PROBIOTIC AND PREBIOTIC COMPOSITIONS, AND METHODS OF USE THEREOF FOR MODULATION OF THE MICROBIOME

• US 20160199424A1
• Filed: 11/25/2015
• Published: 07/14/2016
• Est. Priority Date: 11/25/2014
• Status: Active Grant

• Current Assignee: PharmaBiome AG
• Original Assignee: Epiva Biosciences, Inc. (Evelo Biosciences, Inc.)
• Inventors: Berry, David, Rahman, Shaila, Afeyan, Noubar B., Kaplan, Johanne
• Granted Patent: US 10,980,845 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2035/115 Probiotics
• CPC Class Codes: A61K 31/7004 Monosaccharides having only carbon, hydrogen and oxygen atoms
• CPC Class Codes: A61K 31/7016 Disaccharides, e.g. lactose, lactulose lactobionic acid A61K31/7032
• CPC Class Codes: A61K 31/715 Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
• CPC Class Codes: A61K 35/39 Pancreas; Islets of Langerhans Langerhans cells of epidermis A61K35/36
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61K 35/741 Probiotics probiotic yeast, e.g. saccharomyces A61K36/06
• CPC Class Codes: A61K 35/742 Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
• CPC Class Codes: A61K 35/744 Lactic acid bacteria, e.g. enterococci, pediococci, lactococci, streptococci or leuconostocs
• CPC Class Codes: A61K 35/745 Bifidobacteria
• CPC Class Codes: A61K 35/747 Lactobacilli, e.g. L. acidophilus or L. brevis
• CPC Class Codes: A61K 38/46 Hydrolases (3)
• CPC Class Codes: A61K 9/0031 Rectum, anus
• CPC Class Codes: A61K 9/0053 Mouth and digestive tract, i.e. intraoral and peroral administration rectal administration A61K9/0031
• CPC Class Codes: A61K 9/19 lyophilised , i.e. freeze-dried, solutions or dispersions lyophilised products with subsequent particle size reduction A61K9/14; granules or pellets made by lyphilisation A61K9/1682; solid oral dosage forms made by lyophilisation A61K9/2095; lyophilisation additives A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Probiotic compositions containing non-pathogenic microbial entities, e.g., bacterial entities, are described herein. The probiotic compositions may optionally contain or be used in conjunction with one or more prebiotics. Uses of the probiotic compositions to treat or prevent disorders of the local or systemic microbiome in a subject are also provided.

Claims

1. A method of reducing inflammation in a subject, comprising administering to the subject a probiotic composition comprising an isolated, anti-inflammatory bacterial population, such that inflammation in the subject is reduced.

2. The method of claim 1, wherein the probiotic composition comprises a pharmaceutically acceptable excipient.

3. The method of claim 1, wherein the subject has an autoimmune or inflammatory disorder.

4. The method of claim 3, wherein the autoimmune or inflammatory disorder is selected from the group consisting of graft-versus-host disease (GVHD), an inflammatory bowel disease (IBD), ulterative colitis, Crohn'"'"'s disease, multiple sclerosis (MS), systemic lupus erythematosus (SLE), type I diabetes, rheumatoid arthritis, Sjö

gren'"'"'s syndrome, and Celiac disease.

5. The method of claim 1, wherein administration of the probiotic composition reduces inflammation in the gastrointestinal tract of the subject.

6. The method of claim 1, wherein administration of the probiotic composition at a first site reduces inflammation at a distal site in the subject.

7. The method of claim 6, wherein the distal site is blood, skin, vagina, liver, spleen, fallopian tubes, uterus, or a combination thereof.

8. The method of claim 1, wherein the subject has a dysbiosis.

9. The method of claim 8, wherein the dysbiosis is a gastrointestinal dysbiosis.

10. The method of claim 8, wherein the dysbiosis is a distal dysbiosis.

11. The method of claim 1, wherein the anti-inflammatory bacterial population decreases secretion of pro-inflammatory cytokines and/or increases secretion of anti-inflammatory cytokines by human peripheral blood mononuclear cells (PBMCs).

12. The method of claim 11, wherein the anti-inflammatory bacterial population decreases secretion of a pro-inflammatory cytokine selected from the group consisting of IFNγ

, IL-12p70, IL-1α

, IL-6, IL-8, MCP1, MIP1α

, MIP1β

, TNFα

, and combinations thereof.

13. The method of claim 11, wherein the anti-inflammatory bacterial population increases secretion of an anti-inflammatory cytokine selected from the group consisting of IL-10, IL-13, IL-4, IL-5, TGFβ

, and combinations thereof.

14. The method of claim 1, wherein the anti-inflammatory bacterial population comprises one or more bacterial species of the order Clostridiales.

15. The method of claim 14, wherein the bacterial species is from the genus Blautia, Clostridium, or Ruminococcus.

16. The method of claim 14, wherein the bacterial population comprises a single bacterial species set forth in Table 1.

17. The method of claim 14, wherein the bacterial population comprises two or more bacterial species set forth in Table 1.

18. The method of claim 14, wherein the bacterial population comprises a single bacterial species set forth in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, or Table 1F.

19. The method of claim 14, wherein the bacterial population comprises two or more bacterial species set forth in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, or Table 1F.

20. The method of claim 1, wherein the level of the anti-inflammatory bacteria is augmented in the gastrointestinal tract of the subject.

21. The method of claim 20, wherein the anti-inflammatory bacteria engraft in the gastrointestinal tract of the subject.

22. The method of claim 1, wherein the level of the anti-inflammatory bacteria is augmented at a site distal to the site of administration in the subject.

23. The method of claim 22, wherein the anti-inflammatory bacteria is not detectably present at the site distal to the gastrointestinal tract of the subject prior to administration of the probiotic composition.

24. The method of claim 22, wherein the anti-inflammatory bacteria translocate to a distal site within the subject.

25. The method of claim 22, wherein the site distal to the gastrointestinal tract is the blood, skin, vagina, liver, spleen, fallopian tubes, uterus, or a combination thereof.

26. The method of claim 1, wherein the level of a bacterial species not present in the probiotic composition is augmented in the gastrointestinal tract of the subject.

27. The method of claim 1, wherein the level of a bacterial species not present in the probiotic composition is augmented at a site distal to the gastrointestinal tract of the subject.

28. The method of claim 27, wherein the site distal to the gastrointestinal tract is the blood, skin, vagina, liver, spleen, fallopian tubes, uterus, or a combination thereof.

29. The method of claim 1, further comprising administering a prebiotic to the subject.

30. The method of claim 29, wherein the prebiotic augments the growth of the anti-inflammatory bacterial population present in the probiotic composition.

31. The method of claim 29, wherein the prebiotic comprises a monomer or polymer selected from the group consisting of arabinoxylan, xylose, soluble fiber dextran, soluble corn fiber, polydextrose, lactose, N-acetyl-lactosamine, glucose, and combinations thereof.

32. The method of claim 29, wherein the prebiotic comprises a monomer or polymer selected from the group consisting of galactose, fructose, rhamnose, mannose, uronic acids, 3′

-fucosyllactose, 3′

sialylactose, 6′

-sialyllactose, lacto-N-neotetraose, 2′

-2′

-fucosyllactose, and combinations thereof.

33. The method of claim 29, wherein the prebiotic comprises a monosaccharide selected from the group consisting of arabinose, fructose, fucose, lactose, galactose, glucose, mannose, D-xylose, xylitol, ribose, and combinations thereof.

34. The method of claim 29, wherein the prebiotic comprises a disaccharide selected from the group consisting of xylobiose, sucrose, maltose, lactose, lactulose, trehalose, cellobiose, and combinations thereof.

35. The method of claim 29, wherein the prebiotic comprises a polysaccharide, wherein the polysaccharide is xylooligosaccharide.

36. (canceled)

37. A method of treating a distal dysbiosis in a subject, comprising administering to the subject a probiotic composition comprising an isolated bacterial population in an amount sufficient to alter the microbiome at a site distal to the site of administration, engraftment, or colonization, such that the distal dysbiosis is treated.

38. The method of claim 37, wherein the probiotic composition comprises a species of bacteria that is deficient at the site of the distal dysbiosis.

39. The method of claim 37, wherein a species of bacteria present in the probiotic composition is augmented at the site of the distal dysbiosis.

40. The method of claim 39, wherein the species of bacteria augmented at the site of the distal dysbiosis is not detectably present at the site of the distal dysbiosis prior to administration of the probiotic composition.

41. The method of claim 39, wherein the species of bacteria translocates to the site of the distal dysbiosis.

42. The method of claim 37, wherein a species of bacteria not present in the probiotic composition is augmented at the site of the distal dysbiosis.

43. The method of claim 37, wherein the site of the distal dysbiosis is the blood, skin, vagina, liver, spleen, fallopian tubes, uterus, or a combination thereof.

51. The method of claim 37, wherein the distal dysbiosis is associated with an autoimmune or inflammatory disorder in the subject.

54. The method of claim 37, wherein the subject is a subject receiving a transplant.

62. The method of claim 37, further comprising administering a prebiotic to the subject.

44-50. -50. (canceled)

52-53. -53. (canceled)

55-61. -61. (canceled)

63-69. -69. (canceled)

70. A method of reducing intestinal permeability in a subject, comprising administering to the subject a probiotic composition comprising an isolated bacterial population, wherein administration of the probiotic composition augments a species of bacteria that produces short chain fatty acids, mucin, or a combination thereof, such that the intestinal permeability of the subject is reduced.

80. The method of claim 70, further comprising administering a prebiotic to the subject.

71-79. -79. (canceled)

81-120. -120. (canceled)

121. A pharmaceutical composition comprising an isolated anti-inflammatory bacterial population capable of decreasing secretion of pro-inflammatory cytokines and/or increasing secretion of anti-inflammatory cytokines by human peripheral blood mononuclear cells (PBMCs), and a pharmaceutically acceptable excipient.

122. The pharmaceutical composition of claim 121, wherein the bacterial population comprises one or more bacterial species of the order Clostridiales.

123. The pharmaceutical composition of claim 121, wherein the bacterial population comprises a single bacterial species set forth in Table 1.

124. The pharmaceutical composition of claim 121, wherein the bacterial population comprises two or more bacterial species set forth in Table 1.

125. The pharmaceutical composition of claim 121, wherein the bacterial population comprises a single bacterial species set forth in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, or Table 1F.

126. The pharmaceutical composition of claim 121, wherein the bacterial population comprises two or more bacterial species set forth in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, or Table 1F.

127. The pharmaceutical composition of claim 121, further comprising a prebiotic.

128-133. -133. (canceled)