WO2022051494A1 - Compositions et méthodes de résolution d'inflammation - Google Patents

Compositions et méthodes de résolution d'inflammation Download PDF

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Publication number
WO2022051494A1
WO2022051494A1 PCT/US2021/048866 US2021048866W WO2022051494A1 WO 2022051494 A1 WO2022051494 A1 WO 2022051494A1 US 2021048866 W US2021048866 W US 2021048866W WO 2022051494 A1 WO2022051494 A1 WO 2022051494A1
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Prior art keywords
cells
strain
bacteria
administered
subject
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Mark BODMER
Anupriya Dutta
Andrea Itano
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Evelo Biosciences Inc
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Evelo Biosciences Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/135—Bacteria or derivatives thereof, e.g. probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0008—Antigens related to auto-immune diseases; Preparations to induce self-tolerance
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/02—Bacterial antigens
    • A61K39/0208—Specific bacteria not otherwise provided for
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/35—Allergens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • A61K9/2846—Poly(meth)acrylates
    • A—HUMAN NECESSITIES
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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
    • A61K9/4875—Compounds of unknown constitution, e.g. material from plants or animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4891—Coated capsules; Multilayered drug free capsule shells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/572—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 cytotoxic response
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/58—Medicinal preparations containing antigens or antibodies raising an immune response against a target which is not the antigen used for immunisation
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16111—Cytomegalovirus, e.g. human herpesvirus 5
    • C12N2710/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2710/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA dsDNA viruses
    • C12N2710/00011—Details
    • C12N2710/16011—Herpesviridae
    • C12N2710/16211—Lymphocryptovirus, e.g. human herpesvirus 4, Epstein-Barr Virus
    • C12N2710/16234—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • 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, or inflammatory responses that fail to resolve can result in serious adverse effects, including tissue damage and even death.
  • kits for the resolution of an inflammatory response for the resolution of an inflammatory response (e.g., resolution of an ongoing inflammatory response) in a subject.
  • the methods and compositions provided herein resolve an inflammatory response, e.g., as described herein.
  • Bacteria are anti-inflammatory, e.g., if the bacteria reduce (e.g., significantly reduce) the levels of a pro- inflammatory cytokine such as IL-8, IL-6, IL-ip, and/or TNFa, e.g., in an assay described herein.
  • An inflammatory response is resolved, e.g., if the levels of a pro-inflammatory cytokine such as IL-8, IL-6, IL-ip, and/or TNFa are reduced (e.g., significantly reduced), e.g., in an assay described herein.
  • the methods and compositions provided herein are for the reduction of inflammatory cytokine expression (e.g., IL-8, IL-6, IL-ip, and/or TNFa expression).
  • the methods and compositions provided herein are for the reduction of IL-8, IL-6, and/or TNFa expression.
  • the methods and compositions provided herein are for the reduction of IL-6, IL-8 and/or TNFa production from myeloid cells (e.g., in an assay described herein). In some embodiments, the methods and compositions provided herein are for the reduction of IL-6, IL-8 and/or TNFa production from myeloid cells but not from T-cells (e.g., in an assay described herein).
  • the methods and compositions provided herein do not reduce (e.g., do not significantly reduce or suppress) the Type I interferon response, e.g., do not reduce (e.g., do not significantly reduce or suppress) IFNa and/or IFNp levels, e.g., as determined in an assay described herein. In some embodiments, the methods and compositions provided herein do not reduce (e.g., do not significantly reduce or suppress) IFNa and/or IFNp levels, e.g., as determined in an assay described herein.
  • the methods and compositions provided herein resolve an inflammatory response (e.g., an ongoing inflammatory response) and do not reduce (e.g., do not significantly reduce or suppress) the Type I interferon response, e.g., do not reduce (e.g., do not significantly reduce or suppress) IFNa and/or IFNp levels.
  • the methods and compositions provided herein do not alter (e.g., do not significantly alter) the anti-viral TLR3-mediated Type 1 interferon (alpha and beta) response, e.g., as determined in an assay described herein.
  • the methods and compositions provided herein resolve an inflammatory response (e.g., an ongoing inflammatory response) and do not alter (e.g., do not significantly alter) the anti-viral TLR3 -mediated Type 1 interferon (alpha and beta) response.
  • the methods and compositions provided herein do not alter (e.g., do not significantly alter) interferon-gamma (IFNy) production by immune cells, e.g., as determined in an assay described herein.
  • IFNy interferon-gamma
  • the methods and compositions provided herein resolve an inflammatory response (e.g., an ongoing inflammatory response) and do not alter (e.g., do not significantly alter) interferon-gamma (IFNy) production by immune cells.
  • an inflammatory response e.g., an ongoing inflammatory response
  • do not alter e.g., do not significantly alter
  • IFNy interferon-gamma
  • the methods and compositions provided herein do not alter (e.g., do not significantly alter) an immune cell subset (e.g., as determined by absolute number and/or percentage), wherein the immune cell subset is CD8 T lymphocytes, B lymphocytes, and/or myeloid lineage cells, e.g., as determined in an assay described herein.
  • an immune cell subset e.g., as determined by absolute number and/or percentage
  • the immune cell subset is CD8 T lymphocytes, B lymphocytes, and/or myeloid lineage cells, e.g., as determined in an assay described herein.
  • the methods and compositions provided herein resolve an inflammatory response (e.g., an ongoing inflammatory response) and do not alter (e.g., do not significantly alter) an immune cell subset (e.g., as determined by absolute number and/or percentage), wherein the immune cell subset is CD8 T lymphocytes, B lymphocytes, and/or myeloid lineage cells.
  • the methods and compositions provided herein do not reduce (e.g., do not significantly reduce) an antigen-specific antibody response, e.g., as determined in an assay described herein.
  • the methods and compositions provided herein resolve an inflammatory response (e.g., an ongoing inflammatory response) and do not reduce (e.g., do not significantly reduce) an antigen-specific antibody response.
  • the anti-inflammatory bacteria are a Prevotella histicola strain.
  • the anti-inflammatory bacteria are a.
  • Prevotella histicola strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Prevotella histicola Strain B (NRRL accession number B 50329).
  • the Prevotella histicola strain is Prevotella histicola Strain B (NRRL accession number B 50329).
  • the anti-inflammatory bacteria such as the Prevotella histicola strain are administered in a pharmaceutical composition and/or a solid dosage form (e.g., tablet or capsule).
  • a pharmaceutical composition and/or a solid dosage form e.g., tablet or capsule.
  • the pharmaceutical compositions comprising antiinflammatory bacteria are prepared as solid dosage forms (e.g., such as tablets or capsules).
  • the pharmaceutical compositions comprise about 3 x 10 10 to about 1.5 x 10 12 total cells of the anti-inflammatory bacteria.
  • the pharmaceutical compositions comprise about 8 x 10 10 to about 1.3 x 10 12 total cells of the anti-inflammatory bacteria.
  • the pharmaceutical compositions comprise about 4.5 x 10 10 to about 1.5 x 10 12 total cells of the anti-inflammatory 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 capsule e.g., an enteric coated capsule.
  • the anti-inflammatory bacteria are a. Prevotella histicola strain.
  • the Prevotella histicola strain is Prevotella histicola Strain B (NRRL accession number B 50329).
  • at least 4 x 10 10 cells of the Prevotella histicola strain are administered to the subject daily.
  • from 4 x IO 10 cells to 1.6 x 10 12 cells of the Prevotella histicola strain are administered to the subject daily.
  • from 4 x IO 10 cells to 8 x IO 11 cells of the Prevotella histicola strain are administered to the subject daily.
  • from 8 x IO 10 cells to 8 x IO 11 cells of the Prevotella histicola strain are administered to the subject daily.
  • from 1.6 x IO 11 cells to 8 x IO 11 cells of the Prevotella histicola strain are administered to the subject daily.
  • about 8 x IO 10 cells of the Prevotella histicola strain are administered to the subject daily.
  • about 8 x IO 10 cells of the Prevotella histicola strain are administered to the subject daily.
  • about 8 x IO 10 cells of the Prevotella histicola strain are administered to the subject daily.
  • about 8 x IO 10 cells of the Prevotella histicola strain are administered to the subject daily
  • 1.6 x IO 11 cells of the Prevotella histicola strain are administered to the subject daily.
  • about 3.2 x 10 11 cells of the Prevotella histicola strain are administered to the subject daily.
  • about 8 x 10 11 cells of the Prevotella histicola strain are administered to the subject daily.
  • about 1.6 x 10 11 cells of Prevotella histicola strain are administered to the subject once daily.
  • about 1.6 x 10 11 cells of the Prevotella histicola strain are administered to the subject twice daily.
  • 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).
  • 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 IO 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 (e.g., 3.35 x 10 11 total cells) of the Prevotella histicola bacteria.
  • from 1.6 x IO 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 IO 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 IO 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. In some embodiments, about 8 x 10 11 cells of the Prevotella histicola strain are administered to the subject 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 once 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., 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., 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.
  • 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 pharmaceutical 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).
  • the pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 anti-inflammatory bacteria such as the Prevotella histicola strain are 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 the anti-inflammatory bacteria such as the Prevotella histicola and excipients (e.g., an encapsulated freeze-dried powder of the antiinflammatory bacteria such as a. Prevotella histicola strain provided herein and excipients).
  • the pharmaceutical composition comprises freeze-dried (e.g., lyophilized) powder of anti-inflammatory bacteria in a capsule.
  • the capsule comprises gelatin or HPMC. In some embodiments, the capsule is enteric coated. In some embodiments, the pharmaceutical composition comprises a formulation of Prevotella histicola Strain B comprising freeze-dried powder of Prevotella histicola and excipients. In some embodiments, the excipients include mannitol, magnesium stearate and colloidal silicon dioxide. In some embodiments, each capsule contains about 8.0 x IO 10 cells of a Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B). In some embodiments, 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 ⁇ .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 e.g., each containing about 8.0 x 10 10 cells of ⁇ .Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B) are administered to the subject twice daily.
  • 2 powdercontaining 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).
  • a Prevotella histicola strain provided herein e.g., Prevotella histicola Strain B
  • 1 powder-containing enteric coated capsule e.g., containing about 8.0 x IO 10 cells of a. Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B) is administered to the subject daily.
  • the pharmaceutical composition is formulated as multiple enteric-coated mini-tablets of the anti-inflammatory bacteria such as Prevotella histicola drug product fdled into capsules.
  • the pharmaceutical composition is formulated as multiple enteric-coated mini-tablets of the anti-inflammatory bacteria such as Prevotella histicola drug product fdled into capsules (mini-tablets in capsules (MICs)).
  • the capsule comprises gelatin or HPMC.
  • the pharmaceutical composition comprises excipients (e.g., pharmaceutically acceptable excipients).
  • the pharmaceutical composition comprises mannitol, colloidal silicon dioxide, hydroxypropyl cellulose, crospovidone, and magnesium stearate.
  • each capsule contains about 8.0 x IO 10 cells of ⁇ .Prevotella histicola strain provided herein (e.g., Prevotella histicola Strain B).
  • 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 capsules are administered to a subject daily.
  • 2 capsules are administered to the subject daily.
  • 1 capsule is administered to the subject daily.
  • each MIC 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 MICs are administered to a subject daily.
  • 2 MICs are administered to the subject daily.
  • 1 MIC is administered to the subject daily.
  • the Prevotella histicola strain is a strain comprising 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 histicola Strain B (NRRL accession number B 50329).
  • the Prevotella histicola strain is the Prevotella histicola Strain B (NRRL accession number B 50329).
  • the disclosure provides use of the anti-inflammatory bacteria such as a Prevotella histicola strain provided herein and/or a pharmaceutical composition (e.g., a pharmaceutical 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 the antiinflammatory bacteria such as a Prevotella histicola strain provided herein and/or a pharmaceutical composition (e.g, a pharmaceutical 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.
  • the anti-inflammatory bacteria are a Veillonella parvulci strain.
  • the anti-inflammatory bacteria are a Veillonella parvula strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of the Veillonella parvula strain A (ATCC Deposit Number PTA- 125691).
  • the Veillonella parvula strain is Veillonella parvula strain A (ATCC Deposit Number PTA- 125691).
  • the anti-inflammatory bacteria such as the Veillonella parvula strain are administered in a pharmaceutical composition and/or a solid dosage form.
  • the anti-inflammatory bacteria are a Veillonella parvula strain.
  • the Veillonella parvula strain is Veillonella parvula strain A (ATCC Deposit Number PTA- 125691).
  • the bacterial composition comprises at least about 3 x 10 10 total cells of Veillonella parvula, e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA- 125691).
  • the bacterial composition comprises about 3 x 10 10 total cells of Veillonella parvula, e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA- 125691).
  • the bacterial composition comprises about 4.5 x 10 10 total cells of Veillonella parvula, e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA- 125691).
  • the bacterial composition comprises about 1.5 x 10 n total cells of Veillonella parvula, e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA- 125691).
  • the bacterial composition comprises about 7.5 x 10 11 total cells of Veillonella parvula, e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA- 125691).
  • the bacterial composition comprises about 1.5 x 10 12 total cells of Veillonella parvula, e.g. , of Veillonella parvula strain A (ATCC Deposit Number PTA- 125691). [44] In some embodiments, the bacterial composition comprises about 3 x 10 10 to about 1.5 x 10 12 total cells of Veillonella parvula, e.g., of Veillonella parvulci strain A (ATCC Deposit Number PTA-125691).
  • the bacterial composition comprises about 4.5 x 10 10 to about
  • Veillonella parvula 1.5 x 10 12 total cells of Veillonella parvula, e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).
  • the bacterial composition comprises about 3 x 10 10 to about 1.5 x 10 11 total cells of Veillonella parvula, e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).
  • the bacterial composition comprises about 4.5 x 10 10 to about
  • Veillonella parvula 1.5 x 10 11 total cells of Veillonella parvula, e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).
  • the bacterial composition comprises about 1.5 x 10 n to about
  • Veillonella parvula 1.5 x 10 12 total cells of Veillonella parvula, e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).
  • the bacterial composition comprises about 1.5 x 10 n to about
  • the bacterial composition comprises about 7.5 x 10 n to about
  • Veillonella parvula 1.5 x 10 12 total cells of Veillonella parvula, e.g., of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).
  • the pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x 10 10 total cells, about 2 x 10 10 total cells, about 3 x 10 10 total cells, about 4 x 10 10 total cells, about 4.5 x 10 10 total cells, about 5 x 10 10 total cells, about 6 x 10 10 total cells, about 7 x 10 10 total cells, about 8 x 10 10 total cells, about 9 x 10 10 total cells, about 1 x 10 11 total cells, about 1.5 x 10 11 total cells, about 2 x 10 11 total cells, about 3 x 10 11 total cells, about 4 x 10 11 total cells, about 5 x 10 11 total cells, about 6 x 10 11 total cells, about 7 x 10 11 total cells, about 7.5 x 10 11 total cells, about 8 x 10 11 total cells, about 9 x 10 11 total cells, about 1 x 10 12 total cells, about 1.5 x 10 12 total cells, about 2 x 10 12 total cells of the
  • the pharmaceutical 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 4.5 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 IO 10 total cells, at least 8 x IO 10 total cells, at least 9 x IO 10 total cells, at least 1 x 10 11 total cells, at least 1.5 x 10 11 total cells, at least 2 x 10 11 total cells, at least 3 x
  • 10 11 total cells at least 4 x 10 11 total cells, at least 5 x 10 11 total cells, at least 6 x 10 11 total cells, at least 7 x 10 11 total cells, at least 7.5 x 10 11 total cells, at least 8 x 10 11 total cells, at least 9 x 10 11 total cells, at least 1 x 10 12 total cells, at least 1.5 x 10 12 total cells, at least 2 x
  • the pharmaceutical composition comprises about 3 x 10 10 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 4.5 x 10 10 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 1.5 x 10 11 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 7.5 x 10 11 total cells the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 1.5 x 10 12 total cells the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 3 x 10 10 to about 1.5 x 10 12 total cells of the Veillonella parvula bacteria.
  • the pharmaceutical composition comprises about 4.5 x 10 10 to about 1.5 x 10 12 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 3 x 10 10 to about 1.5 x 10 11 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 4.5 x 10 10 to about 1.5 x 10 11 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 1.5 x 10 n to about 1.5 x 10 12 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 1.5 x 10 n to about 7.5 x 10 11 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 7.5 x 10 11 to about 1.5 x 10 12 total cells of the Veillonella parvula bacteria.
  • solid dosage forms comprising the Veillonella parvula bacteria.
  • the solid dosage form comprises an enteric coating.
  • the solid dosage form is a capsule, e.g., an enteric coated capsule.
  • each capsule comprises about 3 x IO 10 total cells of the Veillonella parvula 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 x IO 10 total cells
  • each capsule comprises about 3 x 10 total cells of the Veillonella parvulci 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 4.5 x IO 10 total cells
  • 2 capsules e.g., each comprising about 4.5 x 10 10 total cells
  • 4 capsules e.g., each comprising about 4.5 x 10 10 total cells
  • 10 capsules are administered, e.g., once or twice daily to a subject.
  • 1 capsule e.g., comprising about 1.5 x 10 11 total cells
  • 2 capsules e.g., each comprising about 1.5 x 10 11 total cells
  • 5 capsules are administered, e.g., once or twice daily to a subject.
  • 10 capsules are administered, e.g., once or twice daily to a subject.
  • the Veillonella parvula bacteria in the capsule are lyophilized (e.g., in a powder).
  • the Veillonella parvula bacteria in the capsule are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.
  • the Veillonella parvula bacteria are gamma irradiated.
  • the solid dosage form comprises a capsule.
  • the capsule is an enteric coated capsule.
  • the capsule comprises about 3 x 10 10 total cells of the Veillonella parvula bacteria (e.g., total dose of a capsule or plurality of capsules).
  • the capsule comprises about 4.5 x 10 10 total cells of the Veillonella parvula bacteria (e.g., total dose of a capsule or plurality of capsules).
  • the capsule comprises about 1.5 x 10 11 total cells of the Veillonella parvula bacteria (e.g., total dose of a capsule or plurality of capsules).
  • the Veillonella parvula bacteria in the capsule are lyophilized (e.g., in a powder). In some embodiments, the Veillonella parvula bacteria in the capsule are lyophilized in a powder, and the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide. In some embodiments, the Veillonella parvula bacteria are gamma irradiated.
  • the solid dosage form comprises a tablet. In some embodiments, the tablet is an enteric coated tablet. In some embodiments, the enteric coated tablet is from 5mm to 18mm in diameter.
  • the tablet comprises about 3 x 10 10 total cells of the Veillonella parvula bacteria (e.g., total dose of a tablet or plurality of tablets). In some embodiments, the tablet comprises about 4.5 x IO 10 total cells of the Veillonella parvula bacteria (e.g., total dose of a tablet or plurality of tablets). In some embodiments, the tablet comprises about 1.5 x 10 11 total cells of the Veillonella parvula bacteria (e.g., total dose of a tablet or plurality of tablets). In some embodiments, the Veillonella parvula bacteria in the tablet are lyophilized. In some embodiments, the Veillonella parvula bacteria of the tablet are gamma irradiated.
  • the solid dosage form comprises a mini-tablet.
  • the mini-tablet is enteric coated.
  • the mini-tablet is from 1mm to 4mm in diameter.
  • the mini-tablet e.g., enteric coated minitablet
  • the solid dosage form comprises mini-tablets that comprise about 3 x IO 10 total cells of the Veillonella parvula bacteria (e.g., total dose of a plurality of mini -tablets).
  • the solid dosage form comprises minitablets that comprise about 1.5 x 10 11 total cells of the Veillonella parvula bacteria (e.g., total dose of a plurality of mini -tablets).
  • the Veillonella parvula bacteria in the mini-tablets are lyophilized.
  • the Veillonella parvula bacteria in the mini-tablet are gamma irradiated.
  • the mini -tablets are contained in a capsule.
  • the capsule is a size 00, size 0, size 1, size 2, size 3, size 4, or size 5 capsule.
  • the capsule comprises a non-enteric coating (e.g., gelatin) (e.g., is coated with a non-enteric coating).
  • the capsule comprises a non-enteric coating.
  • the capsule comprises gelatin or HPMC. In some embodiments, the capsule comprises gelatin or HPMC.
  • the mini-tablets e.g., enteric coated mini -tablets
  • the mini-tablets that comprise about 3 x 10 10 total cells of the Veillonella parvula bacteria are contained in a capsule(s), wherein optionally the capsule comprises gelatin or HPMC.
  • the mini-tablets e.g., enteric coated mini-tablets
  • the mini-tablets that comprise about 4.5 x 10 10 total cells of the Veillonella parvula bacteria are contained in a capsule(s), wherein optionally the capsule comprises gelatin or HPMC.
  • the mini-tablets e.g., enteric coated mini-tablets
  • the mini-tablets that comprise about 1.5 x 10 11 total cells of the Veillonella parvula bacteria are contained in a capsule(s), wherein optionally the capsule comprises gelatin or HPMC.
  • the Veillonella parvulci bacteria of the mini-tablet are gamma irradiated.
  • the pharmaceutical composition comprising Veillonella parvula bacteria is prepared as a powder (e.g. , for resuspension or for use in a solid dose form (such as a capsule)) or as a solid dose form, such as a tablet, a mini-tablet, a capsule, a pill, or a powder; or a combination of these forms (e.g., mini-tablets comprised in a capsule).
  • the powder can comprise lyophilized bacteria.
  • the powder further comprises mannitol, magnesium stearate, and/or colloidal silicon dioxide.
  • the Veillonella parvula bacteria are gamma irradiated.
  • the Veillonella parvula strain is a strain comprising at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Veillonella parvula strain A (ATCC Deposit Number PTA- 125691).
  • the Veillonella parvula strain is the Veillonella parvula strain A (ATCC Deposit Number PTA- 125691).
  • the disclosure provides use of the anti-inflammatory bacteria such as a Veillonella parvula strain provided herein and/or a pharmaceutical composition (e.g., a pharmaceutical 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 the antiinflammatory bacteria such as a Veillonella parvula strain provided herein and/or a pharmaceutical composition (e.g., a pharmaceutical 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.
  • the methods provided herein further comprise administering to the subject an additional therapy.
  • the additional therapy comprises the standard of care for the disease being treated (e.g., an inflammatory condition).
  • the additional therapy is administered at a lower dose than the dose at which it is administered as a monotherapy.
  • the methods provided herein further comprise administering to the subject an anti-inflammatory medication.
  • the method further comprises orally administering an anti-inflammatory agent such as NSAIDs or anti-inflammatory steroids.
  • the method further comprises administering (e.g., orally or intravenously administering) dexamethasone.
  • the method further comprises administering a BTK inhibitor such as ibrutinib. In some embodiments, the method further comprises administering a JAK inhibitor such as baricitinib, ruxolitinib, tofacitinib, and/or pacritinib.
  • a BTK inhibitor such as ibrutinib.
  • a JAK inhibitor such as baricitinib, ruxolitinib, tofacitinib, and/or pacritinib.
  • the method further comprises administering to the subject an antibody specific for IL-6 and/or the IL-6 receptor.
  • the method comprises administering to the subject tocilizumab (Actemra®).
  • the method comprises administering to the subject sarilumab (Kevzara®).
  • FIG. 1 shows a waterfall plot illustrating the percent change in IL-8 expression by subjects after 28 days of treatment with Prevotella histicola Strain B (right) or placebo (left).
  • FIG. 2 shows a waterfall plot illustrating the percent change in IL-6 expression by subjects after 28 days of treatment with Prevotella histicola Strain B (right) or placebo (left).
  • FIG. 3 shows a waterfall plot illustrating the percent change in TNFa expression by subjects after 28 days of treatment with Prevotella histicola Strain B (right) or placebo (left).
  • FIG. 4 shows a waterfall plot illustrating the percent change in IL- 1 [3 expression by subjects after 28 days of treatment with Prevotella histicola Strain B (right) or placebo (left).
  • FIG. 5 is two panels showing IFNa (left panel) and IFNp (right panel) levels in spleen cells removed from animals treated with Prevotella histicola Strain B (“Strain B”) or dexamethasone or a combination thereof.
  • strain B Prevotella histicola Strain B
  • dexamethasone dexamethasone
  • FIG. 6 is two panels showing IL6 (left panel) and TNFa (right panel) levels in spleen cells removed from animals treated with Prevotella histicola Strain B (“Strain B”) or dexamethasone or a combination thereof.
  • Strain B Prevotella histicola Strain B
  • dexamethasone or a combination thereof.
  • FIG. 7 is a graph showing the effects of Prevotella histicola Strain B (“Strain B”) or dexamethasone or a combination thereof on ear inflammation in a KLH DTH model.
  • FIG. 8 is a graph showing inflammation 24 hours after intradermal KLH challenge as determined by measuring basal flow using laser speckle contrast imaging (LCSI) in subjects treated with Prevotella histicola Strain B compared to a pooled placebo group.
  • LCSI laser speckle contrast imaging
  • FIG. 9 shows a waterfall plot illustrating the percent change in IL-8 expression by subjects after 28 days of treatment with low (IX) dose of Prevotella histicola Strain B (“Strain B”) (middle); high (5X) dose of Prevotella histicola Strain B (right); or placebo (left).
  • strain B Prevotella histicola Strain B
  • 5X dose of Prevotella histicola Strain B
  • placebo placebo
  • FIG. 10 shows a waterfall plot illustrating the percent change in IL-6 expression by subjects after 28 days of treatment with low (IX) dose of Prevotella histicola Strain B (“Strain B”) (middle); high (5X) dose of Prevotella histicola Strain B (right); or placebo (left).
  • strain B Prevotella histicola Strain B
  • 5X dose of Prevotella histicola Strain B
  • placebo placebo
  • FIG. 11 shows a waterfall plot illustrating the percent change in TNF-a (TNF- a) expression by subjects after 28 days of treatment with low (IX) dose of Prevotella histicola Strain B (“Strain B”) (middle); high (5X) dose of Prevotella histicola Strain B (right); or placebo (left).
  • FIG. 12 shows a waterfall plot illustrating the percent change in IFN-g (IFN-y) expression by subjects after 28 days of treatment with low (IX) dose of Prevotella histicola Strain B (“Strain B”) (middle); high (5X) dose of Prevotella histicola Strain B (right); or placebo (left).
  • FIG. 13 shows a waterfall plot illustrating the percent change in IL-17A expression by subjects after 28 days of treatment with low (IX) dose of Prevotella histicola Strain B (“Strain B”) (middle); high (5X) dose of Prevotella histicola Strain B (right); or placebo (left).
  • strain B Prevotella histicola Strain B
  • 5X dose of Prevotella histicola Strain B
  • placebo placebo
  • FIG. 14 is a graph showing the effects of Prevotella histicola Strain B or dexamethasone on ear inflammation.
  • FIGS. 15A and 15B are graphs showing the effects of Prevotella histicola Strain B or dexamethasone on the production of IFNa (FIG. 15 A) and IFNp (FIG. 15B) in a spleen cell stimulation assay.
  • FIG. 16 is a graph showing the effects of Prevotella histicola Strain B or dexamethasone on the systemic production of interferon-gamma.
  • FIGS. 17A and 17B are a series of graphs showing the effects of Prevotella histicola Strain B on immune cell subsets.
  • FIG. 18 is a series of graphs showing the effects of Prevotella histicola Strain B on KLH-specific IgG and on peanut-specific IgGl or total IgGl in the peanut allergy model.
  • FIG. 19 is a series of graphs showing the effects of Prevotella histicola Strain B or a strain of Prevotella melaninogenica (“genus Ctrl”) on IFNy response from CD8 T cells to CEF viral peptides as compared to the DC-CD8 T cell co-culture control.
  • FIGS. 20A- 20C are a series of graphs showing the effects of Veillonella parvula strain A- G.I. on ear inflammation (FIG. 20A) and the effects of Veillonella parvula strain A- G.I. on the production of IFNa (FIG. 20B) and IFNp (FIG. 20C) in a spleen cell stimulation assay.
  • FIG. 21 is a graph showing the effects of Veillonella parvula strain A- G.I. on the systemic production of interferon-gamma (IFNy).
  • FIGS. 22A and 22B are a series of graphs showing the effects of Veillonella parvula strain A- G.I. on immune cell subsets.
  • FIG. 23 is a graph showing the effects of Veillonella parvula strain A- G.I. on KLH-specific IgG in a KLH delayed-type hypersensitivity model.
  • FIG. 24 is a graph showing the effects of Veillonella parvula strain A- G.I. on IFNy response from CD8 T cells to CEF viral peptides as compared to the DC-CD8 T cell coculture control.
  • FIG. 25 is a graph showing the ability of Prevotella histicola Strain B to resolve ongoing inflammation rather than suppress the ability of the immune system to respond to later induction of inflammation.
  • FIGS. 26A and 26B are graphs showing the duration of the effect of Prevotella histicola Strain B on inhibition of inflammation.
  • FIG. 26A shows the effects of Prevotella histicola Strain B on ear inflammation after challenge on Day 8.
  • FIG. 26B shows the effects of Prevotella histicola Strain B on ear inflammation after challenge on Day 23.
  • Type I IFN have important anti-inflammatory functions in promoting immune homeostasis. See, e.g.: Perry, et al., Cell Research 15:407-422 (2005); Teijaro, Current Opinion Virology 16:31-40 (2016); Oh et al, Cancer Immunology Res. 7:584-599 (2019).
  • bacteria e.g, anti-inflammatory bacteria
  • This new class of anti-inflammatory agent can produce functional resolution (partial or complete) of inflammation without the adverse side effects (such as suppression of Type I IFN response) associated with current anti-inflammatories.
  • This new class of antiinflammatory agent can induce physiological processes of inflammation resolution rather than suppressing mediators of inflammation.
  • This class of agent can be used alone or in combination with other anti-inflammatory agents (e.g., which can be administered in lower doses than when used alone) to attain beneficial effects with reduced adverse side effects.
  • Treatment with anti-inflammatory bacteria can lead to a prolonged pharmacodynamic effect, which is maintained in the absence of continuous dosing, as compared to a systemic immuno-suppressive drug such as dexamethasone, which requires continuous dosing to maintain its anti-inflammatory effect.
  • an anti-inflammatory bacteria e.g., a composition, e.g., a pharmaceutical composition containing the anti-inflammatory bacteria.
  • Anti-inflammatory bacteria can be identified using methods disclosed herein (e.g., by determining whether they reduce (e.g., significantly reduce) the levels of a pro-inflammatory cytokine such as IL-8, IL-6, IL-1J3, and/or TNFa in an assay described herein).
  • the anti-inflammatory bacteria are a. Prevotella histicola strain.
  • the anti-inflammatory bacteria are a Prevotella histicola strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of Prevotella histicola Strain B (NRRL accession number B 50329).
  • the Prevotella histicola strain is administered in a pharmaceutical composition (e.g., pharmaceutical composition and/or a solid dosage form).
  • the Prevotella histicola strain is Prevotella histicola Strain B (NRRL accession number B 50329).
  • the anti-inflammatory bacteria are a Veillonella parvula strain.
  • the anti-inflammatory bacteria are a Veillonella parvula strain comprising at least 99% genomic, 16S and/or CRISPR sequence identity to the nucleotide sequence of Veillonella parvula strain A (ATCC Deposit Number PTA-125691).
  • the Veillonella parvula strain is administered in a pharmaceutical composition (e.g., pharmaceutical composition and/or a solid dosage form).
  • the Veillonella parvula strain is Veillonella parvula strain A (ATCC Deposit Number PTA- 125691).
  • the Veillonella parvula strain is gamma irradiated.
  • the pharmaceutical composition comprises one anti-inflammatory strain.
  • the pharmaceutical composition comprises one strain of bacteria, wherein the strain is an anti-inflammatory strain.
  • the non-live Prevotella histicola Strain B pharmaceutical composition has demonstrated anti-inflammatory activity with excellent safety and tolerability in three clinical cohorts.
  • Prevotella histicola Strain B dampens multiple pathways of inflammation with a placebo-like safety profile. In preclinical studies, it has antiinflammatory efficacy similar to dexamethasone but with the additional benefit of having no negative impact on Type 1 Interferons required for host anti-viral response.
  • Prevotella histicola Strain B increases secretion of anti-inflammatory cytokines from human immune cells, such as interleukin (IL)- 10 and IL-27, while inducing minimal production of pro-inflammatory cytokines such as IL-6, tumor necrosis factor (TNF) and interferon gamma (IFNy).
  • IL interleukin
  • TNF tumor necrosis factor
  • IFNy interferon gamma
  • anti-inflammatory bacteria such as the Prevotella histicola Strain B are at least as effective as antibodies and oral drugs. Functional inflammatory resolution without complete suppression in both mice and humans is seen.
  • Prevotella histicola Strain B is coordinately resolving systemic inflammation across TH1, TH2 and TH 17 pathways. This suggests the potential for clinical benefit across multiple conditions and populations. 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.
  • DTH delayed-type hypersensitivity
  • FITC fluorescein isothiocyanate
  • CIA collagen- induced arthritis
  • EAE experimental acute encephalomyelitis
  • 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), intratumoral (IT) and subcutaneous (SC) administration.
  • compositions described herein can be administered in any form by any effective route, including but not limited to intratumoral, oral, parenteral, enteral, intravenous, intraperitoneal, topical, transdermal (e.g., using any standard patch), intradermal, ophthalmic, (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), intravesical, intrapulmonary, intraduodenal, intragastrical, and intrabronchial.
  • transdermal e.g., using any standard patch
  • intradermal e.g., using any standard patch
  • intradermal e.g., using any standard patch
  • intradermal e.g.
  • the pharmaceutical compositions described herein are administered orally, rectally, intratumorally, topically, intravesically, by injection into or adjacent to a draining lymph node, intravenously, by inhalation or aerosol, or subcutaneously.
  • the pharmaceutical composition or solid dosage form described herein is administered orally.
  • the term “decrease” or “deplete” or “reduce” 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 number of immune cells (e.g., of a particular immune cell type), bacterial cells, stromal cells, myeloid derived suppressor cells, fibroblasts, metabolites, and level of cytokines (e.g., a pro- inflammatory cytokine).
  • 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 A 3 fold, 10 A 4 fold, 10 A 5 fold, 10 A 6 fold, and/or 10 A 7 fold greater after treatment when compared to a pre-treatment state.
  • Properties that may be increased include number of immune cells (e.g., of a particular immune cell type), bacterial cells, stromal cells, myeloid derived suppressor cells, fibroblasts, metabolites, and level of cytokines (e.g., a pro- inflammatory cytokine).
  • 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.
  • the subject or patient may be healthy, or may be suffering from (or at increased risk of developing) an immune disorder at any developmental stage or from (or at an increased risk of developing) an infection.
  • 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 a disease in a subject or “treating” a subject having or suspected of having a disease refers to subjecting the subject to a pharmaceutical treatment, e.g., the administration of one or more agents, such that at least one symptom of the disease is decreased or prevented from worsening.
  • “treating” may decrease the level of IL-8, IL-6, IL- 1(3, and/or TNFa in a subject, e.g., as compared to the level prior to treatment; “treating” may prevent an increase (or cause a decrease) in the level of IL-8, IL-6, IL- 1(3, and/or TNFa in a subject as compared to a standard, e.g., as compared to the level prior to treatment; “treating” may decrease a clinical factor, such as a clinical score for a particular disease as compared to a standard, e.g., as compared to the time or duration in a cohort of subjects who did not receive the treatment.
  • a clinical factor such as a clinical score for a particular disease as compared to a standard, e.g., as compared to the time or duration in a cohort of subjects who did not receive the treatment.
  • Bacteria are anti-inflammatory, e.g., if the bacteria reduce (e.g., significantly reduce) the levels of a pro-inflammatory cytokine such as IL-8, IL-6, IL- 1 (3, and/or TNFa, e.g., in an assay described herein.
  • the anti-inflammatory bacteria e.g., when orally administered
  • can reduce inflammatory cytokine expression e.g., IL-8, IL-6, IL-ip, and/or TNFa expression
  • a subject e.g., in myeloid cells of the subject.
  • the anti-inflammatory bacteria can reduce inflammatory cytokine expression (e.g., IL-8, IL-6, IL- ip, and/or TNFa expression) in an assay described herein.
  • the antiinflammatory bacteria e.g., when orally administered
  • the anti-inflammatory bacteria can reduce inflammatory cytokine expression (e.g., IL-8, IL-6, and/or TNFa expression) in an assay described herein.
  • the anti-inflammatory bacteria can reduce inflammatory cytokine expression (e.g., IL-8, IL-6, and/or TNFa expression) in a subject, e.g., in myeloid cells of the subject, but not in T cells of the subject.
  • the anti-inflammatory bacteria can reduce inflammatory cytokine expression (e.g., IL-8, IL-6, and/or TNFa expression) in an assay described herein, e.g., in ex vivo stimulated myeloid cells but not in ex vivo stimulated T cells.
  • the antiinflammatory bacteria do not reduce (e.g., do not significantly reduce) the Type I interferon response, e.g., does not reduce (e.g., do not significantly reduce) IFNa and/or IFNp levels in a subject.
  • the antiinflammatory bacteria do not reduce (e.g., do not significantly reduce) the Type I interferon response, e.g., do not reduce (e.g., do not significantly reduce) IFNa and/or IFNp levels in an assay described herein.
  • the anti-inflammatory bacteria do not reduce (e.g., do not significantly reduce) IFNa and/or IFNp levels in a subject. In some embodiments, the anti-inflammatory bacteria do not reduce (e.g., do not significantly reduce) IFNa and/or IFNp levels in an assay described herein.
  • the anti-inflammatory bacteria can be a strain of Prevotella.
  • Anti-inflammatory strains of Prevotella can be identified using methods disclosed herein (e.g., by determining whether they reduce (e.g., significantly reduce) the levels of a pro-inflammatory cytokine such as IL-8, IL-6, IL-ip, and/or TNFa in an assay described herein).
  • the Prevotella strain is a strain of Prevotella histicola.
  • the Prevotella strain is Prevotella histicola Strain B (NRRL accession number B 50329).
  • the Prevotella strain is a strain comprising at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic, 16S or CRISPR nucleotide sequence) of Prevotella histicola Strain B (NRRL accession number B 50329).
  • the Prevotella strain is Prevotella histicola Strain B (NRRL accession number B 50329).
  • Applicant represents that the ATCC is a depository affording permanence of the deposit and ready accessibility thereto by the public if a patent is granted. All restrictions on the availability to the public of the material so deposited will be irrevocably removed upon the granting of a patent. The material will be available during the pendency of the patent application to one determined by the Commissioner to be entitled thereto under 37 CFR 1.14 and 35 U.S.C. 122.
  • the deposited material will be maintained with all the care necessary to keep it viable and uncontaminated for a period of at least five years after the most recent request for the furnishing of a sample of the deposited plasmid, and in any case, for a period of at least thirty (30) years after the date of deposit or for the enforceable life of the patent, whichever period is longer. Applicant acknowledges its duty to replace the deposit should the depository be unable to furnish a sample when requested due to the condition of the deposit.
  • 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.
  • Veillonella Parvula Anti-inflammatory strains of Veillonella Parvula can be identified using methods disclosed herein (e.g., by determining whether they reduce (e.g., significantly reduce) the levels of a pro-inflammatory cytokine such as IE-8, IL-6, IL- 1(3, and/or TNFa in an assay described herein).
  • the Veillonella parvula is Veillonella parvula strain A (ATCC Deposit Number PTA-125691) (also referred to as "Veillonella parvula strain A”).
  • the Veillonella parvula 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 Veillonella parvulci strain A (ATCC Deposit Number PTA- 125691).
  • 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
  • Applicant represents that the ATCC is a depository affording permanence of the deposit and ready accessibility thereto by the public if a patent is granted. All restrictions on the availability to the public of the material so deposited will be irrevocably removed upon the granting of a patent. The material will be available during the pendency of the patent application to one determined by the Commissioner to be entitled thereto under 37 CFR 1.14 and 35 U.S.C. 122.
  • the deposited material will be maintained with all the care necessary to keep it viable and uncontaminated for a period of at least five years after the most recent request for the furnishing of a sample of the deposited plasmid, and in any case, for a period of at least thirty (30) years after the date of deposit or for the enforceable life of the patent, whichever period is longer. Applicant acknowledges its duty to replace the deposit should the depository be unable to furnish a sample when requested due to the condition of the deposit.
  • Veillonella parvula strain A can be cultured according to methods known in the art. For example, Veillonella parvula strain A can be grown under anaerobic conditions in PM1 l+5g/U Na-U-lactate liquid medium supplemented with 0.05g/U FeSC>4, and 0.5 g/L U- cysteine-HCU as reducing agent at 37 degrees C.
  • the bacterial compositions comprise whole Veillonella parvula bacteria (e.g., live bacteria, killed bacteria, attenuated bacteria).
  • the bacterial compositions comprise whole Veillonella parvula bacteria (e.g., gamma irradiated bacteria).
  • compositions comprising anti-inflammatory bacteria.
  • the pharmaceutical composition comprises one antiinflammatory strain of bacteria.
  • the pharmaceutical composition comprises one strain of bacteria, wherein the strain is an anti-inflammatory strain.
  • the pharmaceutical composition is formulated as a solid dose (e.g., solid dosage) form, such as a capsule or a tablet.
  • the pharmaceutical composition comprises an enteric coating or micro encapsulation.
  • the pharmaceutical composition is prepared as a capsule.
  • the capsule is an enteric coated capsule.
  • the pharmaceutical composition is prepared as a tablet.
  • the tablet is an enteric coated tablet.
  • the enteric coating allows release of the pharmaceutical composition in the small intestine, e.g., in the upper small intestine, e.g., in the duodenum.
  • the pharmaceutical composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 3 x IO 10 to about 1.5 x 10 12 total cells of the anti-inflammatory bacteria.
  • the pharmaceutical 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 to about 1.3 x 10 12 total cells of the anti-inflammatory bacteria.
  • the pharmaceutical composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 4.5 x 10 10 to about 1.5 x 10 12 total cells of the anti-inflammatory bacteria.
  • 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.
  • a dose of anti-inflammatory bacteria of about 3 x IO 10 to about 1.5 x 10 12 total cells are administered (e.g., are for administration) per day.
  • a dose of anti-inflammatory bacteria of about 8 x IO 10 to about 1.3 x 10 12 total cells are administered (e.g., are for administration) per day.
  • a dose of anti-inflammatory bacteria of about 4.5 x IO 10 to about 1.5 x 10 12 total cells are administered (e.g., are for administration) per day.
  • the pharmaceutical composition comprising antiinflammatory 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 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 anti-inflammatory 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 anti-inflammatory 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).
  • the pharmaceutical compositions comprise whole antiinflammatory bacteria such as Prevotella histicola (e.g., live bacteria, killed bacteria, attenuated bacteria).
  • Prevotella histicola e.g., live bacteria, killed bacteria, attenuated bacteria.
  • the pharmaceutical compositions comprise live antiinflammatory bacteria such as Prevotella histicola bacteria.
  • the pharmaceutical compositions comprise viable antiinflammatory bacteria such as Prevotella histicola bacteria.
  • the pharmaceutical compositions comprise non-viable anti-inflammatory bacteria such as Prevotella histicola bacteria.
  • the Prevotella histicola is Prevotella histicola Strain B (NRRL accession number B 50329).
  • the Prevotella histicola strain is a strain comprising at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Prevotella histicola Strain B.
  • 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 pharmaceutical composition comprises about 50 mg to about 3 g of Prevotella histicola.
  • the pharmaceutical composition comprises about 55mg, about 550 mg, or about 2.76 g of Prevotella histicola.
  • the pharmaceutical composition comprises about 2xlO 10 , 2.1xlO 10 , 2.2xlO 10 , 2.3xlO 10 , 2.4xlO 10 , 2.5xlO 10 , 2.6xlO 10 , 2.7xlO 10 , 2.8xlO 10 , 2.9xlO 10 , 3xlO 10 , 3.
  • the pharmaceutical composition comprises about 8xl0 10 total cells of Prevotella histicola. In some embodiments, the pharmaceutical composition comprises about 1.6x10“ total cells Prevotella histicola. In some embodiments, the pharmaceutical composition comprises about 8x10“ total cells of Prevotella histicola.
  • total cells is determined by total cell count (e.g., determined by Coulter counter).
  • the pharmaceutical composition comprises at least about 2xlO 10 , 2. IxlO 10 , 2.2xlO 10 , 2.3xlO 10 , 2.4xlO 10 , 2.5xlO 10 , 2.6xlO 10 , 2.7xlO 10 , 2.8xlO 10 , 2.9xlO 10 , 3xl0 10 , 3.
  • the pharmaceutical composition comprises at most about 2xlO 10 , 2. IxlO 10 , 2.2xlO 10 , 2.3xlO 10 , 2.4xlO 10 , 2.5xlO 10 , 2.6xlO 10 , 2.7xlO 10 , 2.8xlO 10 , 2.9xlO 10 , 3xl0 10 , 3.
  • the pharmaceutical composition comprises about 50 mg to about 3 g of Prevotella histicola, e.g., of Prevotella Strain B 50329.
  • the pharmaceutical composition comprises about 55mg, about 550 mg, or about 2.76 g of Prevotella histicola, e.g., of Prevotella Strain B 50329.
  • the pharmaceutical composition comprises about 2xlO 10 , 2.1xlO 10 , 2.2xlO 10 , 2.3xlO 10 , 2.4xlO 10 , 2.5xlO 10 , 2.6xlO 10 , 2.7xlO 10 , 2.8xlO 10 , 2.9xlO 10 , 3xl0 10 , 3.
  • the pharmaceutical composition comprises about 8xl0 10 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the pharmaceutical composition comprises about 1.6x10“ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the pharmaceutical composition comprises about 3.2x10“ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the pharmaceutical composition comprises about 6.4x10“ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
  • the pharmaceutical composition comprises about 8x10“ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the pharmaceutical composition comprises about 9.6x10“ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the pharmaceutical composition comprises about 12.8x10“ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the pharmaceutical composition comprises about 16x10“ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
  • the pharmaceutical composition comprises about 1.6 x 10 10 to about 1.6 x 10“ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the pharmaceutical composition comprises about 1.6 x 10 10 to about 16 x 10“ total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329. In some embodiments, the pharmaceutical composition comprises about 8 x IO 10 to about 8 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
  • the pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical composition comprises about 1.6 x 10 10 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
  • the pharmaceutical composition comprises about 8 x
  • the pharmaceutical composition comprises about 1.6 x
  • the pharmaceutical composition comprises about 3.2 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
  • the pharmaceutical composition comprises about 6.4 x 10 11 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
  • the pharmaceutical composition comprises about 8 x 10 11 total cells oiPrevotella histicola, e.g., of Prevotella Strain B 50329.
  • the pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical composition e.g., pharmaceutical composition (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 8 x IO 10 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
  • the pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 total cells of Prevotella histicola, e.g., of Prevotella Strain B 50329.
  • the pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 oiPrevotella histicola, e.g., of Prevotella Strain B 50329.
  • the pharmaceutical 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 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.
  • 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
  • 1 solid dosage form is administered (e.g., is 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.
  • 2 solid dosage forms e.g., tablets or capsules
  • the solid dosage form e.g., each solid dose form
  • 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
  • the solid dosage form comprises a dose of bacteria of about 3.2 x 10 n 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 n 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 pharmaceutical 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 IO 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 pharmaceutical 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 IO 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 IO 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 IO 10 total cells
  • 6 tablets e.g., each comprising about 8 x IO 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 n 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 n 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.
  • each capsule comprises about 1.6 x 10 n 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 e.g., each comprising about 1.6 x 10 11 total cells
  • 4 capsules are administered, e.g., once or twice daily to a subject.
  • 5 capsules e.g., each comprising about 1.6 x 10 11 total cells
  • 6 capsules e.g., each comprising about 1.6 x 10 n total cells
  • 8 capsules e.g., each comprising about 1.6 x 10 n total cells
  • 10 capsules are administered, e.g., once or twice daily to a subject.
  • 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 n 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. [193] In some embodiments, at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%,
  • the bacteria in the composition are of the Prevotella strain. 10%, 15%, 20%, 25%, 30%, 35%,
  • the bacteria in the composition are of the Prevotella strain. In some embodiments, at least 99% of the bacteria in the composition are of the Prevotella strain. In some embodiments, the bacteria in the composition are essentially (e.g., about 100%) of the Prevotella strain.
  • the pharmaceutical compositions comprise whole Veillonella parvula bacteria (e.g., live bacteria, killed bacteria, attenuated bacteria).
  • the Veillonella parvula bacteria is non-viable.
  • the Veillonella parvula bacteria has been gamma irradiated (e.g., according to a method described herein).
  • the Veillonella parvula bacteria is live.
  • the pharmaceutical composition comprises only one strain of bacteria, e.g., Veillonella parvula.
  • the Veillonella parvula is Veillonella parvula strain A (ATCC Deposit Number PTA-125691).
  • the Veillonella parvula strain is a strain comprising at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity (e.g., at least 99.5% sequence identity, at least 99.6% sequence identity, at least 99.7% sequence identity, at least 99.8% sequence identity, at least 99.9% sequence identity) to the nucleotide sequence (e.g., genomic sequence, 16S sequence, CRISPR sequence) of the Veillonella parvula strain A (ATCC Deposit Number PTA-125691).
  • 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,
  • the pharmaceutical compositions comprise whole Veillonella parvula bacteria (e.g., live bacteria, killed bacteria, attenuated bacteria). [199] In some embodiments, the pharmaceutical compositions comprise whole Veillonella parvulci bacteria (e.g., gamma irradiated bacteria).
  • the pharmaceutical compositions (e.g., composition of the total dose administered, e.g., once or twice daily) comprises about 1 x IO 10 total cells, about 2 x IO 10 total cells, about 3 x IO 10 total cells, about 4 x IO 10 total cells, about 4.5 x IO 10 total cells, about 5 x IO 10 total cells, about 6 x IO 10 total cells, about 7 x IO 10 total cells, about 8 x 10 10 total cells, about 9 x 10 10 total cells, about 1 x 10 11 total cells, about 1.5 x 10 11 total cells, about 2 x 10 11 total cells, about 3 x 10 11 total cells, about 4 x 10 11 total cells, about 5 x 10 11 total cells, about 6 x 10 11 total cells, about 7 x 10 11 total cells, about 7.5 x 10 11 total cells, about 8 x 10 11 total cells, about 9 x 10 11 total cells, about 1 x 10 12 total cells, about 1.5 x 10 12 total cells, about
  • the pharmaceutical 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 4.5 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, at least 1.5 x 10 11 total cells, at least 2 x 10 11 total cells, at least 3 x
  • 10 11 total cells at least 4 x 10 11 total cells, at least 5 x 10 11 total cells, at least 6 x 10 11 total cells, at least 7 x 10 11 total cells, at least 7.5 x 10 11 total cells, at least 8 x 10 11 total cells, at least 9 x 10 11 total cells, at least 1 x 10 12 total cells, at least 1.5 x 10 12 total cells, at least 2 x
  • the pharmaceutical composition comprises about 3 x 10 10 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 4.5 x 10 10 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 1.5 x 10 11 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical compositions comprises about 7.5 x 10 11 total cells the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 1.5 x 10 12 total cells the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 3 x 10 10 to about 1.5 x 10 12 total cells of the Veillonella parvula bacteria.
  • the pharmaceutical composition comprises about 4.5 x 10 10 to about 1.5 x 10 12 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 3 x 10 10 to about 1.5 x 10 11 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 4.5 x 10 10 to about 1.5 x 10 11 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 1.5 x 10 n to about 1.5 x 10 12 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 1.5 x 10 n to about 7.5 x 10 11 total cells of the Veillonella parvula bacteria. In some embodiments, the pharmaceutical composition comprises about 7.5 x 10 11 to about 1.5 x 10 12 total cells of the Veillonella parvula bacteria.
  • At least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the bacteria in the composition are of the Veillonella parvula strain. 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% of the bacteria in the composition are of the Veillonella parvula strain. In some embodiments, at least 99% of the bacteria in the composition are of the Veillonella parvula strain. In some embodiments, the bacteria in the composition are essentially (e.g., about 100%) of the Veillonella parvula strain.
  • the pharmaceutical composition is formulated as a capsule or a tablet or a mini-tablet.
  • the pharmaceutical composition comprises an enteric coating or micro encapsulation.
  • the capsule is an enteric coated capsule.
  • NTA nanoparticle tracking analysis
  • DLS dynamic light scattering
  • Coulter counting reveals the numbers of particles with diameters of 0.7-10 um. NTA reveals the numbers of particles with diameters of 50-1400 nm. For most bacterial samples, the Coulter counter alone can reveal the number of bacteria in a sample. In some embodiments, total cells (total cell count) is determined by Coulter counting.
  • the anti-inflammatory bacteria may be quantified based on total cells, e.g., total cell count (TCC) (e.g., determined by Coulter counter).
  • TCC total cell count
  • compositions for administration subjects 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 pharmaceutical 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 CnFhnOn.
  • a carbohydrate may be a monosaccharide, a disaccharide, trisaccharide, oligosaccharide, or polysaccharide.
  • the most basic carbohydrate is a monosaccharide, such as glucose, sucrose, galactose, mannose, ribose, arabinose, xylose, and fructose.
  • Disaccharides are two joined monosaccharides. Exemplary disaccharides include sucrose, maltose, cellobiose, and lactose.
  • an oligosaccharide includes between three and six monosaccharide units (e.g., raffinose, stachyose), and polysaccharides include six or more monosaccharide units.
  • Exemplary polysaccharides include starch, glycogen, and cellulose.
  • Carbohydrates may contain modified saccharide units such as 2 ’-deoxyribose wherein a hydroxyl group is removed, 2 ’-fluororibose wherein a hydroxyl group is replaced with a fluorine, or N- acetylglucosamine, a nitrogen-containing form of glucose (e.g., 2 ’-fluororibose, deoxyribose, and hexose).
  • Carbohydrates may exist in many different forms, for example, conformers, cyclic forms, acyclic forms, stereoisomers, tautomers, anomers, and isomers.
  • 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 faty acid selected from lauric acid (12:0), myristic acid (14:0), palmitic acid (16:0), palmitoleic acid (16: 1), margaric acid (17:0), heptadecenoic acid (17: 1), stearic acid (18:0), oleic acid (18: 1), linoleic acid (18:2), linolenic acid (18:3), octadecatetraenoic acid (18:4), arachidic acid (20:0), eicosenoic acid (20: 1), eicosadienoic acid (20:2), eicosatetraenoic acid (20:4), eicosapentaenoic acid (20:5) (EP A), docosanoic acid (22:0), docosenoic acid (22: 1), docosapentaenoic acid (22:5), docosahexaenoic acid (22:6) (DHA), and
  • 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-effervescent disintegrant.
  • suitable non-effervescent disintegrants include starches such as com starch, potato starch, pregelatinized and modified starches thereof, sweeteners, clays, such as bentonite, micro-crystalline cellulose, alginates, sodium starch glycolate, gums such as agar, guar, locust bean, karaya, pectin, and tragacanth.
  • the disintegrant is an effervescent disintegrant.
  • suitable effervescent disintegrants include sodium bicarbonate in combination with citric acid, and sodium bicarbonate in combination with tartaric acid.
  • 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.
  • solid dosage forms comprising anti-inflammatory bacteria and a pharmaceutically acceptable carrier.
  • solid dosage forms comprising anti-inflammatory bacteria such as a Prevotella strain such as a strain of Prevotella histicola such as Prevotella histicola Strain B (NRRL accession number B 50329), and a pharmaceutically acceptable carrier.
  • a Prevotella strain such as a strain of Prevotella histicola such as Prevotella histicola Strain B (NRRL accession number B 50329)
  • a pharmaceutically acceptable carrier such as a Prevotella strain such as a strain of Prevotella histicola such as Prevotella histicola Strain B (NRRL accession number B 50329)
  • solid dosage forms comprising anti-inflammatory bacteria such as a Veillonella parvula strain such as a strain of Veillonella parvula such as Veillonella parvula strain A (ATCC Deposit Number PTA-125691), and a pharmaceutically acceptable carrier.
  • anti-inflammatory bacteria such as a Veillonella parvula strain such as a strain of Veillonella parvula such as Veillonella parvula strain A (ATCC Deposit Number PTA-125691)
  • a pharmaceutically acceptable carrier such as a Veillonella parvula strain such as a strain of Veillonella parvula such as Veillonella parvula strain A (ATCC Deposit Number PTA-125691).
  • the solid dosage form described herein can be a capsule, e.g., an enteric coated capsule.
  • the capsule is enteric coated, e.g., for duodenal release at pH 5.5.
  • the capsule can be, e.g., 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 freeze-dried powder that comprises the antiinflammatory bacteria such as the Prevotella strain.
  • the capsule comprises freeze-dried powder that comprises the anti-inflammatory bacteria such as the Veillonella parvula strain.
  • the solid dosage form described herein can be, e.g., a tablet or a mini-tablet.
  • a plurality of mini-tablets can be in (e.g. , loaded into) a capsule.
  • the solid dosage form comprises a tablet (> 4mm) (e.g., 5mm-17mm).
  • the tablet is a 5mm, 6mm, 7mm, 8mm, 9mm, 10mm, 11mm, 12mm, 13mm, 14mm, 15mm, 16mm, 17mm or 18mm tablet.
  • 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 1mm mini-tablet, 1.5 mm mini-tablet, 2mm mini-tablet, 3mm mini-tablet, or 4mm mini-tablet.
  • 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 HPMC (hydroxyl propyl methyl cellulose) or gelatin.
  • HPMC hydroxyl propyl methyl cellulose
  • the mini-tablets can be inside a capsule: the number of minitablets inside a capsule will depend on the size of the capsule and the size of the mini -tablets. As an example, a size 0 capsule can contain 31-35 (an average of 33) mini-tablets that are 3mm mini -tablets.
  • the solid dosage form e.g., tablet or mini-tablet
  • the solid dosage form e.g., tablet or mini-tablet described herein can be enterically coated.
  • an additional therapy is administered to the subject.
  • the additional therapy comprises an anti-inflammatory agent such as NSAIDs or anti-inflammatory steroids.
  • the additional therapy comprises dexamethasone.
  • the additional therapy is administered at a lower dose than the dose at which it is administered as a monotherapy.
  • the methods provided herein further comprise administering to the subject an anti-inflammatory agent.
  • the method further comprises orally administering an anti-inflammatory agent such as an NSAID or an anti-inflammatory steroid.
  • the method further comprises administering (e.g., orally or intravenously administering) 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-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 -IL 1 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.
  • a GMSF inhibitor such as lenzilumab or gimsilumab
  • an anti -IL 1 beta inhibitor such as canakinumab
  • an IL-6 inhibitor such as tocilizumab or siltuximab
  • an IL-6R inhibitor such as sarilumab
  • 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 BTK inhibitor such as ibrutinib.
  • provided herein is a method of delivering a pharmaceutical composition described herein to a subject.
  • the subject is a mammal. In some embodiments, the subject is a human.
  • the pharmaceutical composition is administered orally. In some embodiments, the administration to the subject for a single day followed by a washout period before the next dose. In some embodiments, the washout period is at least 12 hours, 24 hours, 36 hours, 48 hours, 50 hours, 60 hours, or 72 hours.
  • the pharmaceutical composition is administered after the washout period once daily for 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, or 28 days.
  • the pharmaceutical composition is administered after the washout period twice daily for 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, or 28 days.
  • the pharmaceutical composition is administered for 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, or 28 days.
  • the pharmaceutical composition is administered twice daily for 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, or 28 days.
  • the pharmaceutical composition is administered once daily for 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, 30 days, 31 days, 32 days, 33 days, 34 days, 35 days, 36 days, 37 days, 38 days, 39 days, 40 days, 41 days, or 42 days.
  • the pharmaceutical 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 pharmaceutical composition is administered once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. In some embodiments, the pharmaceutical 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 pharmaceutical composition is administered once daily for at least 8 weeks. In some embodiments, the pharmaceutical composition is administered once daily for at least 12 weeks. In some embodiments, the pharmaceutical composition is administered once daily for at least 16 weeks.
  • the pharmaceutical 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 pharmaceutical 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 pharmaceutical composition is administered twice daily for at least 8 weeks. In some embodiments, the pharmaceutical composition is administered twice daily for at least 12 weeks. In some embodiments, the pharmaceutical composition is administered twice daily for at least 16 weeks.
  • the pharmaceutical composition is administered twice daily for three days and then once daily for the remainder of the treatment (e.g., until day 14).
  • the pharmaceutical composition is formulated as a capsule (e.g. containing mini-tablets or powder) or a tablet.
  • the bacterial formulation comprises an enteric coating or micro encapsulation.
  • the capsule is an enteric coated capsule.
  • the capsule is an HPMC capsule.
  • the capsule is a gelatin capsule.
  • the subject is a mammal. In some embodiments, the subject is a human. [248] In some embodiments of the methods provided herein, the pharmaceutical composition is administered in conjunction with the administration of an additional therapeutic. In some embodiments, the pharmaceutical composition comprises antiinflammatory bacteria such as Prevotella histicola or Veillonella parvulci bacteria coformulated with the additional therapeutic. In some embodiments, the pharmaceutical composition is co-administered with the additional therapeutic.
  • the additional therapeutic is administered to the subject before administration of the pharmaceutical 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 pharmaceutical 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 pharmaceutical 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 pharmaceutical composition and the additional therapeutic.
  • different modes of delivery are used to administer the pharmaceutical composition and the additional therapeutic.
  • the pharmaceutical composition is administered orally while the additional therapeutic is administered via injection (e.g., an intravenous, and/or intramuscular injection).
  • the pharmaceutical composition is administered orally. In some embodiments, the administration to the subject for a single day followed by an interval period before the next dose. In some embodiments, the interval period is at least 3 days, 4 days, 5 days, 6 days, or 7 days.
  • the pharmaceutical composition is administered after the interval period once daily for 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, or 28 days.
  • the pharmaceutical composition is formulated as a capsule or a tablet.
  • the bacterial formulation comprises an enteric coating or micro encapsulation.
  • the capsule is an enteric coated capsule.
  • the subject is a mammal. In some embodiments, the subject is a human.
  • the pharmaceutical compositions, dosage forms, and kits described herein can be administered in conjunction with any other conventional treatment. These treatments may be applied as necessary and/or as indicated and may occur before, concurrent with or after administration of the pharmaceutical 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 pharmaceutical 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), delay its onset, or slow or stop its progression.
  • disease e.g., autoimmune disease, inflammatory disease, metabolic disease
  • 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 rangefinding 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 ("MID”) of bioactive agent per kilogram weight. Those skilled in the art regularly extrapolate doses for efficacy, while avoiding toxicity, in other species, including humans.
  • MID 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 pharmaceutical 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 pharmaceutical 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, anaphylasix, 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, dys
  • the therapeutic effects of these orally delivered medicines come from their action on pattern recognition receptors on immune cells in the lining of the small intestine. These cells, in turn, modulate immune cells circulating throughout the body.
  • the medicines are microbes, but do not target the microbiome.
  • monoclonal microbials do not colonize or persist in the gut and do not modify the colonic microbiome. In some embodiments, they are gut-restricted.
  • the methods provided herein result in change (e.g., an increase or a decrease) in serum and/or expression levels of one or more cytokines (or one or more cellular factors) after the subject is treated according to a method provided herein for a set time interval as compared to before treatment and/or at the onset of treatment.
  • the one or more cytokines include TNF-a, IL-ip, IL-6, and IL-8.
  • the time interval is up to 28 days.
  • the time interval is about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days about 25 days, about 26 days, about 27 days, and/or about 28 days.
  • the methods provided herein resolve inflammation in a subject in need thereof (e.g., as compared to a standard).
  • the subject in need thereof suffers from an IL-8, IL-6, IL- 1 P, and/or TNFa mediated disease or condition.
  • a method of resolving an inflammatory response in a subject in need thereof wherein the method dampens (e.g., reduces) the production of IL-6, IL-8 and/or TNFa from myeloid cells.
  • a method of resolving an inflammatory response in a subject in need thereof wherein the method dampens (e.g., reduces) the production of IL-6, IL-8 and/or TNFa from myeloid cells but not from T-cells.
  • IFN Type I interferon
  • provided herein is a method of resolving an inflammatory response in a subject in need thereof, wherein IFNa and/or IFNp levels are not reduced.
  • the subject in need thereof has an infection, e.g., a viral infection.
  • the subject in need thereof is a child (e.g., a child of no more than 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 years old). In certain embodiments, the subject is an infant of no more than 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 months old.
  • the subject is an older adult. In certain embodiments, the subject is at least 50, 55, 60, 65, 70, 75, 80, 80, or 90 years old.
  • the subject is a pregnant woman. In some embodiments, the subject is a woman of child-bearing age.
  • the subject is immunocompromised (e.g., a subject who has undergone radiation therapy, immunotherapy, has received a transplant, is taking anti-rejection medication, is taking immunosuppressant medication, is infected with HIV, etc.).
  • immunocompromised e.g., a subject who has undergone radiation therapy, immunotherapy, has received a transplant, is taking anti-rejection medication, is taking immunosuppressant medication, is infected with HIV, etc.
  • the pharmaceutical compositions and methods provided herein can be used to reduce inflammatory cytokine expression (e.g., IL-8, IL-6, IL-ip, and/or TNFa expression) in a subject.
  • inflammatory cytokine expression e.g., IL-8, IL-6, IL-ip, and/or TNFa expression
  • the pharmaceutical compositions and methods provided herein can be used to treat diseases and conditions associated therewith.
  • the pharmaceutical compositions and methods provided herein can be used to reduce the level of IL-8, IL-6, IL-1J3, and/or TNFa.
  • the pharmaceutical compositions and methods provided herein can be used to reduce the level of IL-8, IL-6, and/or TNFa from myeloid cells.
  • the pharmaceutical compositions and methods provided herein can be used to reduce the level of IL-8, IL-6, and/or TNFa from myeloid cells, but not from T cells.
  • the methods and pharmaceutical compositions described herein relate to the treatment or prevention of a disease or disorder associated with inflammation.
  • the disease or disorder is an inflammatory bowel disease (e.g., Crohn’s disease or ulcerative colitis).
  • the disease or disorder is psoriasis.
  • the disease or disorder is atopic dermatitis.
  • the disease or disorder is an infection, e.g., a viral infection.
  • a “subject in need thereof’ includes any subject that has inflammation, as well as any subject with an increased likelihood of acquiring a such a disease or disorder.
  • the subject may have had an appropriate inflammatory response, such as an immune response, but the subject may be in need to treatment to resolve the inflammation.
  • the pharmaceutical compositions described herein can be used, for example, as a pharmaceutical composition for preventing or treating (reducing, partially or completely, the adverse effects of) inflammation associated with an autoimmune disease, such as chronic inflammatory bowel disease, systemic lupus erythematosus, psoriasis, 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 pharmaceutical composition for suppressing rejection in organ transplantation or other situations in which tissue rejection might occur; a supplement, food, or beverage for improving immune functions; or a reagent
  • the methods 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.
  • compositions described herein can be used, for example, as a pharmaceutical composition for preventing or treating (reducing, partially or completely, the adverse effects of) inflammation associated with an immune disorder of the musculoskeletal system.
  • 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 refers to an immune disorder that affects any structure of the eye, including the eyelids.
  • 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
  • the pharmaceutical compositions described herein can be used, for example, as a pharmaceutical composition for preventing or treating (reducing, partially or completely, the adverse effects of) inflammation associated with nervous system immune disorders.
  • 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.
  • the pharmaceutical compositions described herein can be used, for example, as a pharmaceutical composition for preventing or treating (reducing, partially or completely, the adverse effects of) inflammation associated with the vasculature or lymphatic system.
  • 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.
  • the pharmaceutical compositions described herein can be used, for example, as a pharmaceutical composition for preventing or treating (reducing, partially or completely, the adverse effects of) inflammation associated with digestive system immune disorders.
  • digestive system immune disorders which may be treated with the methods and pharmaceutical 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.
  • inflammatory bowel diseases Several major forms of inflammatory bowel diseases are known, with Crohn's disease (regional bowel disease, e.g., inactive and active forms) and ulcerative colitis (e.g., inactive and active forms) the most common of these disorders.
  • the inflammatory bowel disease encompasses irritable bowel syndrome, microscopic colitis, lymphocytic-plasmocytic enteritis, coeliac disease, collagenous colitis, lymphocytic colitis and eosinophilic enterocolitis.
  • IBD 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.
  • compositions described herein can be used, for example, as a pharmaceutical composition for preventing or treating (reducing, partially or completely, the adverse effects of) inflammation associated with reproductive system immune disorders.
  • reproductive system immune disorders which may be treated with the methods and pharmaceutical 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 pharmaceutical 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, type 2 diabetes, giant cell arteritis, goodpasture'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
  • T-cell mediated hypersensitivity diseases having an inflammatory component.
  • Such conditions include, but are not limited to, contact hypersensitivity, contact dermatitis (including that due to poison ivy), uticaria, skin allergies, respiratory allergies (hay fever, allergic rhinitis, house dustmite allergy) and gluten-sensitive enteropathy (Celiac disease).
  • Other immune disorders which may have an inflammatory component and may be treated with the methods and pharmaceutical 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
  • Preferred treatments include treatment of transplant rejection, rheumatoid arthritis, psoriatic arthritis, multiple sclerosis, Type 1 diabetes, asthma, inflammatory bowel disease, systemic lupus erythematosus, psoriasis, chronic obstructive pulmonary disease, and inflammation accompanying infectious conditions (e.g., sepsis).
  • Example 1 Prevotella histicola Strain B in healthy participants and participants with mild to moderate psoriasis or mild to moderate atopic dermatitis
  • Prevotella histicola Strain B (NRRL accession number B 50329) has recently completed a series of cohorts in a phase lb study in human volunteers and patients with psoriasis.
  • Prevotella histicola Strain B (NRRL accession number B 50329) has a placebo-like profile, consistent with the lack of systemic absorption. There was no persistence beyond the 28-day daily dosing period and no modification of the colonic microbiome by 16S RNA sequencing of patient stool samples.
  • Dexamethose is a corticosteroid often used in the treatment of many inflammatory and autoimmune conditions, including rheumatic diseases, skin diseases, severe allergies, and asthma. While systemic dexamethasone is efficacious in many of these diseases, corticosteroids exert effects on most of the body's systems (heart, immune, muscles and bones, endocrine and nervous system), and therefore chronic treatment with dexamethasone can result in a number of undesirable side effects, including aggression, anxiety, insomnia, weight gain, diarrhea, muscle wasting, and fatigue.
  • dexamethasone is a broad immune-suppressive drug, it may inhibit the production of protective immune responses, such as the secretion of Type 1 interferons that are critical in anti-viral responses.
  • Prevotella histicola Strain B mono-therapy had no impact on these Type 1 interferons. This demonstrates that Prevotella histicola Strain B can selectively inhibit inflammation and pro-inflammatory cytokines, while preserving protective Type 1 interferon responses.
  • mice were immunized by subcutaneous injection with KLH emulsified with Complete Freund’s Adjuvant. On Day 6 after the sensitization, mice were dosed for 3 days with oral Prevotella histicola Strain B, dexamethasone (0. 1 mg/kg or 0.4 mg/kg) given intraperitoneally, or a combination of Prevotella histicola Strain B and dexamethasone. On day 8, mice were challenged by intradermal ear injection with KLH. The DTH response was evaluated 24 hours post-challenge.
  • spleen cells from treated mice were incubated for 48 hours in vitro and stimulated with either LPS or polyinosinic-polycytidylic acid (poly I:C), a potent ligand for Toll-like receptor 3, which induces interferon-alpha (IFNa) and interferon-beta (IFNp )from immune cells.
  • LPS polyinosinic-polycytidylic acid
  • IFNa interferon-alpha
  • IFNp interferon-beta
  • FIG. 8 shows the effects of Prevotella histicola Strain B compared to a pooled placebo group (24 volunteers).
  • Prevotella histicola Strain B reduced basal blood flow close to the pre-challenge baseline, comparable to the effects seen in the equivalent DTH preclinical mouse model.
  • Example 4 Prevotella histicola Strain B in healthy participants and participants with mild to moderate psoriasis or mild to moderate atopic dermatitis
  • Prevotella histicola Strain B (NRRL accession number B 50329) has recently completed a series of cohorts in a phase lb study in human volunteers and patients with psoriasis.
  • Prevotella histicola Strain B (Strain B) treatment does not significantly impact production of the measured cytokines by CD3/CD28 stimulation of whole blood from psoriasis patients. Waterfall plots are percent change from baseline to day 28. Samples from patients treated with a low (IX) dose (1.6xlO n cells per day) and high (5X) dose (8xl0 n cells per day) of Prevotella histicola Strain B (NRRL accession number B 50329) daily for 28 days were analyzed.
  • FIG. 9 shows the levels of IL-8.
  • FIG. 10 shows the levels of IL-6.
  • FIG. 11 shows the levels of TNF-a.
  • FIG. 12 shows the levels of IFN-g.
  • FIG. 13 shows the levels of IL-17A.
  • Example 5 Prevotella histicola Strain B effects on inflammation without impacting innate and adaptive immune responses that mediate host anti-viral responses
  • Antiviral responses are activated rapidly after viral infection in order to control and prevent dissemination of the virus.
  • Virus infection results in two general types of immune response.
  • the first is a rapid-onset innate immune response against the virus, which involves the synthesis of Type 1 interferons and the stimulation of Natural Killer (NK) cells. If the infection proceeds beyond the first few rounds of viral replication, the innate immune response will trigger the adaptive immune response.
  • the adaptive immune response itself has two components, the humoral response (the synthesis of virus-specific immunoglobulins by B lymphocytes) and the cell-mediated response (the synthesis of specific CD8+ cytotoxic T lymphocytes that kill infected cells through secretion of interferon gamma (IFNy)). Both of these components of the adaptive immune response result also in the production of long-lived memory cells that allow for a much more rapid response to a subsequent infection with the same virus.
  • an immune competent host should be able to mount both an innate and adaptive immune response.
  • Prevotella histicola Strain B is administered orally and is gut-restricted. Therefore, Prevotella histicola Strain B exerts its anti-inflammatory effects on peripheral tissue through engagement of cells of the intestine, including small intestinal epithelial cells and immune cells in the lamina propria.
  • IFNy Interferon-gamma
  • Prevotella histicola Strain B did not alter the ability of human dendritic cells to induce the production of IFNy from memory CD8 T cells in response to a viral peptide pool (Cytomegalovirus, Epstein-Bar virus, and Influenza virus), an important component of an anti-viral response.
  • TLR3 Toll-Like Receptor 3
  • TLR3 is a receptor expressed by human immune cells that mediates viral recognition, and the subsequent production of Type 1 interferons. Measuring Type 1 interferons from cells stimulated through TLR3 is a way to measure the strength of the antiviral response.
  • mice were immunized by subcutaneous injection with KLH emulsified with Complete Ereund’s Adjuvant. On Day 6 after the sensitization, mice were dosed for 3 days with oral Prevotella histicola Strain B or dexamethasone given intraperitoneally. On day 8, mice were challenged by intradermal ear injection with KLH. The DTH response was evaluated 24 hours post-challenge.
  • spleen cells from treated mice were incubated for 48 hours in vitro and stimulated with polyinosinic-polycytidylic acid (poly I:C), a molecule that mimics viral double-strained RNA, and a potent ligand for Tolllike receptor 3, which induces interferon-alpha (IFNa) and interferon-beta (IFNP) from immune cells.
  • poly I:C polyinosinic-polycytidylic acid
  • IFNa interferon-alpha
  • IFNP interferon-beta
  • Interferon gamma is another cytokine that is important in controlling virus infections. It does this by exerting cellular effects at multiple levels.
  • IFNy Interferon gamma
  • T cells T cells, monocytes, and resident cells
  • NK Natural Killer
  • IFNy activates cytokine production by T cells, monocytes, and resident cells, and augments cytotoxic T lymphocyte (CTL) and Natural Killer (NK) cell killing by the induction of molecules such as granzyme B or major histocompatibility complex (MHC) class I, and it enhances immune reactivity through the induction of MHC class II molecules. Therefore, another key measure of antiviral competence is the robust production of IFNy.
  • CTL cytotoxic T lymphocyte
  • NK Natural Killer
  • a protective immune response to SARS-CoV-2 involves both cell-mediated immunity and antibody production.
  • T-cell responses against the SARS-CoV-2 spike protein have been characterized and correlate well with IgG antibody titers in COVID- 19 patients.
  • CD8+ T cells are the main inflammatory cells and play a vital role in virus clearance.
  • Total lymphocytes, CD4+ T cells, CD8+ T cells, B cells, and natural killer (NK) cells showed a significant association with inflammatory status in COVID- 19, especially CD8+ T cells and CD4+/CD8+ ratio. Decreased CD4+ T cells and CD8+ T cells have been observed in both mild cases and severe cases but accentuated in the severe cases.
  • T and B cells In multivariate analysis, post-treatment decrease in CD8+ T cells and B cells and increase in were indicated as independent predictors of poor treatment outcome. Therefore, keeping a full complement of immune cells, particularly T and B cells, is important for maintaining viral resistance.
  • Other major cell types that assist in activating the adaptive immune anti-viral response are NK cells, neutrophils, macrophages, and monocytes.
  • Antibodies are one of the essential features of antigen-triggered adaptive immunity against viruses and requires a coordinated response between antigen-presenting cells such as dendritic cells, antigen-specific helper T cells, and antigen-specific B cells. In preclinical models that use a model antigen such as KLH to induce an immune response, antigen-specific antibodies are also generated. KLH-specific IgG were measured from a DTH study, and total and peanut-specific IgGl were measured from a mouse model of peanut allergy.
  • Prevotella histicola Strain B does not broadly impair either innate or adaptive immune responses.
  • Prevotella histicola Strain B is orally delivered and gut restricted, and therefore its effect is exerted through local interactions with cells of the small intestine, which are then translated from the gut to the periphery to resolve inflammation.
  • Anti-viral responses such as cytotoxic T cell production of interferon-gamma, innate anti-viral production of interferon-alpha and interferon-beta, and the generation of high affinity antibodies are all preserved after treatment with Prevotella histicola Strain B.
  • Example 6 Veillonella parvula strain A effects on inflammation without impacting innate and adaptive immune responses that mediate host anti-viral responses
  • Veillonella parvula strain A- G.I. is a pharmaceutical preparation of a single strain of Veillonella parvula (Veillonella parvula strain A), originally isolated from a fresh ileostomy sample of an IBD patient in remission, which has been gamma-irradiated (G.I.). Veillonella parvula strain A- G.I. is administered orally and is gut-restricted. Therefore, Veillonella parvula strain A- G.I. exerts its anti-inflammatory effects on peripheral tissue through engagement of cells of the intestine, including small intestinal epithelial cells and immune cells in the lamina limbal.
  • Veillonella parvula strain A- G.I. has been shown in preclinical mouse inflammation models to reduce inflammation-related antigen-specific T cell responses, without impacting innate and adaptive immune responses that mediate host anti-viral responses. This is demonstrated by:
  • IFNy Interferon-gamma
  • TLR3 Toll-Like Receptor 3
  • TLR3 is a receptor expressed by human immune cells that mediates viral recognition, and the subsequent production of Type 1 interferons. Measuring Type 1 interferons from cells stimulated through TLR3 is a way to measure the strength of the antiviral response.
  • mice were immunized by subcutaneous injection with KLH emulsified with Complete Freund’s Adjuvant. On Day 5 after the sensitization, mice were dosed for 4 days with oral Veillonella parvula strain A- G.I. On day 8, mice were challenged by intradermal ear injection with KLH. The DTH response was evaluated 24 hours post-challenge.
  • spleen cells from treated mice were incubated for 48 hours in vitro and stimulated with polyinosinic-polycytidylic acid (poly EC), a molecule that mimics viral double-strained RNA, and a potent ligand for Toll-like receptor 3, which induces interferon-alpha (IFNa) and interferon-beta (IFNP) from immune cells.
  • poly EC polyinosinic-polycytidylic acid
  • IFNa interferon-alpha
  • IFNP interferon-beta
  • Interferon gamma is another cytokine that is important in controlling virus infections. It does this by exerting cellular effects at multiple levels.
  • IFNy Interferon gamma
  • T cells T cells, monocytes, and resident cells
  • NK Natural Killer
  • IFNy activates cytokine production by T cells, monocytes, and resident cells, and augments cytotoxic T lymphocyte (CTL) and Natural Killer (NK) cell killing by the induction of molecules such as granzyme B or major histocompatibility complex (MHC) class I, and it enhances immune reactivity through the induction of MHC class II molecules. Therefore, another key measure of anti-viral competence is the robust production of IFNy.
  • CTL cytotoxic T lymphocyte
  • NK Natural Killer
  • a protective immune response to SARS-CoV-2 involves both cell-mediated immunity and antibody production.
  • T cell responses against the SARS-CoV-2 spike protein have been characterised and correlate well with IgG antibody titres in COVID- 19 patients.
  • CD8+ T cells are the main inflammatory cells and play a vital role in virus clearance.
  • Total lymphocytes, CD4+ T cells, CD8+ T cells, B cells showed a significant association with inflammatory status in COVID- 19, especially CD8+ T cells and CD4+/CD8+ ratio. Decreased CD4+ T cells and CD8+ T cells have been observed in both mild cases and severe cases but accentuated in the severe cases.
  • T and B cells were indicated as independent predictors of poor treatment outcome. Therefore, keeping a full complement of immune cells, particularly T and B cells, is important for maintaining viral resistance.
  • Other major cell types that assist in activating the adaptive immune anti-viral response are neutrophils, macrophages, and monocytes. These immune cell populations were quantified after 5 days of dosing mice with Veillonella parvula strain A- G.I. Lymphocytes are the predominant leukocyte in most strains of healthy wild-type mice, making up 70% to 80% of the white blood cell differential count. Myeloid cells residing in mucosal tissues like the lining of the small intestine form the first defense against pathogens.
  • Lymphocytes were therefore measured in the spleen, which reflects the cellular composition of the blood, and myeloid cells in the mesenteric lymph nodes that drain the small intestine. Because the MLNs drain the gut-associated tissues, any changes associated with oral dosing of Veillonella parvula strain A- G.I. would likely be observed in the MLNs first.
  • mice were dosed for 5 days with Veillonella parvula strain A- G.I. by oral gavage. Single cell suspensions were made from the spleen and lymph nodes, stained using antibodies against the relevant cell surface markers to identify individual cell types, and quantified by flow cytometry.
  • Antibodies are one of the essential features of antigen-triggered adaptive immunity against viruses and requires a coordinated response between antigen-presenting cells such as dendritic cells, antigen-specific helper T cells, and antigen-specific B cells. In preclinical models that use a model antigen such as KLH to induce an immune response, antigen-specific antibodies are also generated.
  • cryoprotectant may contain, e.g., maltodextrin, sodium ascorbate, sodium glutamate, and/or calcium chloride.
  • a freeze drier e.g., operating in automated mode with defined cycle parameters. The freeze-dried product is fed into a milling machine and the resulting powder is collected.
  • Powders are stored (e.g., in vacuum sealed bags) at 2-8 degrees C (e.g., at 4 degrees C), e.g., in a desiccator.
  • Powders are gamma-irradiated at 17.5 kGy radiation unit at ambient temperature.
  • Frozen biomasses are gamma-irradiated at 25 kGy radiation unit in the presence of dry ice.
  • Table i Prevotella histicola Capsule Composition 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 10 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 11 Tablet Comprising Prevotella histicola
  • Table iii Prevotella histicola Tablet Composition [377]
  • 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 12 Preparation of a capsule comprising Veillonella parvula
  • Veillonella parvula has been deposited as Veillonella parvula Strain A (ATCC Deposit Number PTA- 125691).
  • 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 13 Preparation of a tablet comprising Veillonella parvula
  • the Veillonella parvula strain in Table v is Veillonella parvula Strain A
  • the tablet is enteric coated with Kollidon MAE 100P.
  • mice in the ‘post-immunization’ group were immunized by subcutaneous injection with KLH emulsified with Complete Freund’s Adjuvant.
  • PO Prevotella histicola Strain B powder per os
  • IP intraperitoneally
  • baseline ear thickness was measured using calipers, then mice were challenged by intradermal ear injection with KLH. After 24 hours, the change in ear thickness was evaluated and compared to baseline measurements.
  • mice in the ‘pre-immunization’ group were dosed for 4 or 8 days with lyophilized Prevotella histicola Strain B powder PO. All mice were then immunized by subcutaneous injection with KLH emulsified with Complete Freund’s Adjuvant. On day 8, baseline ear thickness was measured using calipers, then mice were challenged by intradermal ear injection with KLH. After 24 hours, the change in ear thickness was evaluated and compared to baseline measurements.
  • mice were immunized by subcutaneous injection with KLH emulsified with Complete Freund’s Adjuvant.
  • mice were dosed for 8 days with oral Prevotella histicola Strain B (1.82 mg or 10 mg dose; powder form) or dexamethasone (0.1 mg/kg or 0.4 mg/kg) given intraperitoneally.
  • mice were challenged by intradermal ear injection with KLH.
  • the DTH response was evaluated 24 hours post-challenge.
  • No Prevotella histicola Strain B or dexamethasone were administered during this time.
  • mice were challenged by intradermal ear injection with KLH.
  • the DTH response was evaluated 24 hours post-challenge.
  • FIGS. 26A and 26B The results are shown in FIGS. 26A and 26B.
  • dexamethasone efficacy decreased (71% inhibition at Day 8 challenge vs. 55% inhibition at Day 23 challenge) while the effect of Prevotella histicola Strain B on inflammation increased relative to vehicle (32% inhibition at Day 8 challenge vs 48% inhibition at Day 23 challenge for 10 mg dose; 22% inhibition at Day 8 challenge vs 32% inhibition at Day 23 challenge).

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Abstract

L'invention concerne des méthodes et des compositions associés à des bactéries anti-inflammatoires, telles que des bactériesPrevotella ou Veillonella parvula, pour une utilisation dans la résolution d'une inflammation chez un sujet.
PCT/US2021/048866 2020-09-03 2021-09-02 Compositions et méthodes de résolution d'inflammation Ceased WO2022051494A1 (fr)

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Citations (3)

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WO2019051381A1 (fr) * 2017-09-08 2019-03-14 Evelo Biosciences, Inc. Vésicules extracellulaires provenant de prevotella
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