially non-replicating and non-viable. It has not been genetically modified. Veillonella are gram-negative, obligate anaerobes that are natural human commensals found in the oral cavity and GI tract. It therefore presents minimal risk to human subjects. No toxicity or adverse events of special interest are expected in human subjects.

Preclinical studies using Veillonella parvula strain A- G.I. have been carried out across a range of human and mouse in vitro assays as well as key in vivo models of human disease, including delayed type hypersensitivity (DTH), imiquimod-induced skin inflammation, fluorescein isothiocyanate (FITC) cutaneous hypersensitivity, MC903- induced dermatitis, and experimental acute encephalomyelitis (EAE) in-vivo models. Data from the in-vivo models support the use of Veillonella parvula strain A- G.I. in the treatment of Th2-mediated (e.g. atopic dermatitis, asthma) and Thl7-mediated (e.g. psoriasis) immunoinflammatory diseases.

Veillonella parvula strain A- G.I. is predicted to be luminally-restricted with no systemic absorption, instead passing through the gut unchanged. As predicted based on the mechanism of action, no potentially related adverse effects were seen in the animals used in these experiments with daily dosing up to 6 weeks. In addition, while ex vivo immunophenotyping in these models shows decreases in pro-inflammatory cytokines such as IL-6, IL-13, TNFa, 11-17, TSLP and KC (murine IL-8), Veillonella parvula strain A- G.I. does not suppress the expression of interferon gamma (IFNy) in these experiments, suggesting that the broad spectrum of anti-inflammatory effects is achieved without damaging mechanisms of immune surveillance critical for the prevention of malignancy and response to pathogens. Veillonella parvula strain A- G.I. is being investigated for its potential benefit in chronic immunoinflammatory disorders. The initial conditions being tested are atopic dermatitis, psoriasis, and asthma. A well-tolerated oral therapy could offer significant benefit in all of these conditions, preventing or delaying the need for more toxic or poorly tolerated treatments.

1.5. Risk Mitigation and Management

Veillonella parvula strain A- G.I. is a gamma irradiated form of a naturally occurring organism. In addition, as Veillonella parvula strain A- G.I. has been irradiated, it is therefore essentially non-replicating and non-viable. It has not been genetically modified.

The drug product is considered non-replicating and non-colonising and therefore highly unlikely to cause systemic infection in human. However, in the unlikely event of AEs or systemic exposure, Veillonella parvula strain A- G.I. is highly susceptible to most major classes of antibiotics.

In summary, the therapeutic agent is a gamma irradiated form of a common natural organism and is therefore expected to be safe and well tolerated. Each dose level of the healthy volunteer cohort has sentinel pairs, that are dosed as inpatients. The day 2 laboratory data of the sentinel pair must be reviewed prior to the day 3 dosing. Safety data is reviewed prior to opening up the cohort to the remaining participants. All healthy volunteers receive their dose on-site throughout the dosing period. In addition, each clinical cohort also has an in-house sentinel pair, with review of safety data up to day 3, prior to opening up the cohort to the remaining participants. There are multiple SRC reviews of the patient cohorts, at week 2 for Cohorts 3-5 and week 4 for Cohort 3 and week 8 for Cohorts 3-5.

In addition, a SRC will review blinded safety data from all sites and provide governance over the study.

2. Objectives and Endpoints

Table 5: Clinical Trial Objectives and Endpoints

3. Study Design

3.1. Overall Design

Up to 5 cohorts will be studied:

• Cohorts 1 and 2: 7-day daily dosing of Veillonella parvula strain A- G.I. or placebo in 12 healthy volunteers. Each cohort contains 2 periods of dosing with a minimum interval of 14 days between dosing periods 1 and 2. There is a 14-day follow-up at the end of the dosing periods. Sentinel dosing of the first pair (1 active and 1 placebo) will be used at the start of each period (i.e. at each dose level), with the sentinel pair remaining in-house for 3 days. The remainder of the cohort may then be dosed following review of day 3 safety data from the sentinel pair in each cohort. All doses will be given on site. The dosing schedule will proceed in the following order (Table 6), with a Safety Review Committee (SRC) review required before moving to the next dose level:

Table 6: Design and Order of Healthy Volunteer Cohorts

review for first 2 participants who will receive ³ 3 daily doses before randomization is opened to the remaining participants in the cohort. These sentinel participants will be in-house for 3 days as per the SoA.

• Cohort 3: 56-day dosing of Veillonella parvula strain A- G.I. in subjects with moderate atopic dermatitis. Dose level 7.5xlO^u cells (5x the HED). 24 participants, 16 active and 8 placebo. Sentinel dosing of the first pair (1 active and 1 placebo) will be performed, with the sentinel pair in-house for 3 days.

Cohorts 4 and 5 are both optional. Each may run concurrently or sequentially in either order. • Optional Cohort 4: 56-day dosing of Veillonella parvula strain A- G.I. in subjects with moderate psoriasis. Dose level 7.5xlO^u cells (5x the HED). 24 participants, 16 active and 8 placebo. Sentinel dosing of the first pair (1 active and 1 placebo) will be performed, with the sentinel pair in-house for 3 days. · Optional Cohort 5: 56-day dosing of Veillonella parvula strain A- G.I. in subjects with mild asthma and high baseline FeNO levels. Dose level 7.5xlO^u (5x the HED). 24 participants, 16 active and 8 placebo. Sentinel dosing of the first pair (1 active and 1 placebo) will be performed, with the sentinel pair in-house for 3 days.

The dose-range to be tested is therefore 4.5xl0¹⁰ total cells (0.3x the HED) to 1 5xl0¹² total cells (lOx the HED), (Table 7).

Table 7: Summary of Dose Levels

*These participants

same as those dosed in period 1 unless subject replacement is required.

3.2. Scientific Rationale for Study Design

The design of the study allows a dose escalation in healthy volunteers to ensure Veillonella parvula strain A- G.I. is tolerated in humans and this will be followed by the testing of 3 further hypotheses.

Hypothesis 1:

Veillonella parvula strain A- G.I. is well tolerated and not systemically absorbed in humans. Endpoints: standard safety and tolerability endpoints will be measured (including

AEs, safety laboratory assessments, CRP, ECG); as well as assessment for presence of Veillonella parvula strain A- G.I. in the blood.

Hypothesis 2:

Daily administration of Veillonella parvula strain A- G.I. improves moderate atopic dermatitis.

Endpoints:

1. Standard safety and tolerability endpoints

2. EASI 3. SCORAD

4. BSA

5. IGA

6. IGA x BSA

7. DLQI

8. POEM

9. Pruritus NRS Hypothesis 3:

Daily administration of Veillonella parvula strain A- G.L improves moderate psoriasis.

Endpoints:

1. Standard safety and tolerability endpoints

2. PASI score

3. LSS

4. BSA

5. PGA

6. PGA x BSA

7. DLQI Hypothesis 4:

Daily administration of Veillonella parvula strain A- G.L improves mild asthma.

Endpoints:

1. Standard safety and tolerability endpoints

2. FeNO

3. FEV1

4. FVC

5. PEF

3.3. Dose Justification

Dosing will occur in a sequential fashion, with cohort 1 period 1 receiving the lowest dose level, and dosing only proceeding to the next dose level following review of the safety data of the previous dose level by the SRC. The sequential dose regimen is designed to minimise risk to participants, with starting doses guided by (i) the general experience in probiotic formulations and experience from similar microbes already in the clinic whose pharmacodynamic effect is driven through the same mode of action, (ii) confirmation of the non-systemic nature of Veillonella parvula strain A- G.I. which corresponds to an oral bioavailability of 0, and (iii) an understanding of the dose-response relationship as defined in the preclinical models.

For considerations of scaling, the drug product was regarded as having predominantly local interaction with cells of the GI mucosa, with subsequent systemic effects on cells of the immune system. Such a mechanism is not consistent with the assumptions of traditional allometric scaling, therefore 2 other parameters were considered that might reflect the topical interaction in the GI tract, namely relative GI mucosal surface area and relative stool mass. While a complete analysis of relative GI mucosal surface area could not be identified in the literature, it has been estimated as a function of body mass to the ¾ power (Karasov, 2012). Using stool mass ratio, standard allometric scaling, and GI mucosal surface area calculations, humanmouse dose ratios of approximately lOOx, 300x, and 450x, respectively, were calculated. For the purpose of considering a likely efficacious dose, calculations on a 345x scale factor have been used.

When using the above scaling approach, the minimal efficacious dose from pre clinical experiments was determined to lie between 5.2xl0¹⁰ to 5.2xlO^u in humans. The starting dose of 4.5xl0¹⁰ in healthy volunteers therefore lies below all points of this range and is greater than 10 fold lower than the upper end of the range. This starting dose of 4.5xl0¹⁰ represents 0.3x HED Based on these experiments, the lx cell count selected is a conservative dose within this range, and the expectation is that a higher dose will be required to see clinical effect, and therefore a dose level of up to 5x is selected for all clinical cohorts. A highest dose to be investigated in the study has been selected at lOx HED, based on capsule load, as no adverse events have been seen in pre-clinical models..

3.4. End of Study Definition

A participant is considered to have completed the study if he/she has completed treatment to the end of their assigned cohort and completed their final safety follow-up visit.

The end of the study is defined as the date of the last visit of the last participant in the study or last scheduled procedure shown in the Schedule of Activities (SoA). Study Population

This protocol contains healthy volunteers and participants with moderate atopic dermatitis, moderate psoriasis, and mild asthma. 3.5. Inclusion Criteria

3.5.1. All Participants

Participants are eligible to be included in the study only if all of the following criteria apply:

1. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol. Informed consent will be obtained prior to any Screening procedures and in accordance with national, local, institutional guidelines.

2. Age > 18 years to 65 years, inclusive.

3. Participant has a body mass index of > 18 kg/m² to < 35 kg/m² at Screening.

4. Contraception: a. Male participants:

• A male participant with a female partner of child-bearing potential must agree to use contraception as detailed in Appendix 2 of this protocol during their participation in this study and for a period of 90 days after the last dose. All male participants must refrain from donating sperm during this period. b. Female participants:

• A female participant is eligible to participate if she is not pregnant (see Appendix 2), not breastfeeding, and at least 1 of the following conditions applies: i. Not a woman of child-bearing potential (WOCBP) as defined in Appendix 2.

OR ii. A WOCBP who agrees to follow the contraceptive guidance in Appendix 2 during their participation in this study, 28 days prior to the first dose and for at least 1 complete menstrual cycle (> 30 days) after the last dose.

5. The participant has clinical laboratory evaluations (including clinical chemistry, haematology, and complete urinalysis) within the reference range for the testing laboratory, unless the results are deemed not to be clinically significant by the investigator or Sponsor (1 re-test is permitted).

6. CRP < 10 mg/L 7. Participants who are overtly healthy as determined by medical evaluation including medical history, physical examination, laboratory tests, and ECG monitoring at Screening and at Baseline. .5.2. Additional Inclusion Criteria for Participants with Moderate Atopic Dermatitis

8. Participant has moderate atopic dermatitis with a minimum of 5% and a maximum of 40% BSA involvement, and an IGA score of 2 or 3.

9. Participant has had a confirmed diagnosis of atopic dermatitis for at least 6 months. .5.3. Additional Inclusion Criteria for Participants with Moderate Psoriasis

10. Participant has moderate plaque psoriasis with plaque covering BSA of >3% and <10% and meets both of the following additional criteria: a. PASI score of >6 and <15, and b. PGA score of 2 or 3.

11. Participant has a confirmed diagnosis of plaque psoriasis for at least 6 months. .5.4. Additional Inclusion Criteria for Participants with Mild Asthma

12. Participant has a diagnosis of stable asthma for at least six months prior to the start of the study.

13. FeNO of >40ppb.

14. FEV1 >70% of predicted normal. .6. Exclusion Criteria .6.1. All Participants

8. Female participant who is pregnant, or plans to become pregnant during the study, or breastfeeding, or sexually active with child-bearing potential who is not using a highly effective birth control method as indicated in Appendix 2.

9. Participant has received live attenuated vaccination within 6 weeks prior to Screening or intends to have such a vaccination during the course of the study (non-live vaccines are permitted).

10. Participant has received any investigational drug or experimental procedure within 90 days or 5 half-lives, whichever is longer, prior to study intervention administration. 11. Participant requires treatment with an anti-inflammatory drug during the study period. Paracetamol will be permitted for use as an antipyretic and/or analgesic (maximum of 4 grams/day in any 24-hour period).

12. Participant has an active infection (e.g. sepsis, pneumonia, abscess) or has had an infection requiring antibiotic treatment within 6 weeks prior to study intervention administration. When in doubt, the investigator should confer with the Sponsor study physician.

13. Participant has renal or liver impairment, defined as: a. For healthy volunteers (cohorts 1 and 2): i. For both men and women, serum creatinine level > 1.Ox ULN, or ii. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) > 1.5 x upper limit of normal (ULN), or iii. Alkaline phosphatase (ALP) and/or bilirubin > 1.5 x ULN b. For patients (cohorts 3, 4 and 5): i. For both men and women, serum creatinine level > 1.25x ULN, or ii. ALT or AST > 2 x ULN and/or bilirubin > 1.5 x ULN

14. Participant has active neoplastic disease or history of neoplastic disease within

5 years of Screening (except for basal or squamous cell carcinoma of the skin or carcinoma in situ that has been definitively treated with standard of care).

15. Participant has undergone major surgery within the 4 weeks prior to Screening.

16. Impaired cardiac function or clinically significant cardiac diseases, including any of the following: a. Unstable angina or acute myocardial infarction < 3 months prior to Screening; b. Clinically significant heart disease (e.g. symptomatic congestive heart failure [e.g. New York Heart Association [NYHA] > Class 2]; uncontrolled arrhythmia, or hypertension; history of labile hypertension or poor compliance with an antihypertensive regimen).

17. Participant has a known history of human immunodeficiency virus (HIV); HIV testing is required as part of this study.

18. Known, active hepatitis A, hepatitis B (HBV), or hepatitis C (HCV) infection; or known to be positive for HCV ribonucleic acid (RNA) or hepatitis B surface antigen (HBsAg). Participant has active central nervous system (CNS) malignancy. Participants who have only had prophylactic intrathecal or intravenous chemotherapy against CNS disease are eligible. Participant has GI tract disease (e.g. short bowel syndrome, diarrhoea predominant irritable bowel syndrome [IBS]) that could interfere with the GI delivery and transit time of Veillonella parvula strain A- G.I. Serious psychiatric or medical conditions that, in the opinion of the investigator, could interfere with treatment, compliance, or the ability to give consent. Participant has a history of hypersensitivity or allergies to Veillonella (or

Vei I lone I la-coniV g probiotics) including any associated excipients, or has a history of hypersensitivity or allergies to placebo capsule or to the hard capsule shells. The participant has taken any over-the-counter (OTC) or prescription medication including vitamins, herbal supplements and nutraceuticals (e.g. supplements including high doses of probiotics and prebiotics) but with the exception of paracetamol and anti-histamines, within 14 days prior to baseline (Day -1); or anticipates an inability to abstain from these products for the duration of the study period. Note that probiotic and prebiotic foods that contain low doses are allowed (e.g. yoghurt, kefir, kombucha). The use of any concomitant medication, including OTC medications, deemed absolutely necessary for the care of the participant is permitted during the study provided they do not have a known effect on GI transit time or function. In cohort 3 (atopic dermatitis), unmedicated emollients are permitted. In cohort 4 (psoriasis), unmedicated emollients and low-potency topical corticosteroids are permitted. In cohort 5, short-acting inhaled P2-agonists are permitted. The participant has a significant history of drug abuse or regular use of illicit drugs or a history of alcohol abuse within 1 year prior to Screening or has tested positive for drugs of abuse or alcohol at Screening or at baseline. Note: if the drugs of abuse result is positive at Screening/baseline due to use of an OTC or prescription product, where possible the OTC or prescription product should be stopped and the test repeated once within the 28-day Screening period but the second result must be negative. Alternatively, if the OTC or prescription medication cannot be withheld then a participant may be included providing the positive result is attributable to a medication that is approved for use by the Sponsor. Note: if the alcohol test is positive at screening or baseline, the test may be repeated once with the 28-day Screening period, but the second result must be negative.

25. The participant intends to donate sperm during the course of this study and for a period of 90 days after the last dose.

26. The participant has donated more than 400 mL of blood or blood products within 90 days prior to baseline (Day -1) or plans to donate blood during the study.

27. The participant has had an acute, clinically significant illness within 30 days prior to the first dose of study intervention. 2. Additional Exclusion Criteria for Participants with Atopic Dermatitis

28. Evidence of skin conditions that would interfere with atopic dermatitis evaluation.

29. Participant is receiving systemic immunosuppressive or non-biologic atopic dermatitis therapy (such as ciclosporin, MTX, steroids, cyclophosphamide); or psoralen plus ultraviolet A (PUVA)/ultraviolet A (UVA) or psoralen plus ultraviolet B (PUVB)/ultraviolet B (UVB) phototherapy; or has received such therapy within 4 weeks prior to Screening.

30. Participant has received treatment with biologic agents within 12 months prior to first dose.

31. Participant continues to use topical medications that could affect atopic dermatitis 2 weeks prior to the start of dosing. Topical unmedicated emollients are not excluded and may continue to be used if the participant was already using them as part of their care, but should not be applied until after skin assessments on the relevant visit days.

32. Participant intends to continue to use sunbeds and/or increase their sun exposure significantly from their normal lifestyle for the duration of the study. 3. Additional Exclusion Criteria for Participants with Psoriasis

33. Evidence of skin conditions that would interfere with psoriasis evaluation.

34. Psoriasis restricted to scalp, palm, and/or soles only.

35. Non-plaque type of psoriasis.

36. Participant is receiving systemic immunosuppressive or nonbiologic psoriasis therapy (such as methotrexate [MTX], steroids, cyclophosphamide) or psoralen plus ultraviolet A (PUVA)/ultraviolet A (UVA) or psoralen plus ultraviolet B (PUVB)/ultraviolet B (UVB) phototherapy; or has received such therapy within 4 weeks prior to Screening.

37. Participant has received treatment with biologic agents within 12 months prior to first dose.

38. Participant continues to use topical medications that could affect psoriasis (including, but not limited to, high- and mid-potency corticosteroids, anthralin,, topical vitamin D derivatives, retinoids, tazarotene, pimecrolimus, and tacrolimus) within 2 weeks prior to the start of dosing. Topical unmedicated emollients and low-potency topical corticosteroids are not excluded and may continue to be used if the participant was already using them as part of their care, but should not be applied until after skin assessments on the relevant visit days.

39. Participant intends to continue to use sunbeds and/or increase their sun exposure significantly from their normal lifestyle for the duration of the study. 4. Additional Exclusion Criteria for Participants with Asthma

40. Significant risk of exposure to a change in sensitizing environmental substances during the study.

41. History of life-threatening asthma, or a visit to the emergency department for asthma in the 6 months prior to screening, or exacerbation requiring oral corticosteroids within the previous 3 months.

42. Smoker or nicotine user within the 3 months prior to screening; or a previous smoker with a greater than 10 pack year history.

43. Other significant non-reversible pulmonary disease (e.g. Cystic Fibrosis, Pulmonary Fibrosis, or COPD).

44. Use of the following medicines within the specified time-frame prior to screening: a. Long-acting inhaled p2-agonists: 8 weeks. Note: short-acting inhaled b2- agonists are permitted as required. b. Anti-IgE therapy: 6 months c. Inhaled corticosteroids: 8 weeks d. Oral or Injected corticosteroids: 8 weeks e. Intranasal or topical steroids: 4 weeks f. Leukotriene antagonists: 2 weeks g. Long-acting muscarinic antagonist: 8 weeks h. Xanthines (excluding caffeine), anticholinergics, cromogly cates: 1 week. 3.7. Lifestyle Restrictions

In all cohorts, participants in the sentinel dosing group (first two participants) will be asked to stay in the study unit for 3 nights, from Day -1 (24 hours prior to the first dose) until 48 hours following the first dose.

Participants must abstain from taking prescription or OTC drugs (including high doses of probiotics and prebiotics as usually found in capsules/tablets/powders, vitamins and dietary or herbal supplements), but with the exception of paracetamol and anti-histamines for 14 days prior to the baseline visit (Day -1) and until completion of the follow-up visit, unless, in the opinion of the investigator and Sponsor, the medication will not interfere with the study. Note that probiotic and prebiotic foods that contain low doses are allowed (e.g. yoghurt, kefir, kombucha). In cohorts 3 and 4, participants can continue to use non-medicated emollients and should continue to do so in the same manner throughout the study. On the day of study visits with skin assessments, these should not be applied until after the skin assessments. Emollients with medicated ingredients acting as an anti-inflammatory, or anti-pruritic agent, for example, should be avoided. In cohort 4, participants may also continue to use low potency topical steroids, and should continue to do so in the same manner throughout the study. Again, on the day of study visits with skin assessments, these should not be applied until after the skin assessments.

Participants must refrain from consuming acidic drinks for 1 hour either side of dosing and from eating 2 hours before dosing and 1 hour after dosing. In addition, participants should refrain from consuming alcohol for 24 hours before each visit, should not consume poppy seeds throughout the study, and should also refrain from heavy exercise throughout the study. Participants must fast (water permitted) for at least 8 hours prior to fasting glucose samples.

Participants in cohorts 1 and 2 do not need to follow lifestyle restrictions in the time between the follow-up visit at the end of period 1, and the baseline assessment at the start of period 2.

Participants in cohorts 3 and 4 should not use sunbeds and not increase their sun exposure significantly from their normal lifestyle.

Participants in cohort 5 should refrain from eating nitrate-rich foods (e.g. vegetable juices, salads, lettuce, radishes, celery, broccoli, cauliflower, spinach, rockets, beets, parsley, leeks, cabbage, fennel, turnips, carrots, cured meats, bacon, and carbonated drinks) within 6 hours prior to each FeNO measurement and should fast (including water) for at least 1 hour prior to each FeNO measurement. Participant should also refrain from drinking liquids and ingesting food containing caffeine or other xanthines for at least 24 hours prior to and during all visits. Decaffeinated beverages are allowed.

4. Study Interventions

Study intervention is defined as any investigational intervention(s), marketed product(s), placebo, or medical device(s) intended to be administered to a study participant according to the study protocol. 4.1. Study Interventions Administered

The study intervention will be administered orally with water. Veillonella parvula strain A- G.I. will be supplied as enteric-coated capsules, designed to release their contents in the duodenum and jejunum. Two dose levels of Veillonella parvula strain A- G.I. will be provided: · Dose level 1 = 4.5xl0¹⁰ total cells per capsule.

• Dose level 2 = 1.5xl0^u total cells per capsule.

The initial dose, 0.3x HED, for the study will be supplied using low strength drug product (4.5x10¹⁰ total cells per capsule) whereas the dose levels of lx, 5x, and lOx HED will be supplied using high strength drug product (1.5 xlO¹¹ total cells per capsule). All cohorts will use once daily dosing from day 1. In cohorts 1 and 2, there are two separate dosing periods separated by at least a 14 day period off dosing while the safety review committee reviews data from the previous dose level.

Matched placebo capsules will be supplied.

See Table 8 below for a summary of the key information.

Table 8: Treatment Arms

required 4.2. Preparation/Handling/Storage/Accountability

Veillonella parvula strain A- G.I. is formulated as powder in capsule (PIC). The excipients include mannitol, colloidal silicon dioxide, magnesium stearate, hydroxypropyl methylcellulose, methacrylic acid ethyl acrylate copolymer, triethyl citrate, and talc. Two dose strengths are available: 4.5><10¹⁰ and 1.5xl0^u cells of Veillonella parvula strain A- G.I. per capsule, to supply dose ranging from 0.3x to lOx. A total of 10 enteric coated capsules are packaged in a blister card.

Veillonella parvula strain A- G.I. should be stored in a refrigerator between 2°C - 8°C. Once removed from the refrigerator to room temperature (25 °C or below), Veillonella parvula strain A- G.I. should be administered within 24 hours.

4.3. Concomitant Therapy

Participants must abstain from taking prescription or OTC drugs (including high doses of probiotics and prebiotics as usually found in capsules/tablets/powders, vitamins and dietary or herbal supplements) within 14 days before the start of study intervention until completion of the follow-up visit, unless, in the opinion of the investigator and Sponsor, the medication will not interfere with the study. Note that probiotic and prebiotic foods that contain low doses are allowed (e.g. yoghurt, kefir, kombucha).

Participants in Cohort 5 should refrain from taking Short-Acting Beta-Agonists (SABA) for at least 6 hours prior to FeNO and spirometry assessments whenever possible.

Investigational agents other than Veillonella parvula strain A- G.I. are not allowed during the study.

For the atopic dermatitis and psoriasis cohorts, pharmacologically active treatments are contraindicated and should be stopped at least 4 weeks prior to entry into the study, or 12 months in the case of biologic treatments. Of note, low potency topical steroids are permitted in the psoriasis cohort; and non-medicated emollients in both the psoriasis and atopic dermatitis cohorts. Emollients should be used daily on affected sites if the participants were already using them as part of their care. These topical treatments should not be applied on the day of visits with skin assessments, until after those skin assessments have been performed.

For the asthma cohort, the following restrictions in asthma treatments apply: i. Long-acting inhaled p2-agonists: 8 weeks before screening and during the study. Note: short-acting inhaled p2-agonists are permitted as required. j . Anti-IgE therapy: 6 months before screening and during the study k. Inhaled corticosteroids: 8 weeks before screening and during the study l. Oral or Injected corticosteroids: 8 weeks before screening and during the study m. Intranasal or topical steroids: 4 weeks before screening and during the study n. Leukotriene antagonists: 2 weeks before screening and during the study o. Long-acting muscarinic antagonist: 8 weeks before screening and during the study p. Xanthines (excluding caffeine), anticholinergics, cromogly cates: 1 week before screening and during the study

The use of any concomitant medication, including OTC medications, deemed absolutely necessary for the care of the participant is permitted during the study provided they do not have a known effect on GI transit time or function. The use of any immunosuppressive agents must be discussed between the investigator and the Sponsors Medical Monitor on a case-by-case basis. Hormonal contraceptives are permitted in WOCBP (hormonal contraceptives include any marketed contraceptive agent that includes an oestrogen and/or a progestational agent).

Any medication or vaccine (including OTC or prescription medicines, probiotics, and/or herbal supplements) that the participant is receiving at the time of enrolment or receives during the study must be recorded along with:

• Reason for use

• Dates of administration including start and end dates

• Dosage information including dose and frequency

Note that live and live-attenuated vaccines are contraindicated during this study.

Any diagnostic, therapeutic, or surgical procedure performed during the study period should be recorded, including the dates, description of the procedure(s), and any clinical findings, if applicable. The Sponsors Medical Monitor should be contacted if there are any questions regarding concomitant or prior therapy.

Anti-histamines and paracetamol doses of £ 4 grams/day (in any 24-hour period) are permitted for use any time during the study, except for participants enrolled in Cohorts 3-5. Other concomitant medication may be considered on a case-by-case basis by the investigator in consultation with the Sponsors Medical Monitor if required. Participants should be willing to stop their current medication due to intolerability or ineffectiveness of their medication rather than purely for the sake of participation in this study. This should be clearly documented in the participants’ notes.

4.4. Dose Escalations

Dose escalation decisions (only within the healthy volunteer cohorts) will be made when at least 8 participants have completed the dosing period of the stated dose level. To implement these decisions, the available AEs and laboratory test data will be evaluated at a meeting or teleconference by the SRC. Drug administration at the next dose level will not proceed until the investigator receives written confirmation from Sponsor indicating that the results of the previous dose level were evaluated by the SRC, and that it is permissible to proceed.

Dose escalation increments will be up to a maximum of 5-fold, as detailed in Table 7. The rationale for this increment is that Veillonella parvula strain A- G.I. contains a gamma irradiated human commensal organism with minimal risk to participants.

In the patient cohorts 3, 4 and 5, the dose is 2-fold lower than the maximum dose used in the healthy volunteer cohorts. There will be no dose escalation within or between these patient cohorts.

4.5. Study Stopping Criteria

Safety data will be evaluated against the stopping rules below on an ongoing basis. If either the investigator or Sponsor considers an event to be either moderate or severe and possibly related to study treatment, the treatment for that participant(s) will be unblinded to determine if they were receiving Veillonella parvula strain A- G.I. If one or more of the criteria listed below are met for a participant(s) on active treatment, dosing will stop and no other participants will receive this or a higher dose until the data has been reviewed by the SRC. Prior to restarting the dosing, an amended protocol will be submitted for review and approval.

• One participant experiences an SAE that is related to study intervention

• More than one participant experiences an AE of severe intensity that is related to study intervention

• Two participants in the same cohort (within the same period for cohort 1 and 2) experience the same AE of moderate intensity that is related to the study intervention • One participant meets the following criteria for drug-induced liver injury as defined by the US Food and Drug Administration (FDA) in Guidance for Industry Drug Induced Liver Injury: Premarketing Clinical Evaluation (FDA, 2009) o Hepatocellular injury (> 3-fold elevations above ULN for AST or ALT); and o Elevation of serum total bilirubin to > 2 x ULN, without initial findings of cholestasis (serum ALP activity > 2 x ULN); and o No other reason can be found to explain the combination of increased transaminase and serum total bilirubin (such as viral hepatitis, pre-existing or acute liver disease, or another drug capable of causing the observed injury)

Elevations of transaminases and bilirubin of clinical concern should be confirmed on a repeat sample 48 to 72 hours later.

• Two participants experience either AST or ALT > 3 x ULN or elevation of serum total bilirubin to > 2 x ULN

• The Principal Investigator (or delegate) or Sponsor may decide to halt escalation for other reasons.

Participants experiencing any of the above will be followed up until the AE has resolved.

5. Discontinuation of Study Intervention and Participant

Discontinuation/Withdrawal

5.1. Discontinuation of Study Intervention

Discontinuation of study intervention for abnormal liver function should be considered by the investigator when a participant meets the conditions outlined in Appendix 5 or if the investigator believes that it is in the best interest of the participant.

If a clinically significant finding is identified (including, but not limited to changes from baseline in QT interval corrected using Fridericia’s formula [QTcF]) after enrolment, the investigator or qualified designee will determine if the participant can continue in the study and if any change in participant management is needed. This review of the ECG printed at the time of collection must be documented. Any new clinically relevant finding should be reported as an AE. Refer to the SoA for data to be collected at the time of intervention discontinuation and follow-up and for any further evaluations that need to be completed.

A participant who discontinues the study medication may continue with the scheduled visits as per protocol. This will be decided on a case-by-case basis.

5.1.1. Temporary Discontinuation

In the healthy volunteer cohorts (1 and 2), dosing may be temporarily suspended dosing at the investigator's discretion in discussion with the Medical Monitor due to AE, intercurrent illness or any other reason for a period of up to 2 days, following which, the participant may continue with the remaining doses if the investigator considers it safe to do so.

In the clinical cohorts (3, 4 and 5), dosing may be temporarily suspended at the investigator's discretion in discussion with the Medical Monitor due to AE, intercurrent illness or any other reason for a period of up to 1 week, following which, the participant may continue with the remaining doses if the investigator considers it safe to do so.

If dosing is temporarily suspended due to a particular AE, the participant should discontinue permanently if the same AE occurs a second time.

5.1.2. Re-challenge

Re-challenge for participants who have discontinued for liver or cardiac effects is not permitted. If participants have discontinued for other reasons not related to safety or tolerability issues, prior approval is required prior to a participant being re-challenged. 6. Study Assessments and Procedures

• Study procedures and their timing are summarised in the SoA (Section 0).

6.1. Efficacy Assessments

Planned timepoints for all efficacy assessments are provided in the SoA.

In the patient cohorts, the following efficacy measurements will be collected at the planned timepoints as provided in the SoA.

Cohort 3 (atopic dermatitis):

6.1.1. EASI

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.

6.1.2. SCORAD

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.

6.1.3. BSA

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.

6.1.4. IGA

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). 6.1.5. IGAx BSA

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.

6.1.6. DLQI questionnaire

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.

6.1.7. POEM questionnaire

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.

6.1.8. Pruritus NRS questionnaire

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.

Cohort 4 (psoriasis):

6.1.9. PASI score

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.

6.1.10. LSS

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.

6.1.11. BSA

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.

6.1.12. PGA

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.

6.1.13. PGAx BSA

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).

6.1.14. DLQI questionnaire

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. Photographs of Lesions (cohorts 3 and 4 only)

In addition, in cohorts 3 and 4 photographs should be taken of up to 6 lesion sites at baseline (ideally, 3 representative of overall disease and 3 representative of maximal disease). The same sites should be photographed at baseline and at day 56. Where possible photographs should be taken in natural light without using a camera flash.

Cohort 5 (asthma):

6.1.15. FeNO

The Fractional exhaled Nitric Oxide (FeNO) test is a simple test to assess the amount of nitric oxide in the breath; carried out because increased levels are associated with asthma that is characterised by type 2 airway inflammation (Fahy, 2015). A higher score correlates with greater type 2 inflammation (Dweik, 2011).

FeNO will be measured at the timepoints detailed in the SoA, and will be performed in accordance with site SOPs and the ATS/ERS 2005 guidelines (ATS/ERS 2005). At least 2 measurements that agree within 10% of each other will be recorded at each designated visit/time-point, with the average of the 2 chosen values reported. Where more than 2 measurements were performed, the two closest values that meet the reproducibility criteria will be used (not necessarily the highest two values).

6.1.16. FEV1 and FVC

The forced expiratory volume in one second (FEV1) is the amount of air that a participant can exhale in one second. The forced vital capacity (FVC) is the total amount of air that can be exhaled.

These measurements, as well as the FEV1/FVC ratio, are a measure of airflow limitation and lung function. They may be used to diagnose asthma, and also to assess asthma severity and responses to treatment. ATS/ERS criteria will be used to gauge the quality of each measurement. Three acceptable FEV1/FVC ratio readings are required, of which the best two should be within 100 mL and 5% of each other.

Spirometry will be measured as detailed in the SoA using a spirometer that meets the American Thoracic Society (ATS)/European Respiratory Society (ERS) recommendations. Spirometry will be performed in accordance with ATS/ERS 2019 criteria. Predicted normal values to be used are based on the Global Lung Function Initiative predicted values (GLI) (Quanjer, 2012)

6.1.17. PEF

The peak expiratory flow (PEF) is a measure of a participant’s maximum speed (flow-rate) of expiration. It provides another measure of airflow limitation used in the diagnosis and monitoring of asthma.

6.2. Safety Assessments

Planned timepoints for all safety assessments are provided in the SoA.

6.2.1. Physical Examinations

• A complete physical examination will include, at a minimum, assessments of the cardiovascular, respiratory, oral cavity, GI and neurological systems. Height (screening only) and weight will also be measured and recorded.

6.2.2. Vital Signs

• Blood pressure, pulse rate, respiratory rate, oxygen saturations and temperature will be assessed.

• Blood pressure and pulse measurements will be assessed in a sitting position with a completely automated device. • Blood pressure and pulse measurements should be preceded by at least 5 minutes of rest for the participant in a quiet setting without distractions (e.g. television, mobile phones).

• Vital signs (to be checked prior to dosing and/or any procedures) will consist of 3 pulse and 3 blood pressure measurements

(3 consecutive blood pressure readings will be recorded at intervals of at least 1 minute). The average of the 3 pulse and blood pressure readings will be recorded on the CRE

6.2.3. Electrocardiograms

• 12-lead ECGs will be obtained as outlined in the SoA (see Section 0) using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and the corrected QT (QTcf) intervals. Refer to Section 6 for QTc withdrawal criteria and any additional QTc readings that may be necessary.

• ECG measurements will be assessed in a supine position preceded by at least 10 minutes of rest.

• Post-dose ECGs should be conducted within 2 hours after the dose.

• ECGs will be measured in triplicate in the healthy volunteer cohorts (cohorts 1 and 2). For the patient cohorts (cohorts 3, 4 and 5), a single ECG is sufficient.

6.2.4. Strain-specific PCR for Veillonella parvula strain A- G.I.

• Plasma samples will be taken from participants at the specified timepoints, to assess for the presence of Veillonella parvula strain A- G.I. levels by PCR with strain-specific primers that can detect Veillonella parvula strain A- G.I. specifically, even when other strains of Viellonella Parvula are present.

6.2.5. Clinical Safety Laboratory Assessments

• See Appendix 4 for the list of clinical laboratory tests to be performed and the SoA (Section 0) for the timing and frequency.

6.3. Adverse Events and Serious Adverse Events

The definitions of an AE or SAE can be found in Appendix 3. 6.4. Pharmacokinetics

Pharmacokinetic (PK) parameters are not evaluated in this study due to the nature of the therapy. Veillonella parvula strain A- G.I. is orally administered and exposure is restricted to the gut with no expected systemic exposure. Samples will be taken to confirm the lack of systemic absorption (qPCR) through the study but specific PK parameters will not be derived. Microbiome samples will be analysed during the study (see Section 0) to look for colonisation, although this is not expected.

6.5. Biomarkers

Collection of blood samples for other biomarker research is also part of this study.

• Blood samples may be used for ex-vivo stimulation analysis (all cohorts).

• In the asthma and atopic dermatitis cohorts, eosinophil levels (taken from safety laboratory assessment) and serum IgE will be measured as biomarkers of atopic disease.

6.5.1. Microbiome Research

Faeces and faecal fluid analysis may be performed to understand the effects of Veillonella parvula strain A- G.I. on the individual’ s microbiome either during treatment or following cessation of treatment. Associations of specific microbes within the microbiome and drug response may also be investigated if there is marked variability in response. Microbiome analysis will be performed through 16s sequencing and/or whole genome microbial sequencing depending on the question being asked.

7. Statistical Considerations

All analyses will be performed using SAS® version 9.4 or later (SAS Institute, Cary, NC, USA).

For continuous variables, summary statistics will include the number of participants, mean, median, standard deviation (SD), minimum and maximum. For categorical variables, summary statistics will include the number and percentage of participants.

7.1. Sample Size Determination

The primary objective of this FIH study is to assess the safety and tolerability of Veillonella parvula strain A- G.I. A formal statistical power calculation was not performed.

The sample size has been chosen to explore the tolerability and safety of this new treatment, while limiting exposure to a minimum number of participants. A larger sample size has been determined for Cohorts 3 to 5 to allow useful conclusions to be drawn about the disease-related efficacy endpoints.

7.2. Populations for Analyses

For purposes of analysis, the following populations are defined:

7.3. Estimands and Intercurrent Events

All efficacy estimands will be considered secondary as the primary objective of this study is to assess safety and tolerability. Endpoint: Secondary estimands will be constructed for the following endpoints:

Population of interest: For all estimands, the evaluable population relevant to the endpoint will be used. For example, the evaluable-atopic dermatitis population will be used for the estimands which examines the EASI endpoint.

Intercurrent events: For all estimands, a treatment-policy strategy will be used in the case of premature discontinuation of study treatment with only data collected prior to treatment discontinuation used in the analyses. No other intercurrent events will be considered. Population-level summary measure: For continuous endpoints, the population level summary measure of interest will be the difference in mean change and mean percentage change from baseline between Veillonella parvula strain A- G.I. and placebo. For response endpoints, population level summary measure will be the risk difference between Veillonella parvula strain A- G.I. and placebo in rates of response.

7.4. Statistical Analyses

The statistical analysis plan (SAP) will be developed and finalised before database lock and will fully describe participant populations to be included in the analyses, and procedures for accounting for missing, unused, and spurious data. This section is a summary of the planned statistical analysis of the primary and secondary endpoints.

7.4.1. Efficacy Analyses

The primary objective of this FIH study is to assess the safety and tolerability of Veillonella parvula strain A- G.I. and as such all efficacy analyses will be considered as secondary.

All efficacy data will be summarised and analysed within cohort for Cohorts 3, 4 and 5. Baseline will be taken as the Day 1 evaluation. If this is missing, the last non-missing data point before first dose of study treatment will be used.

Continuous data will be summarised and an MMRM will be fitted with treatment, baseline value, visit fitted as fixed effects together with treatment* visit and baseline*visit interactions. Least square mean estimates will be presented for the endpoint value at each visit and the difference between the treatments together with their 95% confidence intervals.

Categorical data will have the number and percentage of participants within each category presented. Shifts from baseline will also be presented.

Response data will show the number and percentage of participants to report the response at each visit with exact 95% confidence intervals given for the percentages. The risk difference and 95% confidence interval for difference between Veillonella parvula strain A- G.I. will be calculated and the treatment groups will also be compared with a Fisher’s exact test.

Count data will have a Poisson regression model fitted with treatment and baseline (number of occurrences in the 7 days before first dose) as covariates. For the number of exacerbations endpoint, the total number of exacerbations across the length of the study will be analysed with an offset of log(days on treatment) included in the model to account for data from any participants who withdraw prematurely. For the number of puffs of SABA medications in the prior 7 days, separate models will be analysed at Days 28 and 56.

Graphical representations of the endpoint data will also be presented.

7.5. Safety Analyses All safety summaries will be performed on the Safety population.

Data will be presented by indication (healthy volunteers, atopic dermatitis, psoriasis, asthma) and treatment.

For two cohorts of the healthy volunteers, adverse events and other safety data will be assigned to treatment dose as follows:

Adverse events will be coded using the latest available version of the Medical Dictionary for Regulatory Activities (MedDRA).

Incidence of all treatment-emergent AEs, SAEs, treatment-related AEs and AEs leading to permanent discontinuation of study treatment will be presented by system organ class and preferred term. Safety laboratory measurements will be summarised by visit, including change from baseline and shifts from baseline with respect to the normal ranges.

ECGs taken in triplicate will be averaged across the three reading prior to any summarisation.

ECG parameters and vital signs will be summarised by visit, including change from baseline.

7.6. Appendix 2: Contraceptive Guidance and Collection of Pregnancy Information

Definitions:

Woman of Child-Bearing Potential (WOCBP) A woman is considered fertile following menarche and until becoming postmenopausal unless permanently sterile (see below).

Women in the following categories are not considered WOCBP:

1. Premenarchal

2. Premenopausal female with 1 of the following:

• Documented hysterectomy

• Documented bilateral salpingectomy

• Documented bilateral oophorectomy

Note: Documentation can come from the site personnel’s review of the participant’s medical records, medical examination, or medical history interview.

3. Postmenopausal female

• A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy (HRT). However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.

• Females on HRT and whose menopausal status is in doubt will be required to use one of the non-oestrogen hormonal highly effective contraception methods if they wish to continue their HRT during the study.

Contraception Guidance:

Male participants with a female partner of child-bearing potential must either

• Be abstinent from penile-vaginal intercourse as their usual and preferred lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent

• Use a male condom during each episode of penile penetration during their participation in the study and for 90 days after the last dose of study drug.

• Have a confirmed vasectomy.

In addition, all male participants must refrain from donating sperm for the duration of the study and for at least 90 days following their final visit. Female participants

Female participants of child-bearing potential are eligible to participate if they agree to use a highly effective method of contraception consistently and correctly as described in Table 9

Table 9: Highly Effective Contraceptive Methods Highly Effective Contraceptive Methods That Are User Dependent³

Failure rate of < 1% per year when used consistently and correctly.

Pregnancy Testing:

• WOCBP should only be included after a confirmed menstrual period and a negative serum HCG pregnancy test.

• Pregnancy testing is required at screening.

• Pregnancy testing will be performed whenever a menstrual cycle is missed or when pregnancy is otherwise suspected.

Collection of Pregnancy Information:

Male participants with partners who become pregnant

• The investigator will attempt to collect pregnancy information on any male participant’s female partner who becomes pregnant while the male participant is in this study. This applies to all male participants who receive Veillonella parvula strain A- G.I.

• After obtaining the necessary signed informed consent from the pregnant female partner directly, the investigator will record pregnancy information on the appropriate form and submit it to the Sponsor within 24 hours of learning of the partner’s pregnancy. The female partner will also be followed to determine the outcome of the pregnancy. Information on the status of the mother and child will be forwarded to the Sponsor. Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated delivery date. Any termination of the pregnancy will be reported regardless of foetal status (presence or absence of anomalies) or indication for the procedure.

Female participants who become pregnant

• The investigator will collect pregnancy information on any female participant who becomes pregnant while participating in this study. Information will be recorded on the appropriate form and submitted to the Sponsor within 24 hours of learning of a participant's pregnancy. The participant will be followed to determine the outcome of the pregnancy. The investigator will collect follow-up information on the participant and the neonate and the information will be forwarded to the Sponsor. Generally, follow-up will not be required for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of pregnancy will be reported, regardless of foetal status (presence or absence of anomalies) or indication for the procedure.

• While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or elective termination of a pregnancy will be reported as an AE or SAE. A spontaneous abortion is always considered to be an SAE and will be reported as such. Any post-study pregnancy related- SAE considered reasonably related to the study intervention by the investigator will be reported to the Sponsor. While the investigator is not obligated to actively seek this information in former study participants, he or she may learn of an SAE through spontaneous reporting.

• Any female participant who becomes pregnant while participating in the study will discontinue study intervention or be withdrawn from the study.

7.7. Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reporting

Definition of AE

Definition of SAE

7.8. Appendix 4: Clinical Laboratory Tests

Tests are detailed in Table 10.

• Protocol-specific requirements for inclusion or exclusion of participants are detailed in Section 4 of the protocol.

• Additional tests may be performed at any time during the study as deemed necessary by the investigator or required by local regulations.

Table 10: Protocol Required Safety Laboratory Assessments

7.9. Appendix 5: Liver Safety: Suggested Actions and Follow-up Assessments

Any participant should stop dosing if ALT or AST is > 3 x ULN and/or bilirubin is > 2 x ULN. Liver function test (LFT) monitoring should be carried out until abnormal LFTs are back to within the normal range. Routine investigations should be performed to exclude viral/infectious causes of liver abnormalities.

References:

ATS/ERS. ATS/ERS Recommendations for Standardized Procedures for the Online and Offline Measurement of Exhaled Lower Respiratory Nitric Oxide and Nasal Nitric Oxide, 2005. Am J Respir Crit Care Med. 2005: 171: 912-930.

Dweik RA, Bogg PB, Erzurum SC et al. An Official ATS Clinical Practice Guideline: Interpretation of Exhaled Nitric Oxide Levels (FENO) for Clinical Applications. Am J Respir Crit Care Med. 2011 May; 184: 602-615.

Eczema Area and Severity Index (EASI) Guidance. 2017 Jan; Version 3.0.

European Task Force on Atopic Dermatitis (ETFAD). Severity Scoring of Atopic Dermatitis: The SCORAD Index. Dermatol. 1993; 186: 23-31.

Fahy JV. Type 2 inflammation in asthma— present in most, absent in many. Nat Rev Immunol. 2015 Jan; 15(l):57-65.

FDA Guidance for Industry: Drug-Induced Liver Injury: Premarketing Clinical Evaluation. 2009 July.

Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI): a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19:210-6.

Feldman SR, Krueger GG. Psoriasis assessment tools in clinical trials. Ann Rheum Dis. 2005 Mar; 64 Suppl 2:ii65-8; discussion U69-73.

Karasov WH. Terrestrial vertebrates. In: Sibly RM, Brown JH, Kodric-Brown A, editors. Metabolic Ecology: A Scaling Approach. Hoboken, NJ: Wiley-Blackwell; 2012. p. 212- 224.

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

Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-Ethnic Reference Values for Spirometry for the 3 - 95 Year Age Range: The Global Lung Function 2012 Equations: Report of the Global Lung Function Initiative (GLI), ERS Task Force to establish improved Lung Function Reference Values. Eur Respir J. 2012 Dec; 40(6): 1324-1343.

Simpson E, Bissonnette R, Eichenfield LF, et al. The Validated Investigator Global Assessment for the Atopic Dermatitis (vIGA-AD): The development and reliability testing of a novel clinical outcome measurement instrument for the severity of atopic dermatitis. J Am Acad Dermatiol. 2020 Sep; 83(3): 839-846.

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.

Example 4: Additional psoriasis read-outs

The effects of Veillonella parvula strain A- G.I. 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

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).

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 (ie, 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.

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.

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.

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).

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: 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).

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).

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 within-subject change (p<0.0001).

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

In embodiments, provided herein is a method of treating psoriasis comprising administering (e.g., orally administering) to a human subject a Veillonella parvula strain and/or a composition (e.g., a bacterial composition and/or a solid dosage form) comprising a strain of a Veillonella parvula 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.

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.

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.

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.

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.

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.

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:

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

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.

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.

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, Ternowitz 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. Unidimensionality and reliability under Mokken scaling of the Dutch language version of the SF-36. Qual Life Res. 2003;12:189-98.

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.

Example 5: Veillonella parvula strain A- G.I. for the treatment of psoriatic arthritis

Veillonella parvula strain A- G.I. can be used for the treatment of psoriatic arthritis (PsA), e.g., at the doses and dosing regimens provided herein. The effects of Veillonella parvula strain A- G.I. on psoriatic arthritis can be evaluated by one or more of the following criteria:

Percentage of patients with anACR20, 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.

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/tenderness score and joint swelling score: improvement = decrease by 30%, worsening = increase by 30%.

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.

Clinical Disease Activity Index (CDAI): The Clinical Disease Activity Index (CDAI) 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.

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. ADAS28 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.

Maastricht Ankylosing Spondylitis Enthesis Score IMASI Sj: 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).

The effects of Veillonella parvula strain A- G.I. 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: Manufacturing conditions

Enriched media is used to grow and prepare the bacterium for in vitro and in vivo use. For example, media may contain sugar, yeast extracts, plant based peptones, buffers, salts, trace elements, surfactants, anti-foaming agents, and vitamins. Composition of complex components such as yeast extracts and peptones may be undefined or partially defined (including approximate concentrations of amino acids, sugars etc.). Microbial metabolism may be dependent on the availability of resources such as carbon and nitrogen. Various sugars or other carbon sources may be tested. Alternatively, media may be prepared and the selected bacterium grown as shown by Saarela et ah, ./. Applied Microbiology . 2005. 99: 1330-1339, which is hereby incorporated by reference. Influence of fermentation time, cryoprotectant and neutralization of cell concentrate on freeze-drying survival, storage stability, and acid and bile exposure of the selected bacterium produced without milk-based ingredients.

At large scale, the media is sterilized. Sterilization may be by Ultra High Temperature (UHT) processing. The UHT processing is performed at very high temperature for short periods of time. The UHT range may be from 135-180°C. For example, the medium may be sterilized from between 10 to 30 seconds at 135°C.

Inoculum can be prepared in flasks or in smaller bioreactors and growth is monitored. For example, the inoculum size may be between approximately 0.5 and 3% of the total bioreactor volume. Depending on the application and need for material, bioreactor volume can be at least 2L, 10L, 80L, 100L, 250L, 1000L, 2500L, 5000L, 10,000L.

Before the inoculation, the bioreactor is prepared with medium at desired pH, temperature, and oxygen concentration. The initial pH of the culture medium may be different that the process set-point. pH stress may be detrimental at low cell centration; the initial pH could be between pH 7.5 and the process set-point. For example, pH may be set between 4.5 and 8.0. During the fermentation, the pH can be controlled through the use of sodium hydroxide, potassium hydroxide, or ammonium hydroxide. The temperature may be controlled from 25°C to 45°C, for example at 37°C. Anaerobic conditions are created by reducing the level of oxygen in the culture broth from around 8mg/L to Omg/L. For example, nitrogen or gas mixtures (N2, C02, and H2) may be used in order to establish anaerobic conditions. Alternatively, no gases are used and anaerobic conditions are established by cells consuming remaining oxygen from the medium. Depending on strain and inoculum size, the bioreactor fermentation time can vary. For example, fermentation time can vary from approximately 5 hours to 48 hours.

For example, a frozen vial is diluted to 0.1% in a 1L media at 37C for 12-16 hours.

The media is PM11 with 1 g/1 L-sodium lactate (no FeS04, no NH4C1, no malate). The 1L media is diluted to 1% in a 15L bioreactor at 37, 150rpm, gas of 5% CO2 and 95% N2, uncontrolled pH for 16-18 hours. The feed is 10X YEP, 33 g/1 L-sodium lactate (no G2) (Constant feed: llmL/Lh). It is then centrifuged at 10,000 g, IOC, for 10 minutes to collect 90 g pellet/15L. Then placed in a new stabilizer: sucrose-dextran-cycteine 0.18 g stab/g pellet.

Reviving microbes from a frozen state may require special considerations. Production medium may stress cells after a thaw; a specific thaw medium may be required to consistently start a seed train from thawed material. The kinetics of transfer or passage of seed material to fresh medium, for the purposes of increasing the seed volume or maintaining the microbial growth state, may be influenced by the current state of the microbes (ex. exponential growth, stationary growth, unstressed, stressed).

Inoculation of the production fermenter(s) can impact growth kinetics and cellular activity. The initial state of the bioreactor system must be optimized to facilitate successful and consistent production. The fraction of seed culture to total medium ( e.g . a percentage) has a dramatic impact on growth kinetics. The range may be 1-5% of the fermenter’s working volume. The initial pH of the culture medium may be different from the process set-point. pH stress may be detrimental at low cell concentration; the initial pH may be between pH 7.5 and the process set-point. Agitation and gas flow into the system during inoculation may be different from the process set-points. Physical and chemical stresses due to both conditions may be detrimental at low cell concentration.

Process conditions and control settings may influence the kinetics of microbial growth and cellular activity. Shifts in process conditions may change membrane composition, production of metabolites, growth rate, cellular stress, etc. Optimal temperature range for growth may vary with strain. The range may be 20-40 °C. Optimal pH for cell growth and performance of downstream activity may vary with strain. The range may be pH 5-8. Gasses dissolved in the medium may be used by cells for metabolism. Adjusting concentrations of O2, CO2, and N2 throughout the process may be required. Availability of nutrients may shift cellular growth. Microbes may have alternate kinetics when excess nutrients are available. The state of microbes at the end of a fermentation and during harvesting may impact cell survival and activity. Microbes may be preconditioned shortly before harvest to better prepare them for the physical and chemical stresses involved in separation and downstream processing. A change in temperature (often reducing to 20-5 °C) may reduce cellular metabolism, slowing growth (and/or death) and physiological change when removed from the fermenter. Effectiveness of centrifugal concentration may be influenced by culture pH. Raising pH by 1-2 points can improve effectiveness of concentration but can also be detrimental to cells. Microbes may be stressed shortly before harvest by increasing the concentration of salts and/or sugars in the medium. Cells stressed in this way may better survive freezing and lyophilization during downstream.

Separation methods and technology may impact how efficiently microbes are separated from the culture medium. Solids may be removed using centrifugation techniques. Effectiveness of centrifugal concentration can be influenced by culture pH or by the use of flocculating agents. Raising pH by 1-2 points may improve effectiveness of concentration but can also be detrimental to cells. Microbes may be stressed shortly before harvest by increasing the concentration of salts and/or sugars in the medium. Cells stressed in this way may better survive freezing and lyophilization during downstream. Additionally, Microbes may also be separated via filtration. Filtration is superior to centrifugation techniques for purification if the cells require excessive g-minutes to successfully centrifuge. Excipients can be added before after separation. Excipients can be added for cryo protection or for protection during lyophilization. Excipients can include, but are not limited to, sucrose, trehalose, or lactose, and these may be alternatively mixed with buffer and anti-oxidants. Prior to lyophilization, droplets of cell pellets mixed with excipients are submerged in liquid nitrogen.

Harvesting can be performed by continuous centrifugation. Product may be resuspended with various excipients to a desired final concentration. Excipients can be added for cryo protection or for protection during lyophilization. Excipients can include, but are not limited to, sucrose, trehalose, or lactose, and these may be alternatively mixed with buffer and anti -oxidants. Prior to lyophilization, droplets of cell pellets mixed with excipients are submerged in liquid nitrogen.

Lyophilization of material, including live bacteria, begins with primary drying.

During the primary drying phase, the ice is removed. Here, a vacuum is generated and an appropriate amount of heat is supplied to the material for the ice to sublime. During the secondary drying phase, product bound water molecules are removed. Here, the temperature is raised higher than in the primary drying phase to break any physico chemical interactions that have formed between the water molecules and the product material. The pressure may also be lowered further to enhance desorption during this stage. After the freeze-drying process is complete, the chamber may be filled with an inert gas, such as nitrogen. The product may be sealed within the freeze dryer under dry conditions, preventing exposure to atmospheric water and contaminants. Incorporation by Reference

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

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 dose of about 3 x 10¹⁰to about 1.5 x 10¹² total cells of a Veillonella parvula strain, wherein the Veillonella parvula strain is a strain comprising at least 95% sequence identity to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

2. The method of claim 1, wherein the Veillonella parvula are Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

3. The method of claim 1 or 2, wherein the Veillonella parvula are formulated in one or more capsules or tablets.

4. The method of any one of claims 1-3, wherein the capsules or tablets are enteric coated.

5. The method of any one of claims 1-4, wherein the Veillonella parvula are gamma irradiated.

6. The method of any one of claims 1-5, wherein the bacterial composition comprises about 3 x 10¹⁰ total cells of Veillonella parvula.

7. The method of any one of claims 1-5, wherein the bacterial composition comprises about 4.5 x 10¹⁰ total cells of Veillonella parvula.

8. The method of any one of claims 1-5, wherein the bacterial composition comprises about 1.5 x 10¹¹ total cells of Veillonella parvula.

9. The method of any one of claims 1-5, wherein the bacterial composition comprises about 7.5 x 10¹¹ total cells of Veillonella parvula.

10. The method of any one of claims 1-5, wherein the bacterial composition comprises about 1.5 x 10¹² total cells of Veillonella parvula.

11. The method of any one of claims 1-10, wherein the bacterial composition is administered at least once daily.

12. The method of any one of claims 1-10, wherein the bacterial composition is administered once daily.

13. The method of any one of claims 1-10, wherein the bacterial composition is administered once daily for at least 15 continuous days.

14. The method of claim 1-10, wherein the bacterial composition is administered once daily for at least 28 continuous days.

15. The method of claim 1-10, wherein the bacterial composition is administered once daily for at least 56 continuous days.

16. The method of any one of claims 1-15, wherein the psoriasis is moderate psoriasis.

17. A method of treating atopic dermatitis in a human subject comprising orally administering to the human subject a dose of about 3 x 10¹⁰to about 1.5 x 10¹² total cells of a Veillonella parvula strain, wherein the Veillonella parvula strain is a strain comprising at least 95% sequence identity to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

18. The method of claim 17, wherein the Veillonella parvula are Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

19. The method of claim 17 or 18, wherein the Veillonella parvula are formulated in one or more capsules or tablets.

20. The method of any one of claims 17-19, wherein the capsules or tablets are enteric coated.

21. The method of any one of claims 17-20, wherein the Veillonella parvula are gamma irradiated.

22. The method of any one of claims 17-21, wherein the bacterial composition comprises about 3 x 10¹⁰ total cells of Veillonella parvula.

23. The method of any one of claims 17-21, wherein the bacterial composition comprises about 4.5 x 10¹⁰ total cells of Veillonella parvula.

24. The method of any one of claims 17-21, wherein the bacterial composition comprises about 1.5 x 10¹¹ total cells of Veillonella parvula.

25. The method of any one of claims 17-21, wherein the bacterial composition comprises about 7.5 x 10¹¹ total cells of Veillonella parvula.

26. The method of any one of claims 17-21, wherein the bacterial composition comprises about 1.5 x 10¹² total cells of Veillonella parvula.

27. The method of any one of claims 17-26, wherein the bacterial composition is administered at least once daily.

28. The method of any one of claims 17-26, wherein the bacterial composition is administered once daily.

29. The method of any one of claims 17-26, wherein the bacterial composition is administered once daily for at least 15 continuous days.

30. The method of claim 17-26, wherein the bacterial composition is administered once daily for at least 28 continuous days.

31. The method of claim 17-26, wherein the bacterial composition is administered once daily for at least 56 continuous days.

32. The method of any one of claims 17-31, wherein the atopic dermatitis is moderate atopic dermatitis.

33. A method of treating asthma in a human subject comprising orally administering to the human subject a dose of about 3 x 10¹⁰to about 1.5 x 10¹² total cells of a Veillonella parvula strain, wherein the Veillonella parvula strain is a strain comprising at least 95% sequence identity to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

34. The method of claim 33, wherein the Veillonella parvula are Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

35. The method of claim 33 or 34, wherein the Veillonella parvula are formulated in one or more capsules or tablets.

36. The method of any one of claims 33-35, wherein the capsules or tablets are enteric coated.

37. The method of any one of claims 33-36, wherein the Veillonella parvula are gamma irradiated.

38. The method of any one of claims 33-37, wherein the bacterial composition comprises about 3 x 10¹⁰ total cells of Veillonella parvula.

39. The method of any one of claims 33-37, wherein the bacterial composition comprises about 4.5 x 10¹⁰ total cells of Veillonella parvula.

40. The method of any one of claims 33-37, wherein the bacterial composition comprises about 1.5 x 10¹¹ total cells of Veillonella parvula.

41. The method of any one of claims 33-37, wherein the bacterial composition comprises about 7.5 x 10¹¹ total cells of Veillonella parvula.

42. The method of any one of claims 33-37, wherein the bacterial composition comprises about 1.5 x 10¹² total cells of Veillonella parvula.

43. The method of any one of claims 33-42, wherein the bacterial composition is administered at least once daily.

44. The method of any one of claims 33-42, wherein the bacterial composition is administered once daily.

45. The method of any one of claims 33-42, wherein the bacterial composition is administered once daily for at least 15 continuous days.

46. The method of claim 33-42, wherein the bacterial composition is administered once daily for at least 28 continuous days.

47. The method of claim 33-42, wherein the bacterial composition is administered once daily for at least 56 continuous days.

48. The method of any one of claims 33-47, wherein the asthma is mild asthma.

49. A method of treating psoriatic arthritis in a human subject comprising orally administering to the human subject a dose of about 3 x 10¹⁰to about 1.5 x 10¹² total cells of a Veillonella parvula strain, wherein the Veillonella parvula strain is a strain comprising at least 95% sequence identity to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

50. The method of claim 49, wherein the Veillonella parvula are Veillonella parvula strain A (ATCC Deposit Number PTA-125691).

51. The method of claim 49 or 50, wherein the Veillonella parvula are formulated in one or more capsules or tablets.

52. The method of any one of claims 49-51, wherein the capsules or tablets are enteric coated.

53. The method of any one of claims 49-52, wherein the Veillonella parvula are gamma irradiated.

54. The method of any one of claims 49-53, wherein the bacterial composition comprises about 3 x 10¹⁰ total cells of Veillonella parvula.

55. The method of any one of claims 49-53, wherein the bacterial composition comprises about 4.5 x 10¹⁰ total cells of Veillonella parvula.

56. The method of any one of claims 49-53, wherein the bacterial composition comprises about 1.5 x 10¹¹ total cells of Veillonella parvula.

57. The method of any one of claims 49-53, wherein the bacterial composition comprises about 7.5 x 10¹¹ total cells of Veillonella parvula.

58. The method of any one of claims 49-53, wherein the bacterial composition comprises about 1.5 x 10¹² total cells of Veillonella parvula.

59. The method of any one of claims 49-58, wherein the bacterial composition is administered at least once daily.

60. The method of any one of claims 49-58, wherein the bacterial composition is administered once daily.

61. The method of any one of claims 49-58, wherein the bacterial composition is administered once daily for at least 15 continuous days.

62. The method of claim 49-58, wherein the bacterial composition is administered once daily for at least 28 continuous days.

63. The method of claim 49-58, wherein the bacterial composition is administered once daily for at least 56 continuous days.