WO2022187064A1 - Compositions et procédés de traitement d'une inflammation à l'aide de prevotella histicola - Google Patents
Compositions et procédés de traitement d'une inflammation à l'aide de prevotella histicola Download PDFInfo
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Classifications
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- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
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- A61K9/4891—Coated capsules; Multilayered drug free capsule shells
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- A61P17/00—Drugs for dermatological disorders
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- A61P37/00—Drugs for immunological or allergic disorders
Definitions
- bacterial compositions comprising Prevotella histicola useful for the treatment and/or prevention of an inflammatory disease.
- the inflammatory disease is a Thl, Th2, or Thl7 inflammatory disease.
- bacterial compositions e.g., pharmaceutical compositions
- Prevotella histicola useful for the treatment and/or prevention of an immune disorder.
- bacterial compositions comprising Prevotella histicola useful for the treatment and/or prevention of psoriasis (e.g., mild to moderate psoriasis) (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of psoriasis, for the reduction of Lesion Severity Scores (LSS), and/or for the reduction of Psoriasis Area Severity Index (PASI) scores).
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- bacterial compositions comprising Prevotella histicola useful for the treatment and/or prevention of atopic dermatitis (e.g., mild, moderate, or severe atopic dermatitis) (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of atopic dermatitis and/or for an improvement in EASI score).
- bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- bacterial compositions comprising Prevotella histicola useful for the treatment and/or prevention of psoriatic arthritis, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of psoriatic arthritis).
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- bacterial compositions comprising Prevotella histicola useful for the treatment and/or prevention of an autoimmune disease, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of an autoimmune disease).
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- bacterial compositions comprising Prevotella histicola useful for the treatment and/or prevention of an inflammatory disease, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of an inflammatory disease).
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- bacterial compositions comprising Prevotella histicola useful for the treatment and/or prevention of a metabolic disease, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of a metabolic disease).
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- bacterial compositions comprising Prevotella histicola useful for the treatment and/or prevention of a dysbiosis, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of a dysbiosis).
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- bacterial compositions e.g.
- compositions comprising Prevotella histicola useful for decreasing inflammatory cytokine expression (e.g., decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels), (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for decreasing inflammatory cytokine expression (e.g., decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels)).
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-bve bacteria, killed bacteria, attenuated bacteria).
- bacterial compositions comprising Prevotella histicola useful for the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of bacterial septic shock, cytokine storm and/or viral infection).
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- bacterial compositions comprising Prevotella histicola useful for the treatment and/or prevention of a viral infection, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of a viral infection).
- the viral infection is a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection.
- the viral infection is a SARS-CoV-2 infection.
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-bve bacteria, killed bacteria, attenuated bacteria).
- the Prevotella histicola is Prevotella Strain B 50329 (NRRL accession number B 50329; Strain B).
- the Prevotella strain is a strain comprising at least at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Prevotella Strain B 50329.
- 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
- the bacterial composition comprises one strain of bacteria, wherein the one strain of bacteria is a strain comprising at least 99.9% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329). In some embodiments, the bacterial composition comprises one strain of bacteria, wherein the one strain of bacteria is the Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
- the bacterial compositions are prepared as solid dosage forms.
- solid dosage forms comprising the Prevotella histicola bacteria.
- the solid dosage form comprises an enteric coating.
- the solid dosage form is a tablet, e.g., an enteric coated tablet.
- each tablet comprises about 3.2 x 10 11 total cells of the Prevotella histicola bacteria.
- the solid dosage form is a capsule e.g., an enteric coated capsule.
- each capsule comprises about 8 x 10 10 total cells of the Prevotella histicola bacteria.
- each capsule comprises about 1.6 x 10 11 total cells of the Prevotella histicola bacteria. In some embodiments, each capsule comprises about 3.2 x 10 11 total cells (e.g., 3.35 x 10 11 total cells) of the Prevotella histicola bacteria.
- from 1.6 x 10 10 cells to 16 x 10 11 cells of the Prevotella histicola strain are administered to the subject daily, e.g., in a solid dosage form.
- from 8 x 10 11 cells to 16 x 10 11 cells of the Prevotella histicola strain are administered to the subject daily, e.g., in a solid dosage form.
- from 8 x 10 10 cells to 8 x 10 11 cells of the Prevotella histicola strain are administered to the subject daily, e.g., in a solid dosage form.
- from 8 x 10 10 cells to 1.6 x 10 11 cells of the Prevotella histicola strain are administered to the subject daily, e.g., in a solid dosage form.
- from 1.6 x 10 11 cells to 8 x 10 11 cells of the Prevotella histicola strain are administered to the subject daily, e.g., in a solid dosage form.
- about 8 x 10 10 cells of the Prevotella histicola strain are administered to the subject daily, e.g., in a solid dosage form.
- about 1.6 x 10 11 cells of the Prevotella histicola strain are administered to the subject daily, e.g., in a solid dosage form.
- about 3.2 x 10 11 cells of the Prevotella histicola strain are administered to the subject daily, e.g., in a solid dosage form.
- about 6.4 x 10 11 cells of the Prevotella histicola strain are administered to the subject daily, e.g., in a solid dosage form.
- about 8 x 10 11 cells of the Prevotella histicola strain are administered to the subject daily, e.g., in a solid dosage form.
- about 1.6 x 10 11 cells of the Prevotella histicola strain are administered to the subject once daily, e.g., in a solid dosage form.
- about 1.6 x 10 11 cells of the Prevotella histicola strain are administered to the subject twice daily, e.g., in a solid dosage form. In some embodiments, about 1.6 x 10 11 cells of the Prevotella histicola strain are administered to the subject twice daily (e.g., for 1-7 days, 3 days, 7 days, 10 days, or 14 days), and then about 1.6 x 10 11 cells of the Prevotella histicola strain are administered to the subject once daily, e.g., for the duration of the treatment period (e.g., up to 14 days of total treatment), e.g., in a solid dosage form.
- the duration of the treatment period e.g., up to 14 days of total treatment
- about 3.2 x 10 11 total cells of the Prevotella histicola strain are administered to the subject daily.
- about 6.4 x 10 11 total cells of the Prevotella histicola strain are administered to the subject daily.
- about 9.6 x 10 11 total cells of the Prevotella histicola strain are administered to the subject daily.
- about 12.8 x 10 11 total cells of the Prevotella histicola strain are administered to the subject daily.
- about 16 x 10 11 total cells of the Prevotella histicola strain are administered to the subject daily.
- about 9.6 x 10 11 to about 16 x 10 11 total cells of the Prevotella histicola strain are administered to the subject daily.
- about 9.6 x 10 11 to about 12.8 x 10 11 total cells of the Prevotella histicola strain are administered to the subject daily.
- about 12.8 x 10 11 to about 16 x 10 11 total cells of the Prevotella histicola strain are administered to the subject daily.
- the bacterial composition comprises about 1.6 x 10 10 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329 (e.g., in a solid dosage form). [27] In some embodiments, the bacterial composition comprises about 8 x 10 10 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329 (e.g., in a solid dosage form).
- the bacterial composition comprises about 1.6 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329 (e.g., in a solid dosage form).
- the bacterial composition comprises about 3.2 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329 (e.g., in a solid dosage form).
- the bacterial composition comprises about 6.4 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329 (e.g., in a solid dosage form).
- the bacterial composition comprises about 8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329 (e.g., in a solid dosage form).
- the bacterial composition comprises about 1.6 x 10 10 to about 8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. (e.g., in a solid dosage form)
- the bacterial composition comprises about 1.6 x 10 10 to about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329 (e.g., in a solid dosage form).
- the bacterial composition comprises about 1.6 x 10 10 to about 1.6 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329 (e.g., in a solid dosage form).
- the bacterial composition comprises about 1.6 x 10 11 to about 8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329 (e.g., in a solid dosage form).
- the bacterial composition comprises about 8 x 10 10 to about 8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329(e.g., in a solid dosage form).
- the bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises at least 1 x 10 10 total cells (e.g., at least 1 x 10 10 total cells, at least 2 x 10 10 total cells, at least 3 x 10 10 total cells, at least 4 x 10 10 total cells, at least 5 x 10 10 total cells, at least 6 x 10 10 total cells, at least 7 x 10 10 total cells, at least 8 x 10 10 total cells, at least 9 x 10 10 total cells, at least 1 x 10 11 total cells of the Prevotella bacteria.
- at least 1 x 10 10 total cells e.g., at least 1 x 10 10 total cells, at least 2 x 10 10 total cells, at least 3 x 10 10 total cells, at least 4 x 10 10 total cells, at least 5 x 10 10 total cells, at least 6 x 10 total cells, at least 7 x 10 10 total cells, at least 8 x 10 10 total cells, at least 9 x 10 10
- the bacterial composition comprises no more than 9 x 10 11 total cells (e.g., no more than 1 x 10 10 total cells, no more than 2 x 10 10 total cells, no more than 3 x 10 10 total cells, no more than 4 x 10 10 total cells, no more than 5 x 10 10 total cells, no more than 6 x 10 10 total cells, no more than 7 x
- the bacterial composition comprises about 6 x 10 9 total cells of the Prevotella bacteria. In some embodiments, the bacterial composition comprises about 1.6 x 10 10 total cells of the Prevotella bacteria. In some embodiments, the bacterial composition comprises about 8 x 10 10 total cells of the Prevotella bacteria.
- the bacterial composition comprises about 1.6 x 10 11 total cells the Prevotella bacteria. In some embodiments, the bacterial composition comprises about 3.2 x 10 11 total cells the Prevotella bacteria. In some embodiments, the bacterial composition comprises about 6.4 x 10 11 total cells the Prevotella bacteria. In some embodiments, the bacterial composition comprises about 8 x 10 11 total cells of the Prevotella bacteria. In some embodiments, the bacterial composition comprises about 1.6 x 10 10 to about 8 x 10 11 total cells of the Prevotella bacteria. In some embodiments, the bacterial composition comprises about 1.6 x 10 10 to about 1.6 x 10 11 total cells ofth Q Prevotella bacteria.
- the bacterial composition comprises about 1.6 x 10 10 to about 16 x 10 11 total cells of the Prevotella bacteria. In some embodiments, the bacterial composition comprises about 8 x 10 10 to about 8 x 10 11 total cells of the Prevotella bacteria. In some embodiments, the bacterial composition comprises about 1.6 x 10 11 to about 8 x 10 11 total cells of the Prevotella bacteria.
- the bacterial composition comprises about 9.6 x 10 11 total cells of the Prevotella bacteria.
- the bacterial composition comprises about 12.8 x 10 11 total cells of the Prevotella bacteria.
- the bacterial composition comprises about 16 x 10 11 total cells of the Prevotella bacteria. [41] In some embodiments, the bacterial composition comprises about 9.6 x 10 11 to about 16 x 10 11 total cells of the Prevotella bacteria.
- the bacterial composition comprises about 9.6 x 10 11 to about 12.8 x 10 11 total cells of the Prevotella bacteria.
- the bacterial composition comprises about 12.8 x 10 11 to about 16 x 10 11 total cells of the Prevotella bacteria.
- the bacterial composition is provided as a solid dosage form (also referred to as a solid dose form).
- a solid dosage form also referred to as a solid dose form.
- solid dosage forms comprising the Prevotella bacteria.
- the solid dosage form comprises an enteric coating (e.g., HPMC coat).
- the solid dosage form comprises about 8 x 10 10 total cells of the Prevotella bacteria (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
- the solid dosage form comprises about 1.6 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
- the solid dosage form comprises about 3.2 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
- the solid dosage form comprises about 6.4 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
- the solid dosage form comprises about 8 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
- the solid dosage form comprises about 9.6 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
- the solid dosage form comprises about 12.8 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a solid dosage form or plurality of solid dosage forms). [52] In some embodiments, the solid dosage form comprises about 16 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a solid dosage form or plurality of solid dosage forms).
- the solid dosage form comprises a capsule.
- the capsule is an enteric coated capsule.
- the enteric coating comprises HPMC.
- the enteric coating comprises a polymethacrylate-based copolymer.
- the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).
- the enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1: 1) (such as Kollicoat MAE 100P).
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered, e.g., once or twice daily to a subject.
- 1 capsule is administered, e.g., once or twice daily to a subject.
- 2 capsules are administered, e.g., once or twice daily to a subject.
- the Prevotella bacteria in the capsule are lyophilized (e.g., in a powder). In some embodiments, the Prevotella bacteria in the capsule are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.
- the capsule comprises about 8 x 10 10 total cells of the Prevotella bacteria (e.g., total dose of a capsule or plurality of capsules).
- the capsule comprises about 1.6 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a capsule or plurality of capsules).
- the capsule comprises about 3.2 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a capsule or plurality of capsules).
- the capsule comprises about 6.4 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a capsule or plurality of capsules).
- the capsule comprises about 8 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a capsule or plurality of capsules).
- the capsule comprises about 9.6 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a capsule or plurality of capsules).
- the capsule comprises about 12.8 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a capsule or plurality of capsules). [63] In some embodiments, the capsule comprises about 16 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a capsule or plurality of capsules).
- each capsule comprises about 1.6 x 10 10 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered, e.g., once or twice daily to a subject.
- 1 capsule e.g., comprising about 1.6 x 10 10 total cells
- 2 capsules e.g., each comprising about 1.6 x 10 10 total cells
- 3 capsules are administered, e.g., once or twice daily to a subject.
- 4 capsules e.g., each comprising about 1.6 x 10 10 total cells
- 5 capsules e.g., each comprising about 1.6 x 10 10 total cells
- 6 capsules are administered, e.g., once or twice daily to a subject.
- 8 capsules e.g., each comprising about 1.6 x 10 10 total cells
- 10 capsules e.g., each comprising about 1.6 x 10 10 total cells
- each capsule comprises about 8 x 10 10 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered, e.g., once or twice daily to a subject.
- 1 capsule e.g., comprising about 8 x 10 10 total cells
- 2 capsules e.g., each comprising about 8 x 10 10 total cells
- 3 capsules are administered, e.g., once or twice daily to a subject.
- 4 capsules e.g., each comprising about 8 x 10 10 total cells
- 5 capsules e.g., each comprising about 8 x 10 10 total cells
- 6 capsules are administered, e.g., once or twice daily to a subject.
- 8 capsules e.g., each comprising about 8 x 10 10 total cells
- 10 capsules e.g., each comprising about 8 x 10 10 total cells
- each capsule comprises about 1.6 x 10 11 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered, e.g., once or twice daily to a subject.
- 1 capsule e.g., comprising about 1.6 x 10 11 total cells
- 2 capsules e.g., each comprising about 1.6 x 10 11 total cells
- 3 capsules are administered, e.g., once or twice daily to a subject.
- 4 capsules e.g., each comprising about 1.6 x 10 11 total cells
- 5 capsules e.g., each comprising about 1.6 x 10 11 total cells
- 6 capsules are administered, e.g., once or twice daily to a subject.
- 8 capsules e.g., each comprising about 1.6 x 10 11 total cells
- 10 capsules e.g., each comprising about 1.6 x 10 11 total cells
- each capsule comprises about 3.2 x 10 11 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered, e.g., once or twice daily to a subject.
- 1 capsule e.g., comprising about 3.2 x 10 11 total cells
- 2 capsules e.g., each comprising about 3.2 x 10 11 total cells
- 3 capsules are administered, e.g., once or twice daily to a subject.
- 4 capsules e.g., each comprising about 3.2 x 10 11 total cells
- 5 capsules e.g., each comprising about 3.2 x 10 11 total cells
- 6 capsules are administered, e.g., once or twice daily to a subject.
- 8 capsules e.g., each comprising about 3.2 x 10 11 total cells
- 10 capsules e.g., each comprising about 3.2 x 10 11 total cells
- the solid dosage form comprises a tablet.
- the tablet is an enteric coated tablet.
- the tablet is from 5mm to 18mm in diameter.
- the enteric coating comprises HPMC.
- the enteric coating comprises a polymethacrylate-based copolymer.
- the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1: 1).
- the enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1: 1) (such as Kollicoat MAE 100P).
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tablets are administered, e.g., once or twice daily to a subject.
- 1 tablet is administered, e.g., once or twice daily to a subject.
- 2 tablets are administered, e.g., once or twice daily to a subject.
- the Prevotella bacteria in the tablet are lyophilized. In some embodiments, the Prevotella bacteria in the tablet are lyophilized (e.g., in a powder). In some embodiments, the Prevotella bacteria in the tablet are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.
- the tablet comprises about 8 x 10 10 total cells of the Prevotella bacteria (e.g., total dose of a tablet or plurality of tablets).
- the tablet comprises about 1.6 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a tablet or plurality of tablets).
- the tablet comprises about 3.2 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a tablet or plurality of tablets).
- the tablet comprises about 6.4 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a tablet or plurality of tablets).
- the tablet comprises about 8 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a tablet or plurality of tablets).
- the tablet comprises about 9.6 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a tablet or plurality of tablets).
- the tablet comprises about 12.8 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a tablet or plurality of tablets). [78] In some embodiments, the tablet comprises about 16 x 10 11 total cells of the Prevotella bacteria (e.g., total dose of a tablet or plurality of tablets).
- each tablet comprises about 8 x 10 10 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tablets are administered, e.g., once or twice daily to a subject.
- 1 tablet e.g., comprising about 8 x 10 10 total cells
- 2 tablets e.g., each comprising about 8 x 10 10 total cells
- 3 tablets are administered, e.g., once or twice daily to a subject.
- 4 tablets are administered, e.g., once or twice daily to a subject.
- 5 tablets e.g., each comprising about 8 x 10 10 total cells
- 6 tablets e.g., each comprising about 8 x 10 10 total cells
- 8 tablets are administered, e.g., once or twice daily to a subject.
- 10 tablets are administered, e.g., once or twice daily to a subject.
- each tablet comprises about 1.6 x 10 11 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tablets are administered, e.g., once or twice daily to a subject.
- 1 tablet e.g., comprising about 1.6 x 10 11 total cells
- 2 tablets e.g., each comprising about 1.6 x 10 11 total cells
- 3 tablets are administered, e.g., once or twice daily to a subject.
- 4 tablets e.g., each comprising about 1.6 x 10 11 total cells
- 5 tablets e.g., each comprising about 1.6 x 10 11 total cells
- 6 tablets are administered, e.g., once or twice daily to a subject.
- 8 tablets e.g., each comprising about 1.6 x 10 11 total cells
- 10 tablets e.g., each comprising about 1.6 x 10 11 total cells
- each tablet comprises about 3.2 x 10 11 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tablets are administered, e.g., once or twice daily to a subject.
- 1 tablet e.g., comprising about 3.2 x 10 11 total cells
- 2 tablets e.g., each comprising about 3.2 x 10 11 total cells
- 3 tablets are administered, e.g., once or twice daily to a subject.
- 4 tablets e.g., each comprising about 3.2 x 10 11 total cells
- 5 tablets e.g., each comprising about 3.2 x 10 11 total cells
- 6 tablets are administered, e.g., once or twice daily to a subject.
- 8 tablets e.g., each comprising about 3.2 x 10 11 total cells
- 10 tablets e.g., each comprising about 3.2 x 10 11 total cells
- 8 tablets are administered, e.g., once or twice daily to a subject.
- 10 tablets are administered, e.g., once or twice daily to a subject.
- the pharmaceutical composition comprising Prevotella 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.
- the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 8 x 10 10 total cells of the Prevotella bacteria.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1.6 x 10 11 total cells the Prevotella bacteria.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 3.2 x 10 11 total cells the Prevotella bacteria.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 6.4 x 10 11 total cells the Prevotella bacteria.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 8 x 10 11 total cells of the Prevotella bacteria.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1.6 x 10 10 to about 8 x 10 11 total cells of the Prevotella bacteria.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1.6 x 10 10 to about 1.6 x 10 11 total cells ofth Q Prevotella bacteria.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1.6 x 10 10 to about 16 x 10 11 total cells of the Prevotella bacteria.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 8 x 10 10 to about 8 x 10 11 total cells of the Prevotella bacteria.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1.6 x 10 11 to about 8 x 10 11 total cells of the Prevotella bacteria.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 9.6 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 12.8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 9.6 x 10 11 to about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 9.6 x 10 11 to about 12.8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition (e.g., prepared as a solid dosage form) (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 12.8 x 10 11 to about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
- the solid dosage form comprises 1.6x 10 11 cells per solid dosage form.
- the solid dosage form comprises 3.2x10 11 cells per solid dosage form.
- one solid dosage form is administered to the subject once daily.
- one solid dosage form is administered to the subject twice daily.
- two solid dosage forms are administered to the subject once daily.
- two solid dosage forms are administered to the subject twice daily.
- three solid dosage forms are administered to the subject once daily.
- three solid dosage forms are administered to the subject twice daily.
- four solid dosage forms are administered to the subject once daily. [109] In some embodiments, four solid dosage forms are administered to the subject twice daily.
- five solid dosage forms are administered to the subject once daily.
- five solid dosage forms are administered to the subject twice daily.
- 1 solid dosage form e.g., tablet or capsule
- 2 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form (e.g., each solid dose form) comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- 3 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- 4 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- 5 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- 6 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- 10 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- 1 solid dosage form e.g., tablet or capsule
- 2 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form (e.g., each solid dose form) comprises a dose of bacteria of about 8 x 10 10 total cells.
- 3 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 8 x 10 10 total cells.
- 4 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 8 x 10 10 total cells.
- 5 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 8 x 10 10 total cells.
- 6 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 8 x 10 10 total cells.
- 8 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 8 x 10 10 total cells.
- 10 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 8 x 10 10 total cells.
- 1 solid dosage form e.g., tablet or capsule
- 2 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form (e.g., each solid dose form) comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- 3 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- 4 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- 5 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- 6 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- 10 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- 1 solid dosage form e.g., tablet or capsule
- 2 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form (e.g., each solid dose form) comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- 3 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- 4 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- 5 solid dosage forms e.g., tablets or capsules
- 5 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- 6 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- 10 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- about 3.2 x 10 11 total cells includes total cell counts within ⁇ 5% of 3.2 x 10 11 total cells e.g., 3.35 x 10 11 total cells.
- the solid dosage form is a tablet.
- the tablet is an enteric coated tablet.
- the enteric coated tablet is from 5mm to 18mm in diameter.
- the tablet comprises about 8 x 10 10 total cells of the Prevotella bacteria.
- the tablet comprises about 1.6 x 10 11 total cells of the Prevotella bacteria.
- the tablet comprises about 3.2 x 10 11 total cells of the Prevotella bacteria.
- the Prevotella bacteria in the tablet are lyophibzed.
- the solid dosage form is a capsule.
- the capsule is an enteric coated capsule.
- the enteric coated capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule.
- the capsule is a size 0 capsule.
- the capsule comprises about 8 x 10 10 total cells of the Prevotella bacteria.
- the capsule comprises about 1.6 x 10 11 total cells of the Prevotella bacteria.
- the capsule comprises about 3.2 x 10 11 total cells of the Prevotella bacteria.
- the Prevotella bacteria in the capsule are lyophibzed.
- the solid dosage form is a tablet, e.g., an enteric coated tablet.
- the solid dosage form is a mini-tablet, e.g., an enteric coated mini-tablet.
- the solid dosage form is a capsule, e.g., an enteric coated capsule.
- the enteric coating comprises a polymethacrylate-based copolymer.
- the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1: 1).
- the enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1: 1) (such as Kolbcoat MAE 100P or Eudragit L30-D55).
- the pharmaceutical composition comprising Prevotella bacteria is prepared as a powder.
- the powder can comprise lyophibzed bacteria.
- the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.
- the pharmaceutical composition comprises a powder comprising Prevotella bacteria.
- the powder comprising Prevotella bacteria e.g., at a dose provided herein
- is resuspended e.g., in a liquid such as a solution, buffer, water or other beverage, or a food), e.g., for use in the methods provided herein.
- the Prevotella histicola strain is administered in a pharmaceutical composition (e.g., a pharmaceutical composition provided herein).
- the pharmaceutical composition is a solid dose form provided herein.
- the pharmaceutical composition comprises a blend of freeze-dried powder of Prevotella histicola and excipients (e.g. an encapsulated freeze- dried powder of a. Prevotella histicola strain provided herein and excipients).
- the pharmaceutical composition comprises freeze-dried (e.g., lyophilized) powder of bacteria in a capsule.
- the capsule is enteric coated.
- the pharmaceutical composition comprises an enteric coated hydroxylpropyl methylcellulose (HPMC) hard capsule.
- the pharmaceutical composition comprises a formulation of Prevotella histicola Strain B comprising freeze-dried powder of Prevotella histicola and excipients.
- the excipients include mannitol, magnesium stearate and colloidal silicon dioxide.
- each capsule contains about 8.0 x 10 10 cells of a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B).
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules are administered to a subject daily.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules are administered to a subject once daily.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules are administered to a subject twice daily.
- 2 powder-containing capsules are administered to the subject daily.
- 1 powder-containing capsule is administered to the subject daily.
- each powder-containing capsule contains about 8.0 x 10 10 cells of a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B).
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 powder-containing capsules are administered to a subject daily.
- 2 powder-containing enteric coated capsules e.g., each containing about 8.0 x 10 10 cells of a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B) are administered to the subject daily.
- 4 powder-containing enteric coated capsules e.g., each containing about 8.0 x 10 10 cells of a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B)
- 4 powder-containing enteric coated capsules are administered to the subject daily.
- 2 powder- containing enteric coated capsules e.g., each containing about 8.0 x 10 10 cells of a Prevotella histicola strain provided herein ⁇ e.g., Prevotella histicola Strain B) are administered to the subject once daily.
- 2 powder-containing enteric coated capsules are administered to the subject twice daily.
- 2 powder-containing enteric coated capsules e.g., each containing about 8.0 x 10 10 cells of a Prevotella histicola strain provided herein ⁇ e.g., Prevotella histicola Strain B
- 2 powder-containing enteric coated capsules are administered to the subject twice daily.
- 2 powder-containing enteric coated capsules e.g., each containing about 8.0 x 10 10 cells of a Prevotella histicola strain provided herein ⁇ e.g.
- Prevotella histicola Strain B are administered to the subject twice daily (e.g., for 1-7 days, 3 days, 7 days, 10 days, or 14 days), and then 2 powder- containing enteric coated capsules (e.g., each containing about 8.0 x 10 10 cells of a Prevotella histicola strain provided herein ⁇ e.g., Prevotella histicola Strain B)) are administered to the subject once daily, e.g., for the duration of the treatment period (e.g., up to 14 days of total treatment).
- 2 powder- containing enteric coated capsules e.g., each containing about 8.0 x 10 10 cells of a Prevotella histicola strain provided herein ⁇ e.g., Prevotella histicola Strain B)
- the duration of the treatment period e.g., up to 14 days of total treatment.
- 1 powder-containing enteric coated capsule e.g., containing about 8.0 x 10 10 cells of a Prevotella histicola strain provided herein ⁇ e.g., Prevotella histicola Strain B) is administered to the subject daily.
- the bacterial composition comprising Prevotella bacteria is prepared as a solid dose form, such as a tablet, capsule, or a powder.
- the powder can comprise lyophilized bacteria.
- the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.
- the bacterial composition comprises a powder comprising Prevotella bacteria.
- the powder comprising Prevotella bacteria e.g., at a dose provided herein
- is resuspended e.g., in a liquid such as a solution, buffer, water or other beverage, or a food), e.g., for use in the methods provided herein.
- the bacterial composition is administered orally. In some embodiments, the administration to the subject is once daily. In some embodiments, the administration to the subject is twice daily.
- the bacterial composition is administered once daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.
- 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.
- 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.
- the bacterial composition comprises lyophilized Prevotella bacteria, e.g., in a powder.
- the lyophilized Prevotella bacteria is formulated into a solid dose form, such as a tablet or capsule.
- the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.
- the bacterial composition is formulated as a tablet.
- the bacterial formulation e.g., composition
- the bacterial composition is formulated as a capsule.
- the bacterial formulation e.g., composition
- the bacterial formulation comprises an enteric coating or micro encapsulation.
- 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).
- 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.
- the disclosure provides use of a Prevotella histicola strain provided herein and/or a bacterial composition (e.g. , a bacterial composition and/or a solid dosage form) described herein (e.g., in an amount described herein) for the preparation of a medicament for the performance of a therapeutic method provided herein.
- the disclosure provides a Prevotella histicola strain provided herein and/or a bacterial composition (e.g. , a bacterial composition and/or a solid dosage form) described herein (e.g., in an amount described herein) for use in the performance of a therapeutic method provided herein.
- a bacterial composition e.g. , a bacterial composition and/or a solid dosage form
- a bacterial composition e.g., a bacterial composition and/or a solid dosage form
- 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.
- 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 Prevotella histicola and/or a composition (e.g., abacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Prevotella histicola provided herein.
- a subject who has a Th2 mediated inflammatory disease comprising administering to the subject a bacterial composition described herein.
- a method of treating a Th2 mediated inflammatory disease 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 Prevotella histicola and/or a composition (e.g., abacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Prevotella histicola provided herein.
- a human subject e.g., a subject with a Th2 mediated inflammatory disease (such as asthma or atopic dermatitis)
- a strain of a Prevotella histicola and/or a composition e.g., abacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form
- a composition e.g., abacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form
- provided herein are methods of treating a subject who has a Thl 7 mediated inflammatory disease (such as psoriasis) comprising administering to the subject a bacterial composition described herein.
- a Thl 7 mediated inflammatory disease such as psoriasis
- a method of treating a Thl 7 mediated inflammatory disease comprising administering (e.g., orally administering) to a human subject (e.g., a subject with a Thl7 mediated inflammatory disease (such as psoriasis)) a strain of a Prevotella histicola and/or a composition (e.g., a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a.
- a Thl 7 mediated inflammatory disease such as psoriasis
- kits for treating a subject who has psoriasis comprising administering to the subject a bacterial composition (e.g., pharmaceutical composition) described herein.
- LSS Lesion Severity Score
- a subject e.g., a subject with psoriasis
- administering to the subject a bacterial composition described herein.
- the LSS in the subject is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more (e.g., by day 7, 14, 21, 28, or 35 of treatment).
- the LSS in the subject is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more after dosing is stopped (e.g., 14 days after treatment has stopped).
- PASI Psoriasis Area and Severity Index
- a subject e.g., a subject with psoriasis
- the PASI score in the subject is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more (e.g., by day 7, 14, 21, 28, or 35 of treatment).
- the PASI score in the subject is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more after dosing is stopped (e.g., 14 days after treatment has stopped).
- a sustained clinical effect e.g., continued reductions from baseline (or placebo) in mean LSS and/or PASI, e.g., 1, 2, 3, 4, 5, 6 or more weeks after completion of dosing
- a subject e.g., a subject with psoriasis
- the LSS and/or PASI score in the subject is reduced by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, or more (e.g., by day 7, 14, 21, 28, or 35 of treatment).
- provided herein are methods of enhancing antiinflammatory cytokine production (e.g., increasing as compared to amount produced (e.g., mRNA and/or protein) in the absence of the bacterial composition) in a subject, the method comprising administering a bacterial composition described herein.
- the anti-inflammatory cytokine is IL-10, IL-27, and/or IL1RA.
- the anti-inflammatory cytokine is expressed by Ml -type APCs.
- enhancing anti-inflammatory cytokine production comprises an increase in anti-inflammatory cytokine (e.g., IL-10, IL-27, and/or IL1RA) mRNA levels (e.g., in skin biopsies).
- enhancing anti-inflammatory cytokine production comprises an increase in anti-inflammatory cytokine (e.g., IL-10, IL-27, and/or ILIRA) protein levels (e.g., in blood samples).
- pro-inflammatory cytokine production e.g., decreasing as compared to amount produced (e.g., mRNA and/or protein) in the absence of the bacterial composition
- the method comprising administering a bacterial composition described herein.
- the pro-inflammatory cytokine is GM-CSF, IL-17A, and/or IL-13.
- the pro-inflammatory cytokine is IL-6, TNF, and/or IL-12p70.
- the pro-inflammatory cytokine is IL-23p40, IL-17, IL-6, TNF, and/or IL- 13.
- the pro-inflammatory cytokine is IL-31, IL-23p40, IL-17, and/or IL-13. In some embodiments, the pro-inflammatory cytokine is IL-4, IL-5, and/or IL-13. In some embodiments, inhibiting pro-inflammatory cytokine production comprises inhibiting pro-inflammatory cytokine production in a draining lymph node (e.g., cervical lymph node). In some embodiments, inhibiting pro-inflammatory cytokine production comprises inhibiting pro-inflammatory cytokine production in the spleen.
- a draining lymph node e.g., cervical lymph node
- inhibiting pro-inflammatory cytokine production comprises a decrease in pro-inflammatory cytokine (e.g., 1117a) mRNA levels (e.g., in skin biopsies). In some embodiments, inhibiting pro-inflammatory cytokine production comprises a decrease in pro-inflammatory cytokine (e.g., IL-17A) protein levels (e.g., in blood samples).
- pro-inflammatory cytokine e.g., 1117a
- mRNA levels e.g., in skin biopsies
- inhibiting pro-inflammatory cytokine production comprises a decrease in pro-inflammatory cytokine (e.g., IL-17A) protein levels (e.g., in blood samples).
- provided herein are methods of inhibiting pro- inflammatory chemokines production (e.g., decreasing as compared to amount produced (e.g., mRNA and/or protein) in the absence of the bacterial composition) in a subject, the method comprising administering a bacterial composition described herein.
- the pro-inflammatory chemokine is keratinocyte chemoattractant (KC).
- cytokine production or chemokine production e.g., altering as compared to amount produced (e.g., mRNA and/or protein) in the absence of the bacterial composition
- the method comprising administering a bacterial composition described herein.
- blood samples from the subject are stimulated ex vivo and analyzed for levels of cytokines and/or chemokines.
- the level of IL-1 beta, IL- 2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-17A, TNFa, and/or IFNy is analyzed.
- a method of treating psoriasis comprising administering (e.g., orally administering) to a human subject a strain of a Prevote lla histicola and/or a composition (e.g., a pharmaceutical composition and/or a solid dosage form) comprising a strain of a Prevotella histicola provided herein.
- 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).
- BSA body surface area
- the human subject has a minimum of 2 psoriatic lesions.
- the subject has not received systemic nonbiologic psoriasis therapy (methotrexate [MTX], steroids, cyclophosphamide) or psoralen plus ultraviolet A (PUVA)/ultraviolet A (UVA) phototherapy within 4 weeks prior to dosing.
- subject has not received treatment with biologic agents within 12 months prior to first dose.
- the subject is not continuing use of topical or oral pharmacologically active agents 2 weeks prior to the start of dosing.
- the human subject has a documented diagnosis of plaque psoriasis for >6 months.
- 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.
- 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).
- PASI Psoriasis Area and Severity Index
- the method increases a PASI percentage response rate (e.g., PASI-50, PASI-75, PASI-90, or PASI-100), e.g., as described herein.
- a PASI percentage response rate e.g., PASI-50, PASI-75, PASI-90, or PASI-100
- PASI-75 value e.g., after 16 weeks of treatment.
- 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.
- LSS Lesion Severity Score
- 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.
- PGA Physical’s Global Assessment
- 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.
- BSA Body Surface Area
- 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.
- mNAPSI Modified Nail Psoriasis Severity Index
- the method improves (e.g., decreases) the DLQI (Dermatology Life Quality Index) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s DLQI score prior to the commencement of treatment), e.g., as described herein.
- DLQI Density Life Quality Index
- the method improves the product of PGA and BSA in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s product of PGA and BSA prior to the commencement of treatment), e.g., as described herein.
- the method improves (e.g., decreases) the PSI (Psoriasis Symptom Inventory) score in the subject, e.g., after 16 weeks of treatment (e.g., as compared to the subject’s PSI score prior to the commencement of treatment), e.g., as described herein.
- PSI Psoriasis Symptom Inventory
- 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.
- pain can be assessed by the SF-36 Bodily Pain Scale (SF-36 BPS) or the VAS Pain.
- 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.
- atopic dermatitis e.g., mild, moderate, or severe atopic dermatitis
- administering comprising administering to the subject a bacterial composition described herein.
- a method of treating atopic dermatitis comprising administering (e.g., orally administering) to a human subject a strain of a Prevotella histicola and/or a composition (e.g., a pharmaceutical composition and/or a solid dosage form) comprising a strain of a. Prevotella histicola.
- the human subject has a confirmed diagnosis of mild to moderate atopic dermatitis for at least 6 months involving a minimum of 3% to a maximum of 15% body surface area.
- the subject has had a confirmed diagnosis of mild to moderate atopic dermatitis with an IGA score of 2 or 3.
- 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 has severe atopic dermatitis. In some embodiments, the subject has at least 2 atopic dermatitis lesions with at least 1 in a site suitable for biopsy. In some embodiments, the subject is not receiving systemic non-biologic atopic dermatitis therapy (methotrexate (MTX), steroids, cyclophosphamide, or has received therapy within 4 weeks prior to dosing. In some embodiments, wherein the human subject is not receiving treatment with biologic agents within 12 months prior to first dose. In some embodiments, wherein the human subject is not continuing to use topical or oral pharmacologically active agents 2 weeks prior to the start of dosing.
- MTX systemic non-biologic atopic dermatitis therapy
- steroids steroids
- cyclophosphamide or has received therapy within 4 weeks prior to dosing.
- the method decreases the EASI (Eczema Area and Severity Index) score in the subject, e.g., after 12 or 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. For example, the percentage of subjects achieving EASI-50; EASI-75; or EASI- 90.
- EASI Equivalent Area and Severity Index
- the method decreases the SCORAD (SCORing Atopic Dermatitis) score in the subject, e.g., after 12 or 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. For example, the percentage of subjects achieving SCORAD-50 or SCORAD-75.
- the method decreases the IGA (Investigator’s Global Assessment) score in the subject, e.g., after 12 or 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.
- the method decreases the Percentage of Body Surface Area (BSA) affected by disease in the subject, e.g., after 12 or 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. For example, the percentage of subjects achieving BSA-50 or BSA- 75; or the percentage of subjects achieving BSA reduction to 3% BSA or less.
- BSA Body Surface Area
- the method improves the product of IGA and BSA in the subject, e.g., after 12 or 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.
- the method improves the Dermatology Fife Quality Index (DFQI) score in the subject, e.g., after 12 or 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.
- DFQI Dermatology Fife Quality Index
- the method improves the Patient-Oriented Eczema Measure (POEM) score in the subject, e.g., after 12 or 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.
- POEM Patient-Oriented Eczema Measure
- the method improves the Pruritus Numerical Rating Scale (Pruritus NRS (e.g., Peak Pruritus Numerical Rating Scale (PP-NRS))) score in the subject, e.g., after 12 or 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.
- Pruritus NRS e.g., Peak Pruritus Numerical Rating Scale (PP-NRS)
- the method improves the number of courses or days of rescue therapy in the subject, e.g., after 12 or 16 weeks of treatment (e.g., as compared to the subject’s SD-NRS score) prior to the commencement of treatment), e.g., as described herein.
- the method improves the Sleep Disturbance Numerical Rating Scale (SD-NRS) score in the subject, e.g., after 12 or 16 weeks of treatment (e.g., as compared to the subject’s number of courses or days of rescue therapy) prior to the commencement of treatment), e.g., as described herein.
- SD-NRS Sleep Disturbance Numerical Rating Scale
- the method improves the blood eosinophils in the subject, e.g., after 12 or 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.
- the method decreases IgE levels in the subject, e.g., after 12 or 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.
- provided herein are methods of treating a subject who has psoriatic arthritis comprising administering to the subject a bacterial composition described herein.
- 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 Prevotella histicola and/or a composition (e.g., a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form) comprising a strain of a Prevotella histicola provided herein.
- a human subject e.g., a subject with psoriatic arthritis
- a composition e.g., a bacterial composition (e.g., pharmaceutical composition) and/or a solid dosage form
- the method improves (e.g., increases) the percentage of subjects with an ACR20 response, e.g., after 8 or 16 weeks of treatment (e.g., as compared to the percentage prior to the commencement of treatment), e.g., as described herein.
- the method improves (e.g., increases) the percentage of subjects with an ACR50 response, e.g., after 8 or 16 weeks of treatment (e.g., as compared to the percentage prior to the commencement of treatment), e.g., as described herein.
- the method improves (e.g., increases) the percentage of subjects with an ACR70 response, e.g., after 8 or 16 weeks of treatment (e.g., as compared to the percentage prior to the commencement of treatment), e.g., as described herein.
- 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.
- PsARC Modified Psoriatic Arthritis Response Criteria
- 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.
- the method decreases the Clinical Disease Activity Index (CDAI) score in 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.
- CDAI Clinical Disease Activity Index
- 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.
- 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.
- MASES Maastricht Ankylosing Spondylitis Enthesis Score
- the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in treating psoriasis (e.g., mild to moderate psoriasis).
- psoriasis e.g., mild to moderate psoriasis
- a bacterial composition described herein e.g., in an amount described herein for use in treating atopic dermatitis (e.g., mild to moderate atopic dermatitis).
- the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in treating psoriatic arthritis.
- the disclosure provides use of a bacterial composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of psoriasis (e.g., mild to moderate psoriasis).
- a bacterial composition described herein e.g., in an amount described herein
- a medicament for the treatment of psoriasis e.g., mild to moderate psoriasis.
- the disclosure provides use of a bacterial composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of atopic dermatitis (e.g., mild, moderate, or severe atopic dermatitis).
- atopic dermatitis e.g., mild, moderate, or severe atopic dermatitis
- the disclosure provides use of a bacterial composition described herein (e.g., in an amount described herein) for the preparation of a medicament for the treatment of psoriatic arthritis.
- the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in treating an inflammatory disease.
- the inflammatory disease is a Thl, Th2, or Thl7 inflammatory disease.
- the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in treating an immune disorder.
- 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.
- the inflammatory disease is a Thl, Th2, or Thl 7 inflammatory disease.
- 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.
- 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 autoimmune disease, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of an autoimmune disease).
- the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in treating an autoimmune disease.
- 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, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of an inflammatory disease).
- the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in treating an inflammatory disease.
- 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 a metabolic disease, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of a metabolic disease).
- the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in treating a metabolic disease.
- 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 a dysbiosis, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of a dysbiosis).
- the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in treating a dysbiosis.
- the disclosure provides use of a bacterial composition described herein (e.g., in an amount described herein) for the preparation of a medicament for decreasing inflammatory cytokine expression (e.g., decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels), (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for decreasing inflammatory cytokine expression (e.g, decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels)).
- a medicament for decreasing inflammatory cytokine expression e.g., decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels
- a subject e.g., a human subject
- methods of using such bacterial compositions e.g., for decreasing inflammatory cytokine expression (e.g, decreased IL-8, IL-6, IL-Ib, and/or
- the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in decreasing inflammatory cytokine expression (e.g., decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels).
- a bacterial composition described herein e.g., in an amount described herein
- inflammatory cytokine expression e.g., decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels.
- the disclosure provides use of a bacterial composition described herein (e.g., in an amount described herein) for the preparation of a medicament for decreasing IL-31, IL-23p40, IL-17, IL-4, IL-5, and/or IL-13 levels (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for decreasing inflammatory cytokine expression (e.g., decreased IL-31, IL-23p40, IL-17, IL-4, IL-5, and/or IL-13 levels)).
- a bacterial composition described herein e.g., in an amount described herein
- methods of using such bacterial compositions e.g., for decreasing inflammatory cytokine expression (e.g., decreased IL-31, IL-23p40, IL-17, IL-4, IL-5, and/or IL-13 levels)).
- 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 bacterial septic shock, cytokine storm and/or viral infection, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of bacterial septic shock, cytokine storm and/or viral infection).
- the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in treating bacterial septic shock, cytokine storm and/or viral infection.
- 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 a viral infection, (e.g., in a subject, e.g., a human subject) and methods of using such bacterial compositions (e.g., for the treatment of a viral infection).
- the viral infection is a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection.
- the viral infection is a SARS-CoV-2 infection.
- the disclosure provides a bacterial composition described herein (e.g., in an amount described herein) for use in treating a viral infection.
- the viral infection is a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection.
- the viral infection is a SARS-CoV-2 infection.
- a subject e.g., a subject who has psoriasis (e.g., mild to moderate psoriasis) comprising administering to the subject a bacterial composition described herein, wherein administration of the bacterial composition results in increased efficacy after 30 days of dosing in the subject (e.g., as compared to the level of efficacy after 15 days of dosing).
- Efficacy can be determined by the decrease in the level of inflammation being greater after 30 days of dosing than the level of inflammation after 15 days of dosing.
- a subject e.g., a subject who has psoriasis (e.g., mild to moderate psoriasis) and/or atopic dermatitis (e.g., mild to moderate atopic dermatitis)) and/or psoriatic arthritis
- administering to the subject a bacterial composition described herein, wherein the effects on inflammation of the administration of the bacterial composition persist for at least 14 days after last dosing the subject (e.g., the level of inflammation is lower 14 days after last dosing the subject, as compared to the level of inflammation prior to commencement of dosing the subject ).
- Persistence can be determined by the decrease in the level of inflammation being greater at 14 days after last dosing the subject than the level of inflammation prior to commencement of dosing the subject.
- the disclosure provides a method of treating psoriasis (e.g., mild to moderate psoriasis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 3.2 x 10 11 total cells of the bacteria.
- psoriasis e.g., mild to moderate psoriasis
- a dose of Prevotella histicola Strain B 50329 NRRL accession number B 50329
- the disclosure provides a method of treating psoriasis (e.g., mild to moderate psoriasis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two solid dosage forms (e.g., tablets or capsules) and each solid dosage form comprises about 3.2 x 10 11 total cells of the bacteria.
- psoriasis e.g., mild to moderate psoriasis
- a dose of Prevotella histicola Strain B 50329 NRRL accession number B 50329
- the disclosure provides a method of treating atopic dermatitis (e.g., mild, moderate, or severe atopic dermatitis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 3.2 x 10 11 total cells of the bacteria.
- atopic dermatitis e.g., mild, moderate, or severe atopic dermatitis
- the disclosure provides a method of treating atopic dermatitis (e.g., mild, moderate, or severe atopic dermatitis) in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two solid dosage forms (e.g., tablets or capsules) and each solid dosage form comprises about 3.2 x 10 11 total cells of the bacteria.
- the disclosure provides a method of reducing inflammation in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in one solid dosage form (e.g., tablet or capsule) and comprises about 3.2 x 10 11 total cells of the bacteria.
- a dose of Prevotella histicola Strain B 50329 NRRL accession number B 50329
- the disclosure provides a method of reducing inflammation in a human subject comprising orally administering (e.g., once or twice daily) to the human subject a dose of Prevotella histicola Strain B 50329 (NRRL accession number B 50329) bacteria, wherein the dose is formulated in two solid dosage forms (e.g., tablets or capsules) and each solid dosage form comprises about 3.2 x 10 11 total cells of the bacteria.
- the inflammation comprises Thl inflammation.
- the inflammation comprises Th2 inflammation.
- the inflammation comprises Thl inflammation
- Figure 1 is a series of bar graphs showing median change from pre-challenge (d26) to post-challenge (d28) in five parameters in the skin at the challenge site in a delayed-type hypersensitivity immunopharmacology model in human volunteers treated with placebo or one of two capsule preparations of Prevotella histicola Strain B, both delivering 8 x 10 11 cells to the volunteers (A’: 10 capsules (8 x 10 10 cells per capsule);
- A2 5 capsules (1.6 x 10 11 cells per capsule)). Height is measured in mm and all other variables measured in AU. The parenthesis after Skin color, Height, and Average redness show the scaling factor applied to each value in order to display all data on a single axis.
- Prevotella histicola is a natural human commensal organism, commonly found on oral, nasopharyngeal, gastrointestinal (GI), and genito-urinary mucosal surfaces.
- GI gastrointestinal
- Preclinical studies using Prevotella histicola Strain B have been carried out across a range of human and mouse primary cell in vitro assays, which support the use of this agent in the treatment of psoriasis, atopic dermatitis, and psoriatic arthritis.
- described herein is an oral therapy for treating an inflammatory disease with Prevotella histicola Strain B.
- the inflammatory disease is a Thl, Th2, or Thl7 inflammatory disease.
- described herein is an oral therapy for treating an immune disorder with Prevotella histicola Strain B.
- described herein is an oral therapy for treating psoriasis with Prevotella histicola Strain B.
- described herein is an oral therapy for treating atopic dermatitis with Prevotella histicola Strain B.
- described herein is an oral therapy for treating psoriatic arthritis with Prevotella histicola Strain B.
- described herein is an oral therapy for treating an autoimmune disease with Prevotella histicola Strain B.
- described herein is an oral therapy for treating a metabolic disease with Prevotella histicola Strain B.
- described herein is an oral therapy for treating a dysbiosis with Prevotella histicola Strain B.
- inflammatory cytokine expression e.g., decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels with Prevotella histicola Strain B.
- described herein is an oral therapy for treating bacterial septic shock with Prevotella histicola Strain B.
- described herein is an oral therapy for treating a viral infection with Prevotella histicola Strain B.
- described herein is an oral therapy for treating a cytokine storm with Prevotella histicola Strain B.
- adjuvant or “Adjuvant therapy” broadly refers to an agent that affects an immunological or physiological response in a patient or subject.
- 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.
- 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.
- an adjuvant might prevent T cell exhaustion and thus increase the effectiveness or safety of a particular immune interacting agent.
- administering broadly refers to a route of administration of a composition to a subject.
- 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 intra
- 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.
- 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.
- the specific genetic sequence may be the 16S sequence or a portion of the 16S sequence.
- the entire genomes of two entities are sequenced and compared.
- select regions such as multilocus sequence tags (MLST), specific genes, or sets of genes may be genetically compared.
- MMT multilocus sequence tags
- 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.
- 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)).
- Dysbiosis refers to a state of the microbiota or microbiome of the gut or other body area, including, e.g., mucosal or skin surfaces (or any other microbiome niche) in which the normal diversity and/or function of the host gut microbiome ecological networks “microbiome”) are disrupted.
- a state of dysbiosis may result in a diseased state, or it may be unhealthy under only certain conditions or only if present for a prolonged period.
- Dysbiosis may be due to a variety of factors, including, environmental factors, infectious agents, host genotype, host diet and/or stress.
- a dysbiosis may result in: a change (e.g., increase or decrease) in the prevalence of one or more bacteria types (e.g., anaerobic), species and/or strains, change (e.g., increase or decrease) in diversity of the host microbiome population composition; a change (e.g., increase or reduction) of one or more populations of symbiont organisms resulting in a reduction or loss of one or more beneficial effects; overgrowth of one or more populations of pathogens (e.g., pathogenic bacteria); and/or the presence of, and/or overgrowth of, symbiotic organisms that cause disease only when certain conditions are present.
- 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.
- 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.
- genomic is used broadly to refer to any nucleic acid associated with a biological function.
- genomic sequence is used broadly to refer to any nucleic acid associated with a biological function.
- 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 el al. (1988) Proc. Natl. Acad. Sci. USA 85:2444 (other programs include the GCG program package (Devereux, J., et al, Nucleic Acids Research 12(I):387 (1984)), BLASTP, BLASTN, FASTA Atschul, S. F., etal, J Molec Biol 215:403 (1990); Guide to Huge Computers, Martin J. Bishop, ed., Academic Press, San Diego, 1994, and Carillo et al.
- 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).
- autoimmune diseases e.g., Lupus, Scleroderma, hemolytic anemia, vasculitis, type one diabetes, Grave’s disease, rheumatoid arthritis, multiple sclerosis, Goodpasture’s syndrome, pernicious
- 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.
- disease e.g., immune disease
- 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 ⁇ 3 fold, 10 ⁇ 4 fold, 10 ⁇ 5 fold, 10 ⁇ 6 fold, and/or 10 ⁇ 7 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).
- 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.
- TLR Toll-Like Receptors
- NOD receptors NOD receptors
- RLRs C-type lectin receptors
- STING-cGAS Pathway components inflammasome complexes.
- 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.
- 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).
- TLR agonists include, but are not limited to, TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLRIO and TLRI 1.
- 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).
- MDP N-acetylmuramyl- L-alanyl-D-isoglutamine
- iE-DAP gamma-D-glutamyl-meso- diaminopimelic acid
- DMP desmuramylpeptides
- 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.
- 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.
- purify 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.”
- 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.
- 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.
- Metal 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.
- Merobe 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, biofdm) 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 biofdms, 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).
- the microbiome occurs at a mucosal surface.
- 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.
- 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.
- 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.
- 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.
- bacterial modifications include genetic modification, gene expression, phenotype modification, formulation, chemical modification, and dose or concentration.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- the specific genetic sequence may be the 16S sequence or a portion of the 16S sequence.
- the entire genomes of two entities are sequenced and compared.
- select regions such as multilocus sequence tags (MLST), specific genes, or sets of genes may be genetically compared.
- 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.
- OTUs 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.
- 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.”
- 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.
- microbial viruses e.g., phage
- 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.
- 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.
- subject 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
- mammals include humans, laboratory animals (e.g., primates, rats, mice), livestock (e.g., cows, sheep, goats, pigs), and household pets (e.g., dogs, cats, rodents).
- 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.
- 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.
- 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.
- regulatory region e.g., a promoter, a terminator,
- strains may be identified by PCR amplification optionally followed by DNA sequencing of the genomic region(s) of interest or of the whole genome.
- strains may be differentiated by selection or counter-selection using an antibiotic or nutrient/metabolite , respectively .
- treating 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.
- 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.
- “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.
- bacterial compositions e.g. , pharmaceutical compositions
- Prevotella histicola useful for the treatment and/or prevention of psoriasis (e.g., mild to moderate psoriasis) and methods of using such bacterial compositions (e.g., for the treatment of psoriasis), e.g., in a subject, e.g., in a human subject.
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- the bacterial composition e.g., pharmaceutical composition
- bacterial compositions e.g. , pharmaceutical compositions
- atopic dermatitis e.g., mild, moderate, or severe atopic dermatitis
- methods of using such bacterial compositions e.g., for the treatment of atopic dermatitis
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- the bacterial composition (e.g., pharmaceutical composition) comprises only one strain of bacteria, e.g., Prevotella histicola.
- bacterial compositions e.g. , pharmaceutical compositions
- Prevotella histicola useful for the treatment and/or prevention of psoriatic arthritis and methods of using such bacterial compositions (e.g., for the treatment of psoriatic arthritis), e.g., in a subject, e.g., in a human subject.
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- the bacterial composition e.g., pharmaceutical composition
- the Prevotella histicola is Prevotella Strain B 50329 (NRRL accession number B 50329) (also referred to as “ Prevotella histicola Strain B” or “ Prevotella Strain B”).
- the Prevotella 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 Prevotella Strain B 50329.
- 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
- Prevotella histicola Strain B can be cultured according to methods known in the art.
- Prevotella histicola can be grown in ATCC Medium 2722, ATCC Medium 1490, or other medium using methods disclosed, for example in Caballero et al, 2017. “Cooperating Commensals Restore Colonization Resistance to Vancomycin- Resistant Enterococcus faecium” Cell Host & Microbe 21:592-602, which is hereby incorporated by reference in its entirety.
- the Prevotella bacteria is quantified based on total cells, e.g., total cell count (TCC) (e.g., determined by Coulter counter).
- TCC total cell count
- the bacterial composition is administered once daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.
- the bacterial composition is administered twice daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.
- the bacterial composition is administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered once daily for at least 8 weeks. In some embodiments, the bacterial composition is administered once daily for at least 12 weeks. In some embodiments, the bacterial composition is administered once daily for at least 16 weeks.
- the bacterial composition is administered twice daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered twice daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered twice daily for at least 8 weeks. In some embodiments, the bacterial composition is administered twice daily for at least 12 weeks. In some embodiments, the bacterial composition is administered twice daily for at least 16 weeks.
- the bacterial composition is formulated as solid dosage form, e.g., a capsule or a tablet.
- the solid dosage form (e.g. , of the composition) comprises an enteric coating or micro encapsulation.
- the capsule is an enteric coated capsule.
- the tablet is an enteric coated tablet.
- 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.
- 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 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.
- the methods provided herein comprise use of bacterial compositions (e.g., pharmaceutical compositions) comprising Prevotella histicola bacteria provided herein.
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- the Prevotella histicola bacteria are non-viable.
- the Prevotella histicola bacteria have been gamma irradiated (e.g., according to a method described herein).
- the Prevotella histicola bacteria are live.
- the Prevotella histicola bacteria are non-live.
- non-live bacteria do not form colonies when plates (e.g., do not have colony forming units (CFUs)).
- CFUs colony forming units
- the bacterial composition (e.g., pharmaceutical composition) comprises only one strain of bacteria, e.g., Prevotella histicola.
- the Prevotella histicola is Prevotella Strain B 50329 (NRRL accession number B 50329).
- the Prevotella 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 Prevotella Strain B 50329.
- 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
- the bacterial compositions comprise whole Prevotella histicola bacteria (e.g., live bacteria, non-live bacteria, killed bacteria, attenuated bacteria).
- the bacterial composition is formulated as a capsule or a tablet.
- the bacterial composition comprises an enteric coating or micro encapsulation.
- the bacterial composition is prepared as a capsule.
- the capsule is an enteric coated capsule.
- the bacterial composition is prepared as a tablet.
- the tablet is an enteric coated tablet.
- 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.
- the bacterial composition comprises about 50 mg to about 3 g of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 55mg, about 550 mg, or about 2.76 g of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 2xl0 10 ,
- the bacterial composition comprises about 8xl0 10 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the bacterial composition comprises about 1.6x10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the bacterial composition comprises about 3.2x10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the bacterial composition comprises about 6.4x10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 8x10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the bacterial composition comprises about 9.6x1o 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the bacterial composition comprises about 12.8x10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the bacterial composition comprises about 16x10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 1.6 x 10 10 to about 1.6 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the bacterial composition comprises about 1.6 x 10 10 to about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the bacterial composition comprises about 8 x 10 10 to about 8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 8 x 10 10 to about 1.6 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the bacterial composition comprises about 1.6 x 10 11 to about 8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the bacterial composition comprises about 9.6 x 10 11 to about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 9.6 x 10 11 to about 12.8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the bacterial composition comprises about 12.8 x 10 11 to about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- total cells is determined by total cell count (e.g., determined by Coulter counter).
- the bacterial composition comprises about 1.6 x 10 10 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 8 x 10 10 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 1.6 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 3.2 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 6.4 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 1.6 x 10 10 to about 8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 1.6 x 10 10 to about 1.6 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 1.6 x 10 11 to about 8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprises about 8 x 10 10 to about 8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 8 x
- the bacterial composition e.g., bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1.6 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 3.2 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 6.4 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 8 x
- the bacterial composition e.g., bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 9.6 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 12.8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 9.6 x 10 11 to about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 9.6 x 10 11 to about 12.8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., bacterial composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 12.8 x 10 11 to about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition comprising Prevotella 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.
- the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 solid dosage forms are administered, e.g., once or twice daily to a subject.
- 1 solid dosage form e.g., tablet or capsule
- 2 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form (e.g., each solid dose form) comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- 3 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- 4 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- 5 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- 6 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- 10 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 10 total cells.
- 1 solid dosage form e.g., tablet or capsule
- 2 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form (e.g., each solid dose form) comprises a dose of bacteria of about 8 x 10 10 total cells.
- 3 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 8 x 10 10 total cells.
- 4 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 8 x 10 10 total cells.
- 5 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 8 x 10 10 total cells.
- 6 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 8 x 10 10 total cells.
- 8 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 8 x 10 10 total cells.
- 10 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 8 x 10 10 total cells.
- 1 solid dosage form e.g., tablet or capsule
- 2 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form (e.g., each solid dose form) comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- 3 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- 4 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- 5 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- 6 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- 10 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 1.6 x 10 11 total cells.
- 1 solid dosage form e.g., tablet or capsule
- 2 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form (e.g., each solid dose form) comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- 3 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- 4 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- 5 solid dosage forms e.g., tablets or capsules
- 5 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- 6 solid dosage forms are administered (e.g., are for administration) e.g., once or twice daily to a subject, wherein the solid dosage form comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- 10 solid dosage forms e.g., tablets or capsules
- the solid dosage form comprises a dose of bacteria of about 3.2 x 10 11 total cells.
- about 3.2 x 10 11 total cells includes total cell counts within ⁇ 5% of 3.2 x 10 11 total cells e.g., 3.35 x 10 11 total cells.
- the bacterial composition is prepared as a solid dosage form.
- solid dosage forms comprising the Prevotella histicola bacteria.
- the solid dosage form comprises an enteric coating.
- the solid dosage form is a tablet, e.g., an enteric coated tablet.
- each tablet comprises about 8 x 10 10 total cells of the Prevotella histicola bacteria.
- each tablet comprises about 1.6 x 10 11 total cells of the Prevotella histicola bacteria.
- each tablet comprises about 3.2 x 10 11 total cells of the Prevotella histicola bacteria.
- the solid dosage form is a capsule, e.g., an enteric coated capsule.
- each capsule comprises about 8 x 10 10 total cells of the Prevotella histicola bacteria.
- each capsule comprises about 1.6 x 10 11 total cells of the Prevotella histicola bacteria.
- each capsule comprises about 3.2 x 10 11 total cells of the Prevotella histicola bacteria.
- the bacterial composition e.g., pharmaceutical composition is a powder.
- the powder can be resuspended (e.g., in a liquid such as a solution, buffer, water or other beverage or a food), e.g., for administration to a subject.
- a dose of Prevotella histicola bacteria of about 8 x 10 10 total cells are administered (e.g., are for administration) per day.
- a dose of Prevotella histicola bacteria of about 1.6 x 10 11 total cells are administered (e.g., are for administration) per day.
- a dose of Prevotella histicola bacteria of about 3.2 x 10 11 total cells are administered (e.g., are for administration) per day.
- a dose of Prevotella histicola bacteria of about 6.4 x 10 11 total cells are administered (e.g., are for administration) per day.
- a dose of Prevotella histicola bacteria of about 8 x 10 11 total cells are administered (e.g., are for administration) per day.
- a dose of Prevotella histicola bacteria of about 9.6 x 10 11 total cells are administered (e.g., are for administration) per day.
- a dose of Prevotella histicola bacteria of about 12.8 x 10 11 total cells are administered (e.g., are for administration) per day.
- a dose of Prevotella histicola bacteria of about 16 x 10 11 total cells are administered (e.g., are for administration) per day.
- the solid dosage form is a tablet.
- the tablet is an enteric coated tablet.
- the enteric coated tablet is from 5mm to 18mm in diameter (size refers to size prior to application of enteric coat).
- the tablet comprises about 8 x 10 10 total cells of the Prevotella bacteria.
- the tablet comprises about 1.6 x 10 11 total cells of the Prevotella bacteria.
- the tablet comprises about 3.2 x 10 11 total cells of the Prevotella bacteria.
- the Prevotella bacteria in the tablet are lyophilized.
- the solid dosage form is a capsule.
- the capsule is an enteric coated capsule.
- the enteric coated capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule.
- the capsule is a size 0 capsule.
- the capsule comprises about 8 x 10 10 total cells of the Prevotella bacteria.
- the capsule comprises about 1.6 x 10 11 total cells of the Prevotella bacteria.
- the capsule comprises about 3.2 x 10 11 total cells of the Prevotella bacteria.
- the Prevotella bacteria in the capsule are lyophilized.
- the capsule comprises gelatin.
- the capsule comprises HPMC.
- the solid dosage form is a tablet, e.g., an enteric coated tablet.
- the solid dosage form is a capsule, e.g., an enteric coated capsule.
- the enteric coating comprises a polymethacrylate-based copolymer.
- the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).
- the enteric coating comprises methacrylic acid ethyl acrylate (MAE) copolymer (1: 1) (such as Kollicoat MAE 100P or Eudragit L30-D55).
- each tablet comprises about 8 x 10 10 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tablets are administered, e.g., once or twice daily to a subject.
- 1 tablet e.g., comprising about 8 x 10 10 total cells
- 2 tablets e.g., each comprising about 8 x 10 10 total cells
- 3 tablets are administered, e.g., once or twice daily to a subject.
- 4 tablets are administered, e.g., once or twice daily to a subject.
- 5 tablets e.g., each comprising about 8 x 10 10 total cells
- 6 tablets e.g., each comprising about 8 x 10 10 total cells
- 8 tablets are administered, e.g., once or twice daily to a subject.
- 10 tablets are administered, e.g., once or twice daily to a subject.
- each tablet comprises about 1.6 x 10 11 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tablets are administered, e.g., once or twice daily to a subject.
- 1 tablet e.g., comprising about 1.6 x 10 11 total cells
- 2 tablets e.g., each comprising about 1.6 x 10 11 total cells
- 3 tablets are administered, e.g., once or twice daily to a subject.
- 4 tablets e.g., each comprising about 1.6 x 10 11 total cells
- 5 tablets e.g., each comprising about 1.6 x 10 11 total cells
- 6 tablets are administered, e.g., once or twice daily to a subject.
- 8 tablets e.g., each comprising about 1.6 x 10 11 total cells
- 10 tablets e.g., each comprising about 1.6 x 10 11 total cells
- each tablet comprises about 3.2 x 10 11 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 tablets are administered, e.g., once or twice daily to a subject.
- 1 tablet e.g., comprising about 3.2 x 10 11 total cells
- 2 tablets e.g., each comprising about 3.2 x 10 11 total cells
- 3 tablets are administered, e.g., once or twice daily to a subject.
- 4 tablets e.g., each comprising about 3.2 x 10 11 total cells
- 5 tablets e.g., each comprising about 3.2 x 10 11 total cells
- 6 tablets are administered, e.g., once or twice daily to a subject.
- 8 tablets e.g., each comprising about 3.2 x 10 11 total cells
- 10 tablets e.g., each comprising about 3.2 x 10 11 total cells
- 8 tablets are administered, e.g., once or twice daily to a subject.
- 10 tablets are administered, e.g., once or twice daily to a subject.
- each capsule comprises about 1.6 x 10 10 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered, e.g., once or twice daily to a subject.
- 1 capsule e.g., comprising about 1.6 x 10 10 total cells
- 2 capsules e.g., each comprising about 1.6 x 10 10 total cells
- 3 capsules are administered, e.g., once or twice daily to a subject.
- 4 capsules e.g., each comprising about 1.6 x 10 10 total cells
- 5 capsules e.g., each comprising about 1.6 x 10 10 total cells
- 6 capsules are administered, e.g., once or twice daily to a subject.
- 8 capsules e.g., each comprising about 1.6 x 10 10 total cells
- 10 capsules e.g., each comprising about 1.6 x 10 10 total cells
- each capsule comprises about 8 x 10 10 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered, e.g., once or twice daily to a subject.
- 1 capsule e.g., comprising about 8 x 10 10 total cells
- 2 capsules e.g., each comprising about 8 x 10 10 total cells
- 3 capsules are administered, e.g., once or twice daily to a subject.
- 4 capsules e.g., each comprising about 8 x 10 10 total cells
- 5 capsules e.g., each comprising about 8 x 10 10 total cells
- 6 capsules are administered, e.g., once or twice daily to a subject.
- 8 capsules e.g., each comprising about 8 x 10 10 total cells
- 10 capsules e.g., each comprising about 8 x 10 10 total cells
- each capsule comprises about 1.6 x 10 11 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered, e.g., once or twice daily to a subject.
- 1 capsule e.g., comprising about 1.6 x 10 11 total cells
- 2 capsules e.g., each comprising about 1.6 x 10 11 total cells
- 3 capsules are administered, e.g., once or twice daily to a subject.
- 4 capsules e.g., each comprising about 1.6 x 10 11 total cells
- 5 capsules e.g., each comprising about 1.6 x 10 11 total cells
- 6 capsules are administered, e.g., once or twice daily to a subject.
- 8 capsules e.g., each comprising about 1.6 x 10 11 total cells
- 10 capsules e.g., each comprising about 1.6 x 10 11 total cells
- each capsule comprises about 3.2 x 10 11 total cells of the Prevotella bacteria.
- 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered, e.g., once or twice daily to a subject.
- 1 capsule e.g., comprising about 3.2 x 10 11 total cells
- 2 capsules e.g., each comprising about 3.2 x 10 11 total cells
- 3 capsules are administered, e.g., once or twice daily to a subject.
- 4 capsules e.g., each comprising about 3.2 x 10 11 total cells
- 5 capsules e.g., each comprising about 3.2 x 10 11 total cells
- 6 capsules are administered, e.g., once or twice daily to a subject.
- 8 capsules e.g., each comprising about 3.2 x 10 11 total cells
- 10 capsules e.g., each comprising about 3.2 x 10 11 total cells
- the Prevotella bacteria in the capsule are lyophilized (e.g., in a powder). In some embodiments, the Prevotella bacteria in the capsule are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.
- 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 Prevotella 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 Prevotella strain.
- at least 99% of the bacteria in the composition are of the Prevotella strain.
- the bacteria in the composition are essentially (e.g., about 100%) of the Prevotella strain.
- the protein in the pharmaceutical composition is Prevotella strain bacteria protein.
- the Prevotella bacteria may be quantified based on total cells, e.g., total cell count (TCC) (e.g., determined by Coulter counter).
- TCC total cell count
- 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).
- 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.
- the bacterial composition is administered once daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.
- the bacterial composition is administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks.
- the bacterial composition is administered twice daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.
- the bacterial composition is administered twice daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the bacterial composition is administered once daily for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks.
- the bacterial composition is formulated as a tablet. In some embodiments, the bacterial composition is formulated as a capsule. In some embodiments, the bacterial formulation (e.g., composition) comprises an enteric coating or micro encapsulation. In some embodiments, the enteric coating allows release of the bacterial composition in the small intestine, e.g., in the upper small intestine, e.g., in the duodenum.
- the subject is a mammal. In some embodiments, the subject is a human.
- 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).
- 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.
- the bacterial composition comprises an enteric coating or micro encapsulation.
- the enteric coating or micro encapsulation improves targeting to a desired region of the gastrointestinal tract.
- the bacterial composition comprises an enteric coating and/or microcapsules that dissolves at a pH associated with a particular region of the gastrointestinal tract.
- 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.
- bacterial compositions for administration subjects.
- 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.
- the bacterial compositions is combined with an adjuvant such as an immuno-adjuvant (e.g., STING agonists, TLR agonists, NOD agonists).
- an adjuvant such as an immuno-adjuvant (e.g., STING agonists, TLR agonists, NOD agonists).
- the composition comprises at least one carbohydrate.
- a “carbohydrate” refers to a sugar or polymer of sugars.
- saccharide polysaccharide
- carbohydrate oligosaccharide
- 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 CnHmOn.
- 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.
- 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.
- the composition comprises at least one lipid.
- 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).
- 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 t
- the composition comprises at least one supplemental mineral or mineral source.
- supplemental mineral or mineral source examples 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.
- the composition comprises at least one supplemental vitamin.
- the at least one vitamin can be fat-soluble or water-soluble vitamins.
- Suitable vitamins include but are not limited to vitamin C, vitamin A, vitamin E, vitamin B12, vitamin K, riboflavin, niacin, vitamin D, vitamin B6, folic acid, pyridoxine, thiamine, pantothenic acid, and biotin.
- Suitable forms of any of the foregoing are salts of the vitamin, derivatives of the vitamin, compounds having the same or similar activity of the vitamin, and metabolites of the vitamin.
- the composition comprises an excipient.
- 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.
- the excipient is a buffering agent.
- suitable buffering agents include sodium citrate, magnesium carbonate, magnesium bicarbonate, calcium carbonate, and calcium bicarbonate.
- the excipient comprises a preservative.
- suitable preservatives include antioxidants, such as alpha-tocopherol and ascorbate, and antimicrobials, such as parabens, chlorobutanol, and phenol.
- the composition comprises a binder as an excipient.
- 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.
- the composition comprises a lubricant as an excipient.
- 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.
- the composition comprises a dispersion enhancer as an excipient.
- 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.
- the composition comprises a disintegrant as an excipient.
- the disintegrant is a non-efferve scent disintegrant.
- suitable non-efferve scent 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.
- the disintegrant is an effervescent disintegrant.
- the composition is a food product (e.g., a food or beverage) such as a health food or beverage, a food or beverage for infants, a food or beverage for pregnant women, athletes, senior citizens or other specified group, a functional food, a beverage, a food or beverage for specified health use, a dietary supplement, a food or beverage for patients, or an animal feed.
- a food product e.g., a food or beverage
- 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.
- 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, carb
- the composition is a food product for animals, including humans.
- the animals, other than humans, are not particularly limited, and the composition can be used for various livestock, poultry, pets, experimental animals, and the like.
- Specific examples of the animals include pigs, cattle, horses, sheep, goats, chickens, wild ducks, ostriches, domestic ducks, dogs, cats, rabbits, hamsters, mice, rats, monkeys, and the like, but the animals are not limited thereto.
- Dose forms comprising Prevotella histicola bacteria are also provided herein, e.g., for use in methods to treat or prevent inflammation (such as inflammation associated with psoriasis or atopic dermatitis or psoriatic arthritis) in a subject (e.g., a human subject).
- a bacterial composition e.g., pharmaceutical composition
- Prevotella histicola bacteria can be formulated as a solid dose form, e.g., for oral administration.
- the bacterial composition comprising Prevotella histicola bacteria is prepared as a powder (e.g., for resuspension or for use in a solid dose form (such as a capsule)) or as a solid dose form, such as a tablet, a mini-tablet, a capsule, or a powder; or a combination of these forms (e.g., mini-tablets comprised in a capsule)).
- the powder can comprise lyophilized bacteria.
- the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.
- the Prevotella histicola bacteria are gamma irradiated.
- the solid dose form (also referred to as solid dosage form herein) can comprise one or more excipients, e.g., pharmaceutically acceptable excipients.
- the Prevotella histicola bacteria in the solid dose form can be isolated Prevotella histicola bacteria.
- the Prevotella histicola bacteria in the solid dose form can be lyophilized.
- the Prevotella histicola bacteria in the solid dose form are live.
- the Prevotella histicola bacteria in the solid dose form are non-live.
- the Prevotella histicola bacteria in the solid dose form are gamma irradiated.
- the solid dose form can comprise a tablet.
- the solid dose form can comprise a capsule.
- the solid dose form can comprise a tablet, a mini-tablet, a capsule, or a powder; or a combination of these forms (e.g., mini -tablets comprised in a capsule).
- the Prevotella histicola bacteria in the solid dose form can be in a powder (e.g., the powder comprises lyophilized Prevotella histicola bacteria).
- the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.
- the powder further comprises mannitol, magnesium stearate, and colloidal silicon dioxide.
- the Prevotella histicola bacteria in the powder can be lyophilized.
- the Prevotella histicola bacteria in the powder are live.
- the Prevotella histicola bacteria in the solid dose form are non-live.
- the Prevotella histicola bacteria in the powder are gamma irradiated.
- the lyophilized Prevotella histicola bacteria (e.g., powder) is resuspended (e.g., in a liquid such as a solution, buffer, water or other beverage or a food), e.g., for administration to a subject.
- the bacterial composition (e.g., pharmaceutical composition) provided herein is prepared as a solid dosage form comprising Prevotella histicola bacteria and a pharmaceutically acceptable carrier.
- the bacterial composition (e.g., pharmaceutical composition) provided herein is prepared as a solid dosage form comprising Prevotella histicola bacteria and a pharmaceutically acceptable carrier.
- the solid dosage form can comprise a tablet, a mini-tablet, a capsule, a pill, or a powder; or a combination of these forms (e.g., mini-tablets comprised in a capsule).
- 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 solid dosage form comprises a tablet (> 4mm) (e.g., 5mm- 18mm).
- the tablet is a 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm or 18mm tablet.
- the size refers to the diameter of the tablet, as is known in the art.
- the solid dosage form comprises a mini-tablet.
- the mini-tablet can be in the size range of lmm-4 mm range.
- the mini-tablet can be a lmm mini-tablet, 1.5 mm mini-tablet, 2mm mini-tablet, 3mm mini-tablet, or 4mm minitablet.
- the size refers to the diameter of the mini-tablet, as is known in the art.
- the size of the mini-tablet refers to the size of the mini-tablet prior to application of an enteric coating.
- the size of the tablet refers to the size of the tablet, mini-tablet or capsule 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, mini-tablet, or capsule) described herein can be enterically coated.
- the enteric coating comprises a polymethacrylate-based copolymer.
- the enteric coating comprises a methacrylic acid ethyl acrylate (MAE) copolymer (1:1).
- 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.
- an inner coating can comprise, e.g., EUDRAGIT L30 D- 55, triethylcitrate, talc, citric acid anhydrous, and sodium hydroxide
- 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 fdm coating applications. Cationic Eudragit E, insoluble at pH ⁇ 5, can prevent drug release in saliva.
- the bacterial composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 8 x 10 10 total cells of Prevotella histicola, e.g., of Prevote lla Strain B 50329.
- the bacterial composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1.6 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 3.2 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 6.4 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition, e.g., pharmaceutical composition e.g., composition of the total dose administered, e.g., once or twice daily
- the bacterial composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 12.8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 9.6 x 10 11 to about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 9.6 x 10 11 to about 12.8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the bacterial composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 12.8 x 10 11 to about 16 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
- the dose of bacterial composition is administered as solid dosage form(s) comprising the Prevotella histicola bacteria.
- the solid dosage form comprises an enteric coating.
- the solid dosage form is a tablet, e.g., an enteric coated tablet.
- the solid dosage form is a mini-tablet, e.g., an enteric coated mini-tablet.
- the solid dosage form is a capsule, e.g., an enteric coated capsule.
- a dose of Prevotella histicola bacteria of about 9.6 x 10 11 total cells are administered (e.g., are for administration) per day.
- a dose of Prevotella histicola bacteria of about 12.8 x 10 11 total cells are administered (e.g., are for administration) per day.
- a dose of Prevotella histicola bacteria of about 16 x 10 11 total cells are administered (e.g., are for administration) per day.
- the Prevotella histicola bacteria are quantified based on total cells, e.g., total cell count (TCC) (e.g., determined by Coulter counter).
- TCC total cell count
- Powders e.g., of Prevotella histicola bacteria
- Powders can be gamma-irradiated at 17.5 kGy radiation unit at ambient temperature.
- Frozen biomasses e.g. , of Prevotella histicola bacteria
- Frozen biomasses can be gamma-irradiated at 25 kGy radiation unit in the presence of dry ice.
- solid dosage forms described herein allow, e.g., for oral administration of a pharmaceutical agent contained therein.
- the solid dosage forms described herein can be used in the treatment and/or prevention of inflammation, autoimmunity, a metabolic condition, or a dysbiosis.
- the solid dosage forms described herein can be used in the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection (such as a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection).
- bacterial septic shock such as a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection.
- viral infection such as a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection.
- solid dosage forms described herein can be used in the treatment and/or prevention of an inflammatory disease.
- solid dosage forms described herein can be used in the treatment and/or prevention of psoriasis.
- solid dosage forms described herein can be used in the treatment and/or prevention of atopic dermatitis.
- solid dosage forms described herein can be used in the treatment and/or prevention of psoriatic arthritis.
- the solid dosage forms described herein can be used in the treatment and/or prevention of an autoimmune disease.
- the solid dosage forms described herein can be used in the treatment and/or prevention of a metabolic disease.
- solid dosage forms described herein can be used in the treatment and/or prevention of a dysbiosis.
- the solid dosage forms described herein can be used to decrease inflammatory cytokine expression (e.g., decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels).
- inflammatory cytokine expression e.g., decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels.
- the solid dosage forms described herein can be used in the treatment and/or prevention of cytokine storm (cytokine release syndrome) in a subject in need thereof.
- the cytokine storm is due to elevation in IL-8, IL-6, IL-Ib, and/or TNFa expression levels.
- solid dosage forms described herein can be used in the treatment and/or prevention of bacterial septic shock.
- solid dosage forms described herein can be used in the treatment and/or prevention of a viral infection.
- a solid dosage form e.g., for oral administration
- a pharmaceutical agent e.g., a therapeutically effective amount thereof
- the pharmaceutical agent comprises Prevotella histicola bacteria
- the solid dosage form further comprises the disclosed components are described herein.
- the methods and administered solid dosage forms described herein allow, e.g., for oral administration of a pharmaceutical agent contained therein.
- the solid dosage form can be administered to a subject is a fed or fasting state.
- the solid dosage form can be administered, e.g., on an empty stomach (e.g., one hour before eating or two hours after eating).
- the solid dosage form can be administered one hour before eating.
- the solid dosage form can be administered two hours after eating.
- the solid dosage form can be administered one hour before drinking (e.g., drinking an acidic drink).
- the solid dosage form can be administered one hour after drinking (e.g., drinking an acidic drink).
- a solid dosage form for use in the treatment and/or prevention of inflammation, autoimmunity, a metabolic condition, or a dysbiosis is provided herein.
- a solid dosage form for use in the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection (such as a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection) is provided herein.
- a solid dosage form for use in decreasing inflammatory cytokine expression e.g., decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels is provided herein.
- a solid dosage form for use in decreasing inflammatory cytokine expression is provided herein.
- the pro-inflammatory cytokine is IL-31, IL- 23p40, IL-17, and/or IL-13.
- the pro-inflammatory cytokine is IL- 4, IL-5, and/or IL-13.
- a solid dosage form for the preparation of a medicament for the treatment and/or prevention of bacterial septic shock, cytokine storm and/or viral infection (such as a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection) is provided herein.
- a solid dosage form for the preparation of a medicament for decreasing inflammatory cytokine expression e.g., decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels
- IL-8, IL-6, IL-Ib, and/or TNFa expression levels e.g., decreased IL-8, IL-6, IL-Ib, and/or TNFa expression levels
- the pro-inflammatory cytokine is IL-31, IL-23p40, IL-17, and/or IL-13. In some embodiments, the pro-inflammatory cytokine is IL-4, IL-5, and/or IL-13.
- 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.
- the additional therapeutic is an immunosuppressant, or a steroid.
- the methods provided herein include use of an emollient cream, gel or ointment.
- a bland additive-free, sodium lauryl sulfate (SLS)-free, and fragrance-free emollient cream, gel or ointment is used.
- the emollient cream, gel or ointment is used daily (e.g., twice daily) (or more, as needed) for at least 14 consecutive days immediately prior use of the Prevotella histicola bacteria.
- the emollient cream, gel or ointment is used daily (e.g., twice daily) (or more, as needed) while the Prevotella histicola bacteria is used.
- the emollient cream, gel or ointment is used daily (e.g., twice daily) (or more, as needed) for at least 14 consecutive days immediately prior use of the Prevotella histicola bacteria and is used daily (e.g., twice daily) (or more, as needed) while the Prevotella histicola bacteria is used.
- the Prevotella histicola bacteria is administered to the subject before the therapeutic is administered (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6,
- the Prevotella histicola bacteria is administered to the subject after the therapeutic is administered (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
- the Prevotella histicola bacteria and the therapeutic are administered to the subject simultaneously or nearly simultaneously (e.g., administrations occur within an hour of each other).
- the subject is administered an antibiotic before the Prevotella bacteria is administered to the subject (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20,
- the subject is administered an antibiotic after the Prevotella bacteria is administered to the subject (e.g., at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 or 24 hours before or at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23 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,
- the Prevotella bacteria and the antibiotic are administered to the subject simultaneously or nearly simultaneously (e.g., administrations occur within an hour of each other).
- 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.
- 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.
- bacteriostatic antibiotics inhibit the activity of bactericidal antibiotics.
- bactericidal and bacteriostatic antibiotics are not combined.
- Antibiotics include, but are not limited to aminoglycosides, ansamycins, carbacephems, carbapenems, cephalosporins, glycopeptides, lincosamides, lipopeptides, macrolides, monobactams, nitrofiirans, 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.
- Gram-negative bacteria such as Escherichia coli, Klebsiella, Pseudomonas aeruginosa, and Francisella tularensis
- 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 Grampositive 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.
- Cephalosporins are effective, e.g., against Gram-negative bacteria and against Gram-positive bacteria, including Pseudomonas, certain Cephalosporins are effective against mcthicillin-rcsistant Staphylococcus aureus (MRS A). 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 Grampositive 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, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, 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, ole
- 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.
- a DMARD a pain-control drug
- a steroid a steroid
- NSAID non-steroidal anti-inflammatory drug
- cytokine antagonist a cytokine antagonist
- Representative agents include, but are not limited to, cyclosporin, retinoids, corticosteroids, propionic acid derivative, acetic acid derivative, enolic acid derivatives, fenamic acid derivatives, Cox-2 inhibitors, lumiracoxib, ibuprophen, cholin magnesium salicylate, fenoprofen, salsalate, difunisal, tolmetin, ketoprofen, flurbiprofen, oxaprozin, indomethacin, sulindac, etodolac, ketorolac, nabumetone, naproxen, valdecoxib, etoricoxib, MK0966; rofecoxib, acetominophen, Celecoxib, Diclofenac, tramadol, piroxicam, meloxicam, tenoxicam, droxicam, lomoxicam, isoxicam, mefanamic acid, meclofenamic acid,
- the additional therapeutic is an oral PDE4 inhibitor (such as apremilast).
- the additional therapeutic is apremilast, etanercept, infliximab, adalimumab, ustekinumab, dupilumab, or secukinumab.
- the agent is an immunosuppressive agent.
- 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, anticholinergic 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
- the additional therapeutic is an oral or injectable corticosteroid, methotrexate, azathioprine, cyclosporine, mycophenolate mofetil, a JAK inhibitor, tacrolimus, and/or leukotriene inhibitor.
- the additional therapeutic is a topical corticosteroid, a topical calcineurin inhibitor (e.g., tacrolimus or pimecrolimus), or a topical PDE-4 inhibitor (e.g., crisaborole).
- a topical corticosteroid e.g., tacrolimus or pimecrolimus
- a topical PDE-4 inhibitor e.g., crisaborole
- the bacterial composition is administered orally. In some embodiments, the administration to the subject once daily. In some embodiments, the administration to the subject twice 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,
- the bacterial composition is administered once daily. In some embodiments, the bacterial composition is administered once daily for at least 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.
- the bacterial composition is administered twice daily. In some embodiments, the bacterial composition is administered twice daily for at least 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.
- the bacterial composition is formulated as a tablet. In some embodiments, the bacterial composition is formulated as a capsule. In some embodiments, the bacterial formulation comprises an enteric coating or micro encapsulation.
- 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).
- 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.
- the bacterial composition is administered in conjunction with the administration of an additional therapeutic.
- the bacterial composition comprises Prevotella bacteria co-formulated with the additional therapeutic.
- the bacterial composition is co administered with the additional therapeutic.
- 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).
- 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).
- the same mode of delivery are used to deliver both the bacterial composition and the additional therapeutic.
- different modes of delivery are used to administer the bacterial composition and the additional therapeutic.
- the bacterial composition is administered orally while the additional therapeutic is administered via injection (e.g., an intravenous, and/or intramuscular injection).
- the bacterial compositions, dosage forms (e.g., solid 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.
- 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.
- 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.
- 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.
- disease e.g autoimmune disease, inflammatory disease, metabolic disease
- 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.
- 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.
- MTD maximal tolerable dose
- 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.
- 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.
- 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.
- 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.
- 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.
- 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,
- 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.
- the disease or disorder is an inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis).
- the disease or disorder is psoriasis (e.g., mild to moderate psoriasis).
- the disease or disorder is atopic dermatitis (e.g., mild to moderate atopic dermatitis).
- the disease or disorder is psoriatic arthritis.
- a “subject in need thereof’ includes any subject that has a disease or disorder associated with a pathological immune response (psoriasis (e.g., mild to moderate psoriasis) or atopic dermatitis (e.g., mild to moderate atopic dermatitis)) or psoriatic arthritis, as well as any subject with an increased likelihood of acquiring a such a disease or disorder.
- psoriasis e.g., mild to moderate psoriasis
- atopic dermatitis e.g., mild to moderate atopic dermatitis
- compositions described herein can be used, for example, as a bacterial composition for preventing or treating (reducing, partially or completely, the adverse effects of) an autoimmune disease, such as chronic inflammatory bowel disease, systemic lupus erythematosus, psoriasis, psoriatic arthritis, muckle-wells syndrome, rheumatoid arthritis, multiple sclerosis, or Hashimoto's disease; an allergic disease, such as a food allergy, pollenosis, or asthma; an infectious disease, such as an infection with Clostridium difficile; an inflammatory disease such as a TNF-mediated inflammatory disease (e.g., an inflammatory disease of the gastrointestinal tract, such as pouchitis, a cardiovascular inflammatory condition, such as atherosclerosis, or an inflammatory lung disease, such as chronic obstructive pulmonary disease); a bacterial composition for suppressing rejection in organ transplantation or other situations in which tissue rejection might occur; a supplement, food, or beverage for improving immune functions; or
- the methods and compositions provided herein are useful for the treatment of inflammation.
- 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.
- 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).
- 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, ten
- Ocular immune disorders refer to an immune disorder that affects any structure of the eye, including the eye lids.
- 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.
- Crohn's disease regional bowel disease, e.g., inactive and active forms
- ulcerative colitis e.g., inactive and active forms
- 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.
- 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
- 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).
- immune disorders which may be treated with the methods and compositions include, for example, appendicitis, dermatitis, dermatomyositis, endocarditis, fibrositis, gingivitis, glossitis, hepatitis, hidradenitis suppurativa, ulceris, 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 v
- 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).
- bacterial compositions for use of treating psoriasis are disclosed.
- a bacterial composition comprising Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) for use in treating psoriasis is described herein.
- a bacterial composition for the preparation of a medicament for treating psoriasis e.g., mild to moderate psoriasis
- use of a bacterial composition for the preparation of a medicament for treating psoriasis wherein the bacterial composition comprises Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) is described herein.
- bacterial compositions for use of treating psoriatic arthritis are disclosed.
- a bacterial composition comprising Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) for use in treating psoriatic arthritis is described herein.
- a bacterial composition for the preparation of a medicament for treating psoriatic arthritis uses of a bacterial composition for the preparation of a medicament for treating psoriatic arthritis.
- bacterial compositions for use of treating atopic dermatitis are disclosed.
- a bacterial composition comprising Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) for use in treating atopic dermatitis is described herein.
- a bacterial composition for the preparation of a medicament for treating atopic dermatitis e.g., mild, moderate, or severe atopic dermatitis
- use of a bacterial composition for the preparation of a medicament for treating atopic dermatitis wherein the bacterial composition comprises Prevotella histicola, wherein the Prevotella histicola is a strain comprising at least 85% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329) is described herein.
- the Prevotella histicola is a strain comprising at least 99.9% sequence identity to the nucleotide sequence of the Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
- the Prevotella histicola is the Prevotella histicola Strain B 50329 (NRRL accession number B 50329).
- the bacterial composition is administered orally.
- the bacterial composition is formulated as a tablet.
- the bacterial composition is formulated as a capsule.
- the bacterial composition is administered once daily. In some embodiments, the bacterial composition is administered once daily for 15 continuous days. In some embodiments, the bacterial composition is administered once daily for 28 continuous days. In some embodiments, the bacterial composition is administered once daily for 29 continuous days. In some embodiments, the bacterial composition is administered once daily for 8 continuous weeks. In some embodiments, the bacterial composition is administered once daily for 12 continuous weeks. In some embodiments, the bacterial composition is administered once daily for 16 continuous weeks.
- the psoriasis is mild to moderate psoriasis. In some embodiments, the atopic dermatitis is mild, moderate, or severe atopic dermatitis.
- the bacterial composition is administered twice daily. In some embodiments, the bacterial composition is administered twice daily for 15 continuous days. In some embodiments, the bacterial composition is administered twice daily for 28 continuous days. In some embodiments, the bacterial composition is administered twice daily for 29 continuous days. In some embodiments, the bacterial composition is administered twice daily for 8 continuous weeks. In some embodiments, the bacterial composition is administered twice daily for 12 continuous weeks. In some embodiments, the bacterial composition is administered twice daily for 16 continuous weeks.
- the psoriasis is mild to moderate psoriasis. In some embodiments, the atopic dermatitis is mild, moderate, or severe atopic dermatitis.
- the methods and compositions described herein relate to the treatment or prevention of a metabolic disease or disorder a, such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, non-alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, ketoacidosis, hypoglycemia, thrombotic disorders, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), Nonalcoholic Steatohepatitis (NASH) or a related disease.
- a metabolic disease or disorder a such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, non-alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, ketoacidosis, hypoglycemia, thrombotic disorders, dyslipidemia, non-alcoholic fatty
- the related disease is cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, or edema.
- the methods and pharmaceutical compositions described herein relate to the treatment of Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH).
- NAFLD Nonalcoholic Fatty Liver Disease
- NASH Nonalcoholic Steatohepatitis
- compositions described herein can be used to treat any subject in need thereof.
- a “subject in need thereof’ includes any subject that has a metabolic disease or disorder, as well as any subject with an increased likelihood of acquiring a such a disease or disorder.
- compositions described herein can be used, for example, for preventing or treating (reducing, partially or completely, the adverse effects of) a metabolic disease, such as type II diabetes, impaired glucose tolerance, insulin resistance, obesity, hyperglycemia, hyperinsulinemia, fatty liver, non-alcoholic steatohepatitis, hypercholesterolemia, hypertension, hyperlipoproteinemia, hyperlipidemia, hypertriglylceridemia, ketoacidosis, hypoglycemia, thrombotic disorders, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), Nonalcoholic Steatohepatitis (NASH), or a related disease.
- the related disease is cardiovascular disease, atherosclerosis, kidney disease, nephropathy, diabetic neuropathy, diabetic retinopathy, sexual dysfunction, dermatopathy, dyspepsia, or edema.
- the methods and compositions described herein relate to the treatment of liver diseases.
- diseases include, but are not limited to, Alagille Syndrome, Alcohol-Related Liver Disease, Alpha- 1 Antitrypsin Deficiency, Autoimmune Hepatitis, Benign Liver Tumors, Biliary Atresia, Cirrhosis, Galactosemia, Gilbert Syndrome, Hemochromatosis, Hepatitis A, Hepatitis B, Hepatitis C, Hepatic Encephalopathy, Intrahepatic Cholestasis of Pregnancy (I CP), Lysosomal Acid Lipase Deficiency (LAL-D), Liver Cysts, Liver Cancer, Newborn Jaundice, Primary Biliary Cholangitis (PBC), Primary Sclerosing Cholangitis (PSC), Reye Syndrome, Type I Glycogen Storage Disease, and Wilson Disease.
- I CP Pregnancy
- LAL-D Lysosomal Acid Lipase Def
- the methods and compositions described herein may be used to treat neurodegenerative and neurological diseases.
- the neurodegenerative and/or neurological disease is Parkinson’s disease, Alzheimer’s disease, prion disease, Huntington’s disease, motor neuron diseases (MND), spinocerebellar ataxia, spinal muscular atrophy, dystonia, idiopathicintracranial hypertension, epilepsy, nervous system disease, central nervous system disease, movement disorders, multiple sclerosis, encephalopathy, peripheral neuropathy or postoperative cognitive dysfunction.
- gut microbiota also called the “gut microbiota”
- gut microbiota can have a significant impact on an individual’s health through microbial activity and influence (local and/or distal) on immune and other cells of the host
- a healthy host-gut microbiome homeostasis is sometimes referred to as a “eubiosis” or “normobiosis,” whereas a detrimental change in the host microbiome composition and/or its diversity can lead to an unhealthy imbalance in the microbiome, or a “dysbiosis” (Hooks and O’Malley. Dysbiosis and its discontents. American Society for Microbiology. Oct 2017. Vol. 8. Issue 5. mBio 8:e01492-17. https://doi.org/10.1128/mBio.01492-17).
- Dysbiosis, and associated local or distal host inflammatory or immune effects may occur where microbiome homeostasis is lost or diminished, resulting in: increased susceptibility to pathogens; altered host bacterial metabolic activity; induction of host proinflammatory activity and/or reduction of host anti-inflammatory activity.
- Such effects are mediated in part by interactions between host immune cells (e.g., T cells, dendritic cells, mast cells, NK cells, intestinal epithelial lymphocytes (IEC), macrophages and phagocytes) and cytokines, and other substances released by such cells and other host cells.
- host immune cells e.g., T cells, dendritic cells, mast cells, NK cells, intestinal epithelial lymphocytes (IEC), macrophages and phagocytes
- a dysbiosis may occur within the gastrointestinal tract (a “gastrointestinal dysbiosis” or “gut dysbiosis”) or may occur outside the lumen of the gastrointestinal tract (a “distal dysbiosis”).
- Gastrointestinal dysbiosis is often associated with a reduction in integrity of the intestinal epithelial barrier, reduced tight junction integrity and increased intestinal permeability.
- Citi, S. Intestinal Barriers protect against disease, Science 359: 1098-99 (2016); Srinivasan et al., TEER measurement techniques for in vitro barrier model systems. J. Lab. Autom. 20: 107-126 (2015).
- a gastrointestinal dysbiosis can have physiological and immune effects within and outside the gastrointestinal tract.
- dysbiosis has been associated with a wide variety of diseases and conditions including: infection, cancer, autoimmune disorders (e.g., systemic lupus erythematosus (SLE)) or inflammatory disorders (e.g., functional gastrointestinal disorders such as inflammatory bowel disease (IBD), ulcerative colitis, and Crohn’s disease), neuroinflammatory diseases (e.g., multiple sclerosis), transplant disorders (e.g., graft-versus-host disease), fatty liver disease, type I diabetes, rheumatoid arthritis, Sjogren’s syndrome, celiac disease, cystic fibrosis, chronic obstructive pulmonary disorder (COPD), and other diseases and conditions associated with immune dysfunction.
- autoimmune disorders e.g., systemic lupus erythematosus (SLE)
- inflammatory disorders e.g., functional gastrointestinal disorders such as inflammatory bowel disease (IBD), ulcerative colitis, and Crohn’s disease
- neuroinflammatory diseases e.g.
- Exemplary bacterial compositions disclosed herein can treat a dysbiosis and its effects by modifying the immune activity present at the site of dysbiosis. As described herein, such compositions can modify a dysbiosis via effects on host immune cells, resulting in, e.g., an increase in secretion of anti-inflammatory cytokines and/or a decrease in secretion of pro-inflammatory cytokines, reducing inflammation in the subject recipient or via changes in metabolite production.
- Exemplary bacterial compositions disclosed herein that are useful for treatment of disorders associated with a dysbiosis contain one or more types of immunomodulatory bacteria (e.g., anti-inflammatory bacteria) derived from such bacteria. Such compositions are capable of affecting the recipient host’s immune function, in the gastrointestinal tract, and/or a systemic effect at distal sites outside the subject’s gastrointestinal tract.
- immunomodulatory bacteria e.g., anti-inflammatory bacteria
- Exemplary bacterial compositions disclosed herein that are useful for treatment of disorders associated with a dysbiosis contain a population of immunomodulatory bacteria of a single bacterial species (e.g., a single strain) (e.g., anti-inflammatory bacteria). Such compositions are capable of affecting the recipient host’s immune function, in the gastrointestinal tract, and /or a systemic effect at distal sites outside the subject’s gastrointestinal tract.
- bacterial compositions containing an isolated population of immunomodulatory bacteria e.g., anti-inflammatory bacterial cells
- the dysbiosis may be a gastrointestinal tract dysbiosis or a distal dysbiosis.
- compositions of the instant invention can treat a gastrointestinal dysbiosis and one or more of its effects on host immune cells, resulting in an increase in secretion of anti-inflammatory cytokines and/or a decrease in secretion of pro-inflammatory cytokines, reducing inflammation in the subject recipient.
- the bacterial compositions can treat a gastrointestinal dysbiosis and one or more of its effects by modulating the recipient immune response via cellular and cytokine modulation to reduce gut permeability by increasing the integrity of the intestinal epithelial barrier.
- the bacterial compositions can treat a distal dysbiosis and one or more of its effects by modulating the recipient immune response at the site of dysbiosis via modulation of host immune cells.
- compositions are useful for treatment of disorders associated with a dysbiosis, which compositions contain one or more types of bacteria capable of altering the relative proportions of host immune cell subpopulations, e.g., subpopulations of T cells, immune lymphoid cells, dendritic cells, NK cells and other immune cells, or the function thereof, in the recipient.
- host immune cell subpopulations e.g., subpopulations of T cells, immune lymphoid cells, dendritic cells, NK cells and other immune cells, or the function thereof, in the recipient.
- compositions are useful for treatment of disorders associated with a dysbiosis, which compositions contain a population of immunomodulatory bacteria of a single bacterial species e.g., a single strain) capable of altering the relative proportions of immune cell subpopulations, e.g., T cell subpopulations, immune lymphoid cells, NK cells and other immune cells, or the function thereof, in the recipient subject.
- a population of immunomodulatory bacteria of a single bacterial species e.g., a single strain
- immune cell subpopulations e.g., T cell subpopulations, immune lymphoid cells, NK cells and other immune cells, or the function thereof, in the recipient subject.
- the invention provides methods of treating a gastrointestinal dysbiosis and one or more of its effects by orally administering to a subject in need thereof a bacterial composition which alters the microbiome population existing at the site of the dysbiosis.
- the bacterial composition can contain one or more types of immunomodulatory bacteria or a population of immunomodulatory bacteria of a single bacterial species (e.g., a single strain).
- the invention provides methods of treating a distal dysbiosis and one or more of its effects by orally administering to a subject in need thereof a bacterial composition which alters the subject’s immune response outside the gastrointestinal tract.
- the bacterial composition can contain one or more types of immunomodulatory bacteria or a population of immunomodulatory bacteria of a single bacterial species (e.g., a single strain).
- bacterial compositions useful for treatment of disorders associated with a dysbiosis stimulate secretion of one or more antiinflammatory cytokines by host immune cells.
- Anti-inflammatory cytokines include, but are not limited to, IL-10, IL-13, IL-9, IL-4, IL-5, TGFp, and combinations thereof.
- bacterial compositions useful for treatment of disorders associated with a dysbiosis that decrease (e.g., inhibit) secretion of one or more pro- inflammatory cytokines by host immune cells.
- Pro-inflammatory cytokines include, but are not limited to, IFNy, IL-12p70, IL-la, IL-6, IL-8, MCP1, MIPla, MIRIb, TNFa, and combinations thereof.
- Other exemplary cytokines are known in the art and are described herein.
- the invention provides a method of treating or preventing a disorder associated with a dysbiosis in a subject in need thereof, comprising administering (e.g., orally administering) to the subject a therapeutic composition in the form of a probiotic or medical food comprising bacteria an amount sufficient to alter the microbiome at a site of the dysbiosis, such that the disorder associated with the dysbiosis is treated.
- a therapeutic composition of the instant invention in the form of a probiotic or medical food may be used to prevent or delay the onset of a dysbiosis in a subject at risk for developing a dysbiosis.
- Inflammation can be a protective response to harmful stimuli, such as invading pathogens, damaged cells, toxic compounds, or cancerous cells.
- harmful stimuli such as invading pathogens, damaged cells, toxic compounds, or cancerous cells.
- excessive inflammatory responses to such stimuli can result in serious adverse effects, including tissue damage and even death.
- pro-inflammatory cytokines such as interleukin-8 (IL-8), interleukin-6 (IL-6), interleukin- 1 beta (IL-Ib), and tumor necrosis factor alpha (TNFa) in response to many viral infections is one of the primary causes of the adverse symptoms associated with infection (including, in some cases, death).
- inflammatory cytokines has been associated with disease severity resulting from infection by a number of viruses, including infection by coronaviruses (e.g., SARS-CoV-2, the virus that causes Coronavirus Disease 2019 (COVID-19)), influenza viruses, and respiratory syncytial viruses.
- coronaviruses e.g., SARS-CoV-2, the virus that causes Coronavirus Disease 2019 (COVID-19)
- influenza viruses e.g., influenza viruses that causes Coronavirus Disease 2019 (COVID-19)
- respiratory syncytial viruses e.g., aviruses (e.g., SARS-CoV-2, the virus that causes Coronavirus Disease 2019 (COVID-19)
- coronaviruses e.g., SARS-CoV-2, the virus that causes Coronavirus Disease 2019 (COVID-19)
- influenza viruses e.g., influenza viruses that causes Coronavirus Disease 2019 (COVID-19)
- respiratory syncytial viruses e.g., a
- the methods and compositions described herein relate to the treatment or prevention of bacterial septic shock, cytokine storm and/or viral infection.
- the methods and compositions described herein relate to the treatment or prevention of a viral infection such as a respiratory viral infection, such as a coronavirus infection (e.g., a MERS (Middle East Respiratory Syndrome) infection, a severe acute respiratory syndrome (SARS) infection, such as a SARS-CoV-2 infection), an influenza infection, and/or a respiratory syncytial virus infection.
- a respiratory viral infection such as a coronavirus infection
- a MERS Middle East Respiratory Syndrome
- SARS severe acute respiratory syndrome
- the methods and solid dosage forms described herein provided herein are for the treatment of a coronavirus infection (e.g., a MERS infection, a severe acute respiratory syndrome (SARS) infection, such as a SARS-CoV-2 infection).
- a coronavirus infection e.g., a MERS infection, a severe acute respiratory syndrome (SARS) infection, such as a SARS-CoV-2 infection
- provided herein are methods and solid dosage forms for
- the methods and compositions described herein relate to the treatment or prevention of a viral infection.
- the infection is a coronavirus infection, an influenza infection, and/or a respiratory syncytial virus infection.
- the viral infection is a SARS-CoV-2 infection.
- an additional therapy is administered to the subject.
- the additional therapy comprises an antiviral medication.
- the additional therapy comprises an antiviral medication such as ribavirin, neuraminidase inhibitor, protease inhibitor, recombinant interferons, antibodies, oseltamivir, zanamivir, peramivir or baloxavir marboxil.
- the additional therapy comprises hydroxychloroquine and/or chloroquine.
- the additional therapy comprises remdesivir.
- the additional therapy comprises plasma from a subject who has recovered from infection by the same virus that is infecting the subject (e.g., plasma from a subject who has recovered from SARS-CoV-2 infection).
- the additional therapy comprises an anti-inflammatory agent such as NSAIDs or anti-inflammatory steroids.
- the additional therapy comprises dexamethasone.
- the additional therapy comprises an antibody specific for IL-6 and/or the IL-6 receptor.
- the additional therapy comprises tocilizumab (Actemra®).
- the additional therapy comprises sarilumab (Kevzara®).
- the additional therapy can comprise an anti-viral therapy.
- the anti-viral therapy can comprise a nucleotide analog, such as remdesivir, galidesivir or clevudine; a viral RNA polymerase inhibitor such as favipiravir or galidesivir; a protease inhibitor such as ritonavir, darunavir, or danoprevir; an inhibitor of viral membrane fusion such as umifenovir; and/or anti-SARS-CoV-2 plasma.
- the additional therapy can comprise an anti-inflammatory therapy.
- the anti-inflammatory therapy can comprise a corticosteroid; sirolimus; anakinra; filamod; or an antibody.
- the antibody can comprise a GMSF inhibitor, such as lenzilumab or gimsilumab; an anti-ILl beta inhibitor such as canakinumab; an IL-6 inhibitor such as tocilizumab or siltuximab; an IL-6R inhibitor such as sarilumab; and/or a CCR5 antagonist such as leronlimab.
- the additional therapy can comprise a JAK inhibitor such as baricitinib, ruxolitinib, tofacitinib, and/or pacritinib.
- a JAK inhibitor such as baricitinib, ruxolitinib, tofacitinib, and/or pacritinib.
- the additional therapy can comprise a TLR7 agonist such as imiquimod or reisquimod.
- the additional therapy can comprise a cell based therapy.
- the cell based therapy can comprise Remestemcel- L; bone marrow stem cell therapy, such as MultiStem or Bm-Allo-MSC; mesenchymal stromal cells; and/or adiopose derived mesenchymal stem cells such as AstroStem.
- the additional therapy can comprise an ACE receptor inhibitor.
- the additional therapy can comprise a regulator of the Sigma 1 and/or Sigma 2 receptor.
- Example 1 Prevotella histicola Strain B Treatment for Mild to Moderate Psoriasis
- Prevotella Strain B 50329 is a pharmaceutical preparation of a strain of Prevotella histicola isolated from a human duodenal biopsy: it has not been genetically modified. Strains of the Prevotella genus of microbes have been found in all human populations tested to date, at abundances ranging from less than 1% to nearly 50% of total fecal microbial load (Vandeputte 2017). Prevotella are gram-negative, obligate anaerobes that are natural human commensals in the oral cavity and GI tract.
- Prevotella Strain B 50329 is a gram-negative bacterium sensitive to the major classes of antibiotics, e.g., penicillins and cephalosporins. In non-clinical and clinical studies, its therapeutic effects have been dose-dependent.
- Prevotella Strain B 50329 Studies of Prevotella Strain B 50329 in vitro in a range of human and mouse assays and studies in vivo in model symptoms support the use of Prevotella Strain B 50329 in the treatment of inflammatory diseases including psoriasis.
- Prevotella Strain B 50329 increases secretion of anti-inflammatory cytokines such as IL-10, ILIRA, and IL- 27 from human immune cells, while inducing minimal production of pro-inflammatory cytokines such as IL-6, TNFa, and IFNy.
- Immunophenotyping ex vivo in these models shows increased regulatory T cell numbers and regulatory dendritic cells in spleen and mesenteric lymph nodes, as well as decreases in pro-inflammatory cytokines such as IL-23p40, IL-17, TNF, IL-6, and IL-13.
- Treatment also led to enhancement of gut intestinal barrier integrity, which is often disrupted in patients with inflammatory diseases.
- Psoriasis is a chronic immune-mediated type 1/3 inflammatory skin disease in which hyperactive T cells trigger excessive keratinocyte proliferation. This results in the formation of raised erythematous plaques with scaling. Psoriatic lesions can appear anywhere on the body but are most often seen on the knees, elbows, scalp, and lumbar area. Critical events in the inflammatory process include activation of Langerhans cells and T cells, selective trafficking of activated T cells to the skin, and induction of an inflammatory cytokine and chemokine cascade in skin lesions. Clinical data have validated the role of anti -TNF a, anti-IL-17, and anti-IL-23 therapy in moderate to severe psoriasis.
- topical agents topical corticosteroids, vitamin D3 analogs
- topical corticosteroids providing the greatest range of efficacy and a wide range of formulations.
- physicians are prescribing apremilast, a first-in-class oral PDE4 inhibitor, ahead of biological therapy, which includes etanercept, infliximab, adalimumab, ustekinumab, and secukinumab.
- Cohort 3.2 x 10 11 cells of Prevotella Strain B 50329 or matching placebo administered as capsules or tablets, once daily to subjects with psoriasis for 4, 6, 8, 12, and/or 16 weeks.
- Cohort 8 x 10 11 cells of Prevotella Strain B 50329 or matching placebo administered as capsules or tablets, once daily to subjects with psoriasis for 4, 6, 8, 12, and/or 16 weeks.
- endpoints can be evaluated prior to first administration of a bacterial composition described herein, and/or at intervals during administration (e.g., 4, 6, 8, 12, and/or 16 weeks) of a bacterial composition described herein and/or after administration has terminated (e.g., 2 and/or 4 weeks after termination):
- the PASI score will be assessed as described by Langley and Ellis (2004).
- the PASI is a physician assessment that combines the assessment of the severity of and area affected by psoriasis into a single score in the range 0 (no disease) to 72 (maximal disease).
- the absolute PASI score in this study is used as part of inclusion criterion #4.
- the PASI percentage response rates are efficacy endpoints (i.e., PASI-50, PASI-75, PASI-90, and PASI-100). For example, the percentage of participants who achieve a 75% or greater reduction in PASI score from baseline is represented by the PASI-75 value. Details of the PASI assessment will be provided in the study manual.
- 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.
- the National Psoriasis Foundation Psoriasis Score version of a static PGA is calculated by averaging the total body erythema, induration, and desquamation scores (Feldman and Krueger 2005). Erythema, induration, and desquamation will be scored on a 6-point scale, ranging from 0 (clear) to 5 (severe): the total PGA score is defined as the average of the erythema, induration, and desquamation scores. Details of the PGA assessment will be provided in the study manual.
- 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).
- the mNAPSI is a numeric, reproducible, objective, and simple tool for physicians to evaluate the severity of nail bed psoriasis and nail matrix psoriasis by area of involvement in the nail unit (Cassell et al 2007). Details of conducting the mNAPSI will be provided in the study manual.
- the DLQI is a patient reported outcomes instrument for assessing the impact of dermatologic conditions on patients’ quality of life (Finlay and Khan 1994). Details of administering the DLQI will be provided in the study manual.
- the PSI is a patient reported outcomes instrument that is used to assess the severity of plaque psoriasis symptoms (Bushnell et al 2013). All symptoms (itch, redness, scaling, burning, cracking, stinging, flaking, and pain) are rated on a 5 -point severity scale. The PSI demonstrated good construct validity and was sensitive to within-subject change (p ⁇ 0.0001). Details of administering the PSI will be provided in the study manual.
- Pain will be assessed by the SF-36 Bodily Pain Scale (SF-36 BPS) and the VAS Pain (Hawker et al 2011). Details of administering the pain assessments will be provided in the study manual. Fatigue
- Blood samples will be stimulated ex vivo and analyzed for levels of cytokines and chemokines, including IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-17A, TNFa, and IFNy.
- cytokines and chemokines including IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p40, IL-17A, TNFa, and IFNy.
- Bomkamp B Practical considerations for using functional uniform prior distributions for dose-response estimation in clinical trials. Biom J. 2014;56(6):947-62.
- Marietta EV Murray JA, Luckey DH, et al. Human gut-derived Prevote lla histicola suppresses inflammatory arthritis in humanized mice. Arthritis Rheumatol. 2016;68(12):2878-88.
- Example 2 Prevotella histicola Strain B Treatment for Mild to Moderate Psoriasis
- endpoints can be evaluated at intervals prior to first administration of a bacterial composition described herein, and/or during administration (e.g., 4, 6, 8, 12, and/or 16 weeks) of a bacterial composition described herein and/or after administration has terminated (e.g., 2 and/or 4 weeks after termination):
- 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.
- 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.
- the Body Surface Area 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.
- 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.
- [335] Cohort: 8 x 10 10 cells of Prevotella Strain B 50329 or matching placebo administered as capsules or tablets, once daily to subjects with psoriasis for 4, 6, 8, 12, and/or 16 weeks.
- [336] Cohort: 1.6 x 10 11 cells of Prevotella Strain B 50329 or matching placebo administered as capsules or tablets, once daily to subjects with psoriasis for 4, 6, 8, 12, and/or 16 weeks.
- Cohort 8 x 10 11 cells of Prevotella Strain B 50329 or matching placebo administered as capsules or tablets, once daily to subjects with psoriasis for 4, 6, 8, 12, and/or 16 weeks.
- Cohort 9.6 x 10 11 cells of Prevotella Strain B 50329 or matching placebo administered as capsules or tablets, once daily to subjects with psoriasis for 4, 6, 8, 12, and/or 16 weeks.
- PASI50 Percentage of patients achieving at least a 50% improvement in PASI from baseline (PASI50) (e.g., at weeks 4, 8, 12 and 16)
- PASI75 Percentage of patients achieving at least a 75% improvement in PASI from baseline (PASI75) (e.g., at weeks 4, 8, 12 and/or 16)
- TQM Treatment Satisfaction Questionnaire for Medication
- HADS Hospital Anxiety and Depression Scale
- PI-ED Paediatric Index of Emotional Distress
- 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 (i.e., PASI-50, PASI-75, PASI-90, and PASI-100). For example, the percentage of participants who achieve a 75% or greater reduction in PASI score from baseline is represented by the PASI-75 value.
- 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 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).
- a method of treating psoriasis comprising administering (e.g., orally administering) to a human subject a Prevotella histicola strain and/or a composition (e.g., a bacterial composition and/or a solid dosage form) comprising a strain of a Prevotella histicola .
- 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).
- BSA body surface area
- the human subject has a minimum of 2 psoriatic lesions.
- 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.
- subject has not received treatment with biologic agents within 12 months prior to first dose.
- the subject is not continuing use of topical or oral pharmacologically active agents 2 weeks prior to the start of dosing.
- the human subject has a documented diagnosis of plaque psoriasis for >6 months.
- 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.
- 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).
- PASI Psoriasis Area and Severity Index
- the method increases a PASI percentage response rate (e.g., PASI-50, PASI-75, PASI-90, or PASI-100), e.g., as described herein.
- a PASI percentage response rate e.g., PASI-50, PASI-75, PASI-90, or PASI-100
- PASI-75 value e.g., after 16 weeks of treatment.
- 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.
- LSS Lesion Severity Score
- 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.
- PGA Physical’s Global Assessment
- 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.
- BSA Body Surface Area
- 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.
- 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.
- 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.
- PSI Psoriasis Symptom Inventory
- 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.
- pain can be assessed by the SF-36 Bodily Pain Scale (SF-36 BPS) or the VAS Pain.
- 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.
- Example 4 Prevotella histicola Strain B Treatment for Mild to Moderate Atopic
- Prevotella histicola Strain B can be used for the treatment of atopic dermatitis, e.g., at the doses and dosing regimens provided herein.
- [366] Cohort: 8 x 10 10 cells of Prevotella Strain B 50329 or matching placebo administered as capsules or tablets, once daily to subjects with atopic dermatitis for 4, 6, 8, 12, and/or 16 weeks.
- Cohort 1.6 x 10 11 cells of Prevotella Strain B 50329 or matching placebo administered as capsules or tablets, once daily to subjects with atopic dermatitis for 4, 6, 8, 12, and/or 16 weeks.
- Cohort 3.2 x 10 11 cells of Prevotella Strain B 50329 or matching placebo administered as capsules or tablets, once daily to subjects with atopic dermatitis for 4, 6, 8, 12, and/or 16 weeks.
- Cohort 9.6 x 10 11 cells of Prevotella Strain B 50329 or matching placebo administered as capsules or tablets, once daily to subjects with atopic dermatitis for 4, 6, 8, 12, and/or 16 weeks.
- endpoints can be evaluated at intervals prior to first administration of a bacterial composition described herein, and/or during administration (e.g., 4, 6, 8, 12, and/or 16 weeks) of a bacterial composition described herein and/or after administration has terminated (e.g., 2 and/or 4 weeks after termination):
- EASI Eczema Area and Severity Index
- SCORing Atopic Dermatitis is a clinical tool which is also used to assess the extent and severity of eczema, to assess treatment effects (ETFAD, 1993).
- SCORAD score ranges from 0 - 103.
- the Body Surface Area 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.
- the Validated Investigator Global Assessment scale for Atopic Dermatitis will be used to describe the overall appearance of lesions, at a given time-point (Simpson, 2020). There is a standardized 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).
- the Patient-Orientated Eczema Measure includes 7 questions about the participant’s atopic dermatitis. Each of the 7 questions is scored from 0 to 4, giving a POEM score range from 0 to 28.
- Pruritus Numerical Rating Scale is a 10-point scale for participants to rate both their average and worst itch that they have experienced over the previous 24 hours.
- Example 5 Prevotella histicola Strain B for the Treatment of Psoriatic Arthritis
- Prevotella histicola Strain B can be used for the treatment of psoriatic arthritis (PsA), e.g., at the doses and dosing regimens provided herein.
- PsA psoriatic arthritis
- ACR American College of Rheumatology
- 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).
- PtGA Patient Global Assessment
- PhGA Physician's Global Assessment of Disease Activity
- PhGA physical function
- HAQ-DI visual analog pain scale
- 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.
- PsARC Modified Psoriatic Arthritis Response Criteria
- 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.
- a DAS28 score higher than 5.1 indicates high disease activity
- a DAS28 score of 3.2 to 5.1 indicates moderate disease activity
- a DAS28 score of 2.6 to 3.2 indicates low disease activity
- a DAS28 score less than 2.6 indicates clinical remission.
- Maastricht Ankylosing Spondylitis Enthesis Score (MASES): The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right.
- the MASES ranging from 0 to 13, is the number of painful entheses out of 13 entheses. See also L Heuft-Dorenbosch et al., Ann. Rheum. Dis. 62: 127-132 (2003).
- the effects of Prevotella histicola Strain B on psoriatic arthritis can be evaluated by one or more of the following criteria:
- Psoriasis Area and Severity Index Psoriasis Area and Severity Index
- NAPSI Nail Psoriasis Severity Index
- mNAPSI Modified Nail Psoriasis Severity Index
- MEI Mander/Newcastle Enthesitis Index
- LEI Leeds Enthesitis Index
- SPARCC Maastricht Ankylosing Spondylitis Enthesis Score
- MASES Leeds Dactylitis Index
- LPI Leeds Dactylitis Index
- Psoriatic Arthritis Dermatology Life Quality Index
- Psoriatic Arthritis Quality of Life (PsAQOL Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F)
- Psoriatic Arthritis Response Criteria Psoriatic Arthritis Response Criteria
- PsAJAI Psoriatic Arthritis Joint Activity Index
- DAPSA Disease Activity in Psoriatic Arthritis
- Composite Psoriatic Disease Activity Index CP
- Table i Prevotella histicola Capsule Composition a Composed of hydroxypropyl methylcellulose and titanium dioxide. b Adjusted based on the potency of drug substance to ensure targeted strength.
- the Prevotella histicola strain referred to above has been deposited as Prevotella histicola Strain B (NRRL accession number B 50329).
- the capsule was banded with an HPMC-based banding solution.
- the banded capsule was enteric coated with a poly(methacrylic acid-co-ethyl acrylate) copolymer.
- Example 7 Capsule Comprising Prevotella histicola
- Prevotella histicola strain referred to above has been deposited as Prevotella histicola Strain B (NRRL accession number B 50329).
- the banded capsule was enteric coated with Eudragit L30-D55, a poly(methacrylic acid-co-ethyl acrylate) copolymer.
- Example 8 Tablet Comprising Prevotella histicola
- Table iii Prevotella histicola Tablet Composition
- the tablet is prepared as a 17.4mm x 7.1 mm tablet.
- the tablet is enteric coated.
- the tablet contains 3.2 x 10 11 TCC of Prevotella histicola Strain B (NRRL accession number B 50329).
- the Prevotella histicola strain referred to above has been deposited as Prevotella histicola Strain B (NRRL accession number B 50329).
- Example 9 Testing Prevotella histicola in a Delaved-Tvne Hypersensitivity
- a trial evaluating Prevotella histicola Strain B was conducted in a delayed-type hypersensitivity immunopharmacology model in human volunteers. This model is very similar in design to the standard preclinical model of T cell driven inflammation. This model was used to test two different formulations of Prevotella histicola Strain B.
- the participants were immunized with keyhole limpet hemocyanin (KLH) on day 2 of dosing and then an intradermal antigen challenge with KLH was performed on day 27.
- KLH keyhole limpet hemocyanin
- Prevotella histicola Strain B were both lyophilized powder in enteric-coated capsules. Participants in cohort 1 were dosed with 8 x 10 11 cells of Prevotella histicola Strain B manufactured using Process A’ and given in 10 capsules once a day. Participants in cohort 2 received 8 x 10 11 cells of Prevotella histicola Strain B manufactured using Process A2 in 5 capsules for the same daily dose as the A’ cohort. The concentration of Prevotella histicola Strain B in the capsules in cohort 2 was twice that of the capsules used in cohort 1. Information on the A’ and A2 formulations are provided in Example 6.
- Example 10 A Phase 2, Multicenter, Double-Blind, Placebo-Controlled, Multiple- Cohort Study Investigating the Effect of Prevotella histicola Strain B in Participants for the Treatment of Mild, Moderate and Severe Atopic Dermatitis
- the primary objective of the study is to show superiority of Prevotella histicola Strain B over placebo in the treatment of atopic dermatitis.
- the secondary objectives are to further evaluate the efficacy, safety, and tolerability of Prevotella histicola Strain B.
- Exploratory objectives aim to evaluate the best daily dose and frequency of dosing for Prevotella histicola Strain B in the treatment of atopic dermatitis, the time to onset of clinical response to Prevotella histicola Strain B and the effect of Prevotella histicola Strain B treatment on blood biomarkers.
- EASI Eczema Area and Severity Index
- the EASI Score will also be utilized to measure other aspects of clinical benefit of Prevotella histicola Strain Bin the treatment of atopic dermatitis.
- the Investigator s Global Assessment (IGA), the SCORing Atopic Dermatitis (SCORAD), the use of Rescue Medications, the Dermatology Life Quality Index (DLQI), the Peak Pruritus Numerical Rating Scale (PP-NRS), the Sleep Disturbance Numerical Rating Scale (SD-NRS), and the Patient Oriented Eczema Measure (POEM) will be measured throughout the study.
- IGA Global Assessment
- DLQI Dermatology Life Quality Index
- PP-NRS Peak Pruritus Numerical Rating Scale
- SD-NRS Sleep Disturbance Numerical Rating Scale
- POEM Patient Oriented Eczema Measure
- a number of exploratory endpoints will be evaluated to determine further aspects of treatment efficacy including time to achieve clinical response and patient reported health outcomes. Changes in eosinophils, immune protein markers, and immune cell RNA profile will be used to evaluate the effect of Prevotella histicola Strain B treatment on biomarkers in blood. A fecal sample will be used for microbiome profiling. Human Leukocyte Antigen (HLA) typing will be performed in those participants who consent to assess the correlation with clinical outcomes.
- HLA Human Leukocyte Antigen
- This study will evaluate Prevotella histicola Strain B in participants with mild, moderate, and severe atopic dermatitis to compare efficacy, safety, and tolerability to placebo.
- the Investigational Medicinal Product (IMP) is Prevotella histicola Strain B (drug product thereof) or matching placebo. The study will be blinded to the participants, Investigator, and Sponsor.
- Study Duration The maximum study duration is up to 20 weeks for all participants. Following informed consent, participants will have up to a 4-week screening period, followed by a 12-week treatment period and a post treatment follow-up visit 4 weeks later. Should a participant elect to participate in the OLE protocol, their study duration during this study would be a maximum of 16 weeks.
- Atopic dermatitis also known as (atopic) eczema
- AD is a chronic, highly symptomatic relapsing inflammatory skin disease, affecting up to 30% of children and 10% of adults (Bieber, Atopic Dermatitis, 2010). While AD often begins in infancy or childhood, it may become chronic and persist into adulthood (Katoh, 2019). Depending on factors such as severity of skin lesions or body surface area coverage, the disease can be classified clinically as mild, moderate, or severe.
- Patients with AD typically have highly symptomatic skin lesions that may present acutely with erythema, exudates, papulovesicles, scales and crusts, often symmetrically distributed on the body (Katoh, 2019).
- the disease typically follows a variable course with acute flares, often triggered by external factors, which cause a worsening of skin disease and symptoms.
- More chronic lesions are associated with thickened lichenified skin which may be accompanied by pigmentary changes and further excoriations (Bieber, Atopic Dermatitis, 2010).
- the primary symptom at both stages of disease is typically pruritus (itch).
- Such signs and symptoms are associated with a substantial patient burden that typically includes sleep disturbance, mood disturbance and mental health problems (Simpson, 2012), poor quality of life, and social functioning (Kiebert, 2002).
- AD like other atopic diseases, is characterized by a T helper type 2 (Th2) cell- mediated inflammation, with up-regulation of Th2 cytokines including IL-4, IL-5, and IL- 13 (Indra, 2013).
- Th2 cytokines including IL-4, IL-5, and IL- 13
- B-cells which can trigger release of cytokines and chemical mediators such as histamine from mast cells and Langerhans cells.
- thymic stromal lymphoprotein is thought to be a critical cytokine in the triggering and maintenance of AD (Indra, 2013) and is associated with migration of Th2 cells into the skin lesion (Katoh, 2019).
- systemic inflammation drives the disease pathology and patient symptoms, with the resultant scratching of pruritic lesions further worsening the skin lesions and the skin barrier function, further driving the disease process. Therefore, targeting systemic inflammation improves disease signs and symptoms - for example systemic corticosteroids typically lead to rapid clinical improvements, but generally are not acceptable as a long-term treatment due to associated side-effects (Lee, 2016).
- Emollients also known as moisturizers, are the first-line and baseline therapy for all severities of disease, and act by treating the defective skin barrier and providing cutaneous hydration (Lee, 2016).
- topical corticosteroids TCS
- topical calcineurin inhibitors TCI
- a 2016 patient survey (National Eczema Association, 2016) highlights and summarizes what it is like for patient living with atopic dermatitis:
- AD interferes with their job and house chores, 71% say it interferes with hobbies, and 65% don’t feel as healthy because of AD • Nearly half of people with moderate to severe AD report their disease “interferes with their social life, intimate relations, and relationships with their spouse and children”
- SINTAXTM small intestinal axis
- the inflammatory control mechanisms of SINTAX down-regulate multiple inflammatory pathways including those which have been validated with targeted antibody therapies, but without the side effects seen with antibody therapeutics or broadly acting oral kinase inhibitors. This occurs via specific interactions between the oral SINTAX therapy and small intestine enterocytes and immune cells. These interactions drive the development of an immune-regulatory subset of lymphocytes that travel from the gut to the systemic circulation, via the mesenteric lymph nodes. Here, these circulating cells mediate their effects on peripheral inflammation at the target sites (e.g., atopic dermatitis skin).
- target sites e.g., atopic dermatitis skin.
- Prevotella histicola Strain B is a pharmaceutical preparation of a single strain of Prevotella histicola, originally isolated from a duodenal biopsy.
- the drug substance is essentially non-viable and non-replicating, with a cell viability of ⁇ 0.02%. It has not been genetically modified. It does not colonize the gut nor alter the microbiome and has no detectable systemic exposure following oral dosing to date - i.e., it is gut-restricted.
- Prevotella as a genus are gram-negative, obligate anaerobic bacteria that are natural human commensals found in the oral cavity and gastrointestinal (GI) tract. Strains of Prevotella have been found in all human populations tested to date, at abundances ranging from ⁇ 1% to nearly 50% of total fecal microbial load (Vandeputte, Kathagen, & D'hoe, 2017).
- Prevotella histicola Strain B in human and mouse cellular assays and in vivo models support its use in the treatment of immunoinflammatory diseases, including atopic dermatitis.
- DTH delayed-type hypersensitivity
- FITC fluorescein isothiocyanate
- CIA collagen-induced arthritis
- EAE experimental acute encephalomyelitis
- Prevotella histicola Strain B was shown to down-regulate key Th2-related cytokines including IL-4 and IL-31. No potentially related adverse effects were seen in the animals used in these experiments with daily dosing for up to 3 weeks, or alternate day dosing for over 7 weeks.
- Ex vivo immunophenotyping in these models shows increased regulatory T cell numbers and regulatory dendritic cells (DCs) in spleen and mesenteric lymph nodes, as well as decreases in pro-inflammatory cytokines such as IL- 23p40, IL-17, and IL-13.
- DCs regulatory dendritic cells
- Prevotella histicola Strain B does not suppress the expression of Type 1 interferons in these ex vivo experiments, suggesting that the broad spectrum of anti-inflammatory effects is achieved without damaging mechanisms of immune surveillance critical for avoiding cancers and pathogens. Treatment also led to enhancement of gut intestinal barrier integrity, which is often disrupted in patients with inflammatory diseases. The effects on immune parameters have been observed both within and outside of the GI tract, which demonstrates that host-microbe interactions in the gut can affect the immune response in peripheral tissues.
- the primary comparison of interest is the mean difference between Prevotella histicola Strain B and placebo in the percentage change from baseline in EASI score at Week 12.
- the primary trial objective is to show superiority of Prevotella histicola Strain B over placebo.
- the primary efficacy endpoint of the study is the effect of Prevotella histicola Strain B on the percent change in the Eczema Area and Severity Index (EASI) score from baseline to Week 12.
- EASI Eczema Area and Severity Index
- This study will consist of 3 parallel run cohorts with a possible interim analysis after approximately 50% of participants have completed at least 8 weeks of treatment.
- Cohort 1 3.2x10 11 total cells of Prevotella histicola Strain B or matching placebo administered as 1 capsule once daily.
- Cohort 2 6.4x10 11 total cells of Prevotella histicola Strain B or matching placebo administered as 2 capsules once daily.
- Cohort 3 6.4x10 11 total cells of Prevotella histicola Strain B or matching placebo administered as 1 capsule of 3.2x10 11 cells twice daily.
- Total participant duration is up a maximum of 20 weeks from screening to safety follow-up, unless they elect to participate in the OLE protocol, and their maximum participation in this study would be 16 weeks.
- This study will be conducted as a multi-center study at approximately 55 centers globally. Approximately 264 total participants will be randomized and treated with Prevotella histicola Strain B or matching placebo.
- Informed consent (and re-consent, as applicable) must be obtained by the Principal Investigator or a licensed physician investigator (i.e., Sub-Investigator) per Good Clinical Practice (GCP) and local guidelines.
- GCP Good Clinical Practice
- Inclusion/exclusion criteria to be assessed before first dose of IMP. Screening laboratory results will be used to confirm eligibility at Day 1 Visit.
- Smoking status to include whether current- smoker, ex-smoker or never smoker, and to quantify current usage and total pack-year history.
- a physical examination will be conducted at every visit.
- Day 1 and Week 12 a full PE will be performed and the following body systems will be evaluated: general appearance, cardiovascular, lungs, abdomen, musculoskeletal, central nervous system, lymph nodes and skin.
- Weeks 2, 4, 8 and 16 a brief PE will be performed and the following body systems will be evaluated: general appearance, cardiovascular, lungs, abdomen and skin.
- BMI will be calculated from the height (collected at Screening) and weight.
- a single ECG tracing is to be obtained on the day of the visit approximately 5 minutes after the participant has rested. If, in the opinion of the Investigator, there appear to be clinically significant findings, repeat tracings should be obtained, as necessary. Blood pressure, heart rate, respiratory rate, and temperature will be measured after approximately 5 minutes after the participant has rested.
- the first IMP dose will be given at the Day 1 visit after all procedures are completed following randomization. Subsequent doses are taken daily in the morning at approximately the same time ⁇ 2 hours where possible. On study visit days, dosing may occur at home prior to the study visit, even if dosing falls outside the dosing window. Participants should refrain from consuming acidic drinks 1 hour either side of dosing and from eating 2 hours before dosing and 1 hour after dosing.
- AD Investigator rating scales Participants will be asked to withhold all emollients, sunscreens, or moisturizers on the day of these study visits until all study assessments are completed.
- the Pruritus-NRS (worst itch) will be asked daily from the Screening Visit to the Week 16 Visit via a participant diary.
- SD-NRS Sleep Disturbance-NRS
- AE Adverse Events
- SAE Serious Adverse Events
- Study staff will review the patient diary with participants at each visit. Diaries will be reviewed for completeness and accuracy, and participants will be coached as needed on compliance with the protocol.
- This study will utilize a matching placebo control in order to fulfill the double- blind design of the study, so that neither the investigator nor subject has knowledge of the treatment being administered.
- the purpose of this study design is to control for the placebo effect, control for variables caused by knowledge of treatment assignment, control for other factors that can influence study outcomes, and finally to allow for a more complete understanding of the risk-benefit profile of the active study drug.
- a position statement from the International Eczema Council (Leshem, et ah, 2019) has given clear guidance on the design of studies in atopic dermatitis, including supporting and giving a scientific rationale for the use of placebo-control in studies in this condition. Placebo- controlled studies are the recommended standard.
- we are minimizing the proportion of placebo subjects by using a 3: 1 randomization ratio between active and placebo, and then pooling the placebo subjects together for comparison.
- the study is designed to evaluate the efficacy of Prevotella histicola Strain B in the treatment of atopic dermatitis at two different doses across three regimens, namely 3.2x10 11 total cells daily (administered as one capsule once daily) and 6.4x10 11 total cells daily (administered as either two capsules once daily or one capsule twice daily).
- Prevotella histicola Strain B The pharmacological site of action of Prevotella histicola Strain B is within the epithelium of the small intestine where Prevotella histicola Strain B interacts with immune and epithelial cells. These interactions modify the systemic immune system and promote inflammation resolution throughout the body.
- the preclinical and clinical data generated to date suggest this is a broad effect working across Thl, Th2 and Thl7 pathologies. As the intent is to generate a maximal inflammation-resolving phenotype regardless of inflammation pathology, the dose response is expected to be common across indications, and therefore we aim to cross compare to previous studies to support this hypothesis.
- a Phase 2 dose ranging study in psoriasis is currently being conducted in approximately 225 participants for 16 weeks, at doses of 0.8x10 11 , 3.2x10 11 , and 8.0x10 11 cells.
- the doses selected for evaluation in this study represent commercially acceptable dosing regimens in terms of capsule load and frequency for patients.
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Abstract
L'invention concerne des procédés et des compositions associés à des bactéries Prevotella utiles en tant qu'agents thérapeutiques, par exemple, pour le traitement d'une maladie inflammatoire.
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