COMPOSITIONS AND METHODS FOR TREATING OBESITY AND RELATED DISORDERS BY CHARACTERIZING AND RESTORING MAMMALIAN BACTERIAL MICROBIOTA

• US 20110280840A1
• Filed: 05/04/2011
• Published: 11/17/2011
• Est. Priority Date: 05/04/2010
• Status: Active Grant

• Current Assignee: New York University
• Original Assignee: New York University
• Inventors: Cho, IIseung, Nonodorf, Laura, Blaser, Martin J.
• Granted Patent: US 8,951,512 B2
• Time in Patent Office: Days
• US Class Current: 424/93.4
• CPC Class Codes: A23L 33/135 Bacteria or derivatives thereof, e.g. probiotics
• CPC Class Codes: A23L 33/21 Addition of substantially indigestible substances, e.g. dietary fibres
• CPC Class Codes: A23L 33/40 Complete food formulations for specific consumer groups or specific purposes, e.g. infant formula
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A23V 2200/306 having an effect on bone mass, e.g. osteoporosis prevention
• CPC Class Codes: A23V 2200/3262 having an effect on blood cholesterol
• CPC Class Codes: A23V 2200/328 having effect on glycaemic control and diabetes
• CPC Class Codes: A23V 2200/332 Promoters of weight control and weight loss
• CPC Class Codes: A61K 2035/11 Medicinal preparations comprising living procariotic cells
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 35/74 Bacteria therapeutic use of a bacterial protein A61K38/00
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin

Abstract

The present invention relates to characterizing changes in mammalian gastrointestinal microbiota associated with antibiotic treatment and various disease conditions (such as obesity, metabolic syndrome, insulin-deficiency or insulin-resistance related disorders, glucose intolerance, diabetes, non-alcoholic fatty liver, abnormal lipid metabolism, short stature, osteoporosis, and other disorders of bone formation and mineralization, etc.) and related diagnostic and therapeutic methods. Therapeutic methods of the invention involve the use of probiotics, prebiotics, or narrow spectrum antibiotics/anti-bacterial agents that are capable of restoring healthy mammalian bacterial gastrointestinal microbiota.

Claims

1. A method of treating a disease in a mammal comprising administering to the mammal a therapeutically effective amount of a probiotic composition comprising one or more bacterial strains, wherein the composition (i) stimulates growth or activity of one or more bacterial taxa which are under-represented in microbiota of the mammal as compared to a healthy control or (ii) inhibits growth or activity of one or more bacterial taxa which are over-represented in microbiota of the mammal as compared to a healthy control.

2. The method of claim 1, wherein the disease is selected from the group consisting of obesity, metabolic syndrome, insulin-deficiency, insulin-resistance related disorders, glucose intolerance, diabetes, non-alcoholic fatty liver, abnormal lipid metabolism, short stature, osteoporosis, and other disorders of bone formation and mineralization.

3. The method of claim 1, wherein the bacterial strain contained in the probiotic composition is a live bacterial strain.

4. The method of claim 1, wherein the bacterial strain contained in the probiotic composition is a conditionally lethal bacterial strain.

5. The method of claim 1, wherein the bacterial strain contained in the probiotic composition is an H. pylori strain.

6. The method of claim 1, wherein the probiotic composition further comprises a buffering agent selected from the group consisting of sodium bicarbonate, milk, yogurt, and infant formula.

7. The method of claim 1, wherein the healthy control is a healthy subject of the same age, gender and enterotype as the mammal being treated or an average of several such subjects.

8. The method of claim 1, wherein the mammal is human.

9. The method of claim 8, wherein the healthy control is a healthy human of the same age, gender and ethnicity as the human being treated or an average of several such healthy subjects.

10. The method of claim 1, wherein the microbiota is gastrointestinal microbiota.

11. The method of claim 1, wherein the probiotic composition is administered orally.

12. A method for treating a disease associated with antibiotic treatment in a mammal comprising (i) stimulating growth or activity of one or more bacterial taxa which have been depleted in microbiota of the mammal as a result of antibiotic treatment of the mammal or (ii) inhibiting growth or activity of one or more bacterial taxa which are over-represented in microbiota of the mammal as a result of antibiotic treatment of the mammal.

13. The method of claim 12, wherein the disease is selected from the group consisting of obesity, metabolic syndrome, insulin-deficiency, insulin-resistance related disorders, glucose intolerance, diabetes, non-alcoholic fatty liver, abnormal lipid metabolism, short stature, osteoporosis, and other disorders of bone formation and mineralization.

14. The method of claim 12, wherein the mammal is human.

15. The method of claim 12 comprising inhibiting growth or activity of one or more species of Lachnospiraceae.

16. The method of claim 12 comprising administering a therapeutically effective amount of a probiotic composition comprising one or more bacterial strains which have been depleted as a result of antibiotic treatment.

17. The method of claim 16, wherein the bacterial strain contained in the probiotic composition is a live bacterial strain.

18. The method of claim 16, wherein the bacterial strain contained in the probiotic composition is a conditionally lethal bacterial strain.

19. The method of claim 16, wherein the bacterial strain contained in the probiotic composition is an H. pylori strain.

20. The method of claim 16, wherein the probiotic composition further comprises a buffering agent selected from the group consisting of sodium bicarbonate, milk, yogurt, and infant formula.

21. The method of claim 16, wherein and the probiotic composition is administered orally.

54. The method of claim 12, wherein the microbiota is gastrointestinal microbiota.

22. A method for restoring at least one bacterial taxa depleted as a result of antibiotic treatment or disease in a mammal comprising:

a) identifying under-represented bacterial taxa in an antibiotic-treated or diseased microbiota sample from the mammal as compared to a healthy control;

b) culturing the identified under-represented bacteria from step a); and

c) administering the bacterial inoculant(s) from step b) to the mammal, wherein the inoculant(s) increases growth of the under-represented bacteria in the mammal.

23. The method of claim 22, wherein the microbiota is gastrointestinal microbiota.

24. The method of claim 22, wherein step a) involves screening bacterial 16S rRNA genes using PCR.

25. The method of claim 22, wherein step a) involves high-throughput sequencing or PCR methods which detect over- and under-represented genes in the total bacterial population.

26. The method of claim 22, wherein step a) involves transcriptomic or proteomic studies that identify lost or gained microbial transcripts or proteins within total bacterial populations.

27. The method of claim 22, wherein the disease is selected from the group consisting of obesity, metabolic syndrome, insulin-deficiency, insulin-resistance related disorders, glucose intolerance, diabetes, non-alcoholic fatty liver, abnormal lipid metabolism, short stature, osteoporosis, and other disorders of bone formation and mineralization.

28. The method of claim 22, wherein the bacterial inoculant(s) is administered orally.

29. The method of claim 22, wherein the bacterial inoculant(s) is administered together with a buffering agent selected from the group consisting of sodium bicarbonate, milk, yogurt, and infant formula.

30. The method of claim 22, wherein the healthy control is a microbiota sample from a healthy subject of the same age, gender and enterotype as the mammal being treated or an average of several such subjects.

31. The method of claim 22, wherein the mammal is human.

32. The method of claim 31, wherein the healthy control is a microbiota sample from a healthy human of the same age, gender and ethnicity as the human being treated or an average of several such healthy subjects.

33. A method of treating a disease in a mammal, wherein said disease is associated with a change in microbiota of the mammal as compared to a healthy control, comprising administering to the mammal a therapeutically effective amount of a narrow spectrum antibiotic or another anti-bacterial agent to inhibit growth or activity of one or more bacterial taxa which are over-represented in the microbiota of the mammal as compared to the healthy control.

34. The method of claim 33, wherein the disease is selected from the group consisting of obesity, metabolic syndrome, insulin-deficiency, insulin-resistance related disorders, glucose intolerance, diabetes, non-alcoholic fatty liver, abnormal lipid metabolism, short stature, osteoporosis, and other disorders of bone formation and mineralization.

35. The method of claim 33, wherein the microbiota is gastrointestinal microbiota.

36. The method of claim 33, comprising identifying over-represented bacterial taxa in the diseased microbiota sample from the mammal as compared to the healthy control.

37. The method of claim 36, wherein identifying over-represented bacterial taxa involves screening bacterial 16S rRNA genes using PCR.

38. The method of claim 36, wherein identifying over-represented bacterial taxa involves high-throughput sequencing or PCR methods.

39. The method of claim 36, wherein identifying over-represented bacterial taxa involves transciptomic or proteomic studies.

40. The method of claim 33, wherein the healthy control is a healthy subject of the same age, gender and enterotype as the mammal being treated or an average of several such subjects.

41. The method of claim 33, wherein the mammal is human.

42. The method of claim 41, wherein the healthy control is a healthy human of the same age, gender and ethnicity as the human being treated or an average of several such healthy subjects.

43. A method for increasing adult height or muscle mass in a mammal in need thereof comprising administering to the mammal a sub-therapeutic concentration of an antibiotic early in life.

44. The method of claim 43, wherein the mammal is human.

45. A method for increasing adult height or muscle mass in a mammal in need thereof comprising (i) stimulating growth or activity of one or more bacterial taxa which is over-represented in microbiota of the mammal as a result of treatment with a sub-therapeutic concentration of an antibiotic early in life or (ii) inhibiting growth or activity of one or more bacterial taxa which is depleted in microbiota of the mammal as a result of treatment with a sub-therapeutic concentration of an antibiotic early in life.

46. The method of claim 45, wherein the microbiota is gastrointestinal microbiota.

47. The method of claim 45, comprising identifying over-represented or depleted bacterial taxa in the microbiota from the mammal as compared to a healthy control.

48. The method of claim 45, wherein identifying over-represented or depleted bacterial taxa involves screening bacterial 16S rRNA genes using PCR.

49. The method of claim 45, wherein identifying over-represented or depleted bacterial taxa involves high-throughput sequencing or PCR methods.

50. The method of claim 45, wherein identifying over-represented or depleted bacterial taxa involves transciptomic or proteomic studies.

51. The method of claim 47, wherein the healthy control is a healthy subject of the same age, gender and enterotype as the mammal being treated or an average of several such subjects.

52. The method of claim 45, wherein the mammal is human.

53. The method of claim 52, wherein the healthy control is a healthy human of the same age, gender and ethnicity as the human being treated or an average of several such healthy subjects.