PROBIOTIC RECOLONISATION THERAPY

Abstract

The present invention relates to pharmaceutical compositions suitable for the treatment of chronic diseases associated with the presence of abnormal or an abnormal distribution of microflora in the gastrointestinal tract of a mammalian host, which compositions comprise viable non-pathogenic or attenuated pathogenic Clostridia. The compositions further comprise one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, E. coli, Gemmiger, Desulfomonas, Peptostreptococcus, and fungi. The present invention also provides pharmaceutical compositions suitable for the treatment of the same chronic diseases comprising viable non-pathogenic or attenuated pathogenic Escherichia coli, at least one strain of viable non-pathogenic or attenuated pathogenic Bacteroides and at least one strain of viable non-pathogenic or attenuated pathogenic microorganism.

Claims

1. A pharmaceutical composition useful for the treatment and/or prophylaxis of chronic disorders associated with the presence in the gastrointestinal tract of a mammalian host of abnormal or an abnormal distribution of microflora, which composition comprises viable non-pathogenic or attenuated pathogenic Clostridia.

2. A composition according to claim 1, wherein the Clostridia is selected from the group consisting of Clostridium absonum, Clostridium argentinense, Clostridium baratii, Clostridium bifermentans, Clostridium botulinum, Clostridium butyricum, Clostridium cadaveris, Clostridium carnis, Clostridium celatum, Clostridium chauvoei, Clostridium clostridioforme, Clostridium cochlearium, Clostridium difficile, Clostridium fallax, Clostridium felsineum, Clostridium ghonii, Clostridium glycolicum, Clostridium haemolyticum, Clostridium hastiforme, Clostridium histolyticum, Clostridium indolis, Clostridium innocuum, Clostridium irregulare, Clostridium limosum, Clostridium malenominatum, Clostridium novyi, Clostridium oroticum, Clostridium paraputrificum, Clostridium perfringens, Clostridium piliforme, Clostridium putrefaciens, Clostridium putrificum, Clostridium ramosum, Clostridium sardiniense, Clostridium sartagoforme, Clostridium scindens, Clostridium septicum, Clostridium sordellii, Clostridium sphenoides, Clostridium spiroforme, Clostridium sporogenes, Clostridium subterminale, Clostridium symbiosum, Clostridium tertium, Clostridium tetani, Clostridium welchii, Clostridium villosum.

3. A composition according to either claim 1 or claim 2, wherein the composition further comprises at least one strain of viable non-pathogenic or attenuated pathogenic Bacteroides.

4. A composition according to claim 3, wherein said Bacteroides is selected from the group consisting of Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides fragilis-ryhm, Bacteroides gracilis, Bacteroides levii, Bacteroides macacae, Bacteroides merdae, Bacteroides ovatus, Bacteroides pneumosintes, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides splanchnicus, Bacteroides stercoris, Bacteroides tectum, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgatus.

5. A composition according to any one of claims 1 to 3, wherein the composition further comprises one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas, Peptostreptococcus, species.

6. A composition according to claim 5, wherein the one or more additional viable non-pathogenic or attenuated pathogenic microorganisms are Bacteroides fragilis ss. Vulgatus, Eubacterium aerofaciens, Bacteroides fragilis ss. Thetaiotaomicron, Peptostreptococcus productus II, Bacteroides fragilis ss. Distasonis, Fusobacterium prausnitzii, Coprococcus eutactus, Eubacterium aerofaciens III, Peptostreptococcus productus I, Ruminococcus bronii, Bifidobacterium adolescentis, Gemmiger formicilis, Bifidobacterium longum, Eubacterium siraeum, Ruminococcus torques, Eubacterium rectale III-H, Eubacterium rectale IV, Eubacterium eligens, Bacteroides eggerthii, Clostridium leptum, Bacteroides fragilis ss. A, Eubacterium biforme, Bifidobacterium infantis, Eubacterium rectale III-F, Coprococcus comes, Bacteroides capillosus, Ruminococcus albus, Eubacterium formicigenerans, Eubacterium haffii, Eubacterium ventriosum I, Fusobacterium russii, Ruminococcus obeum, Eubacterium rectale II, Clostridium ramosum I, Lactobacillus leichmanii, Ruminococcus cailidus, Butyrivibrio crossotus, Acidaminococcus fermentans, Eubacterium ventriosum, Bacteroides fragilis ss. fragilis, Bacteroides AR, Coprococcus catus, Eubacterium hadrum, Eubacterium cylindroides, Eubacterium ruminantium, Eubacterium CH-1, Staphylococcus epidermidis, Peptostreptococcus BL, Eubacterium limosum, Bacteroides praeacutus, Bacteroides L, Fusobacterium mortiferum I, Fusobacterium naviforme, Clostridium innocuum, Clostridium ramosum, Propionibacterium acnes, Ruminococcus flavefaciens, Ruminococcus AT, Peptococcus AU-1, Eubacterium AG, -AK, -AL, -AL-1, -AN; Bacteroides fragilis ss. ovatus, -ss. d, -ss. f; Bacteroides L-1, L-5; Fusobacterium nucleatum, Fusobacterium mortiferum, Escherichia coli, Streptococcus morbillorum, Peptococcus magnus, Peptococcus G, -AU-2; Streptococcus intermedius, Ruminococcus lactaris, Ruminococcus CO Gemmiger X, Coprococcus BH, CC; Eubacterium tenue, Eubacterium ramulus, Eubacterium AE, -AG-H, -AG-M, -AJ, -BN-1; Bacteroides clostridiiformis ss. clostridliformis, Bacteroides coagulans, Bacteroides orails, Bacteroides ruminicola ss. brevis, -ss. ruminicola, Bacteroides splanchnicus, Desuifomonas pigra, Bacteroides L-4, -N-i; Fusobacterium H, Lactobacillus G, or Succinivibrio A.

7. A composition according to any one of claims 1 to 6, wherein the composition further comprises fungi.

8. A composition according to claim 7, wherein the fungi are Monilia.

9. A composition according to any one of claims 1 to 8, wherein the composition further comprises at least one strain of viable non-pathogenic or attenuated pathogenic Bifidobacterium.

10. A pharmaceutical composition useful for the treatment and/or prophylaxis of chronic disorders associated with the presence in the gastrointestinal tract of a mammalian host of abnormal or an abnormal distribution of microflora, which composition comprises viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Clostridia, Bacteroides, Peptostreptococcus, Escherichia coli, Bifidobacterium, and Lactobacillus.

11. A composition according to claim 10, wherein the composition further comprises one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas, Peptostreptococcus, species.

12. A pharmaceutical composition useful for the treatment and/or prophylaxis of chronic disorders associated with the presence in the gastrointestinal tract of a mammalian host of abnormal or an abnormal distribution of microflora, which composition comprises viable non-pathogenic or attenuated pathogenic Escherichia coli, at least one strain of viable non-pathogenic or attenuated pathogenic Bacteroides and at least one other viable non-pathogenic or attenuated pathogenic microorganism.

13. A composition according to claim 10, wherein the Bacteroides is selected form the group consisting of Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides fragilis-ryhm, Bacteroides gracilis, Bacteroides levii, Bacteroides macacae, Bacteroides merdae, Bacteroides ovatus, Bacteroides pneumosintes, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides splanchnicus, Bacteroides stercoris, Bacteroides tectum, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgatus.

14. A composition according to claim 12 or claim 13, wherein the composition further comprises one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas, Peptostreptococcus, species.

15. A composition according to any one of claims 12 to 14, wherein the other viable non-pathogenic or attenuated pathogenic microorganism is selected from the group consisting of Clostridia, Peptostreptococcus, Bifidobacterium, and Lactobacillus.

16. A composition according to any one of claims 1 to 15, further comprising an acid suppressant.

17. A composition according to any one of claims 1 to 16, further comprising an antacid.

18. A composition according to any one of claims 1 to 17, further comprising an H2 antagonist.

19. A composition according to any one of claims 1 to 18, further comprising a proton pump inhibitor.

20. A composition according to any one of claims 1 to 19, wherein said microorganisms are spores.

21. A composition according to any one of claims 1 to 19, wherein the composition is lyophilised, pulverised and powdered.

22. A composition according to any one of claims 1 to 19, wherein the composition is a liquid culture.

23. A composition according to any one of claims 1 to 22, in the form of an enteric coated capsule, an enteric coated microcapsule, or a powder suitable for reconstitution.

24. A composition according to any one of claims 1 to 23, presented in the form of an enema.

25. A composition according to any one of claims 1 to 23, in the form of a food additive.

26. A composition according to claim 25, wherein said food is a dairy-based product, a soy-based product, or a derivative thereof.

27. A composition according to either claim 25 or claim 26, wherein said food is yogurt.

28. A food or food supplement containing a composition according to any one of claims 1 to 23.

29. A method for the treatment and/or prophylaxis of a chronic disorder associated with the presence in the gastrointestinal tract of a mammalian host of abnormal or an abnormal distribution of microflora, which method comprises administering an effective amount of a composition comprising viable non-pathogenic or attenuated pathogenic Clostridia for a period of time sufficient to displace the existing microflora.

30. The method of claim 29, wherein the Clostridia is selected from the group consisting of Clostridium absonum, Clostridium argentinense, Clostridium baratii, Clostridium bifermentans, Clostridium botulinum, Clostridium butyricum, Clostridium cadaveris, Clostridium carnis, Clostridium celatum, Clostridium chauvoei, Clostridium clostridioforme, Clostridium cochlearium, Clostridium difficile, Clostridium fallax, Clostridium felsineum, Clostridium ghonii, Clostridium glycolicum, Clostridium haemolyticum, Clostridium hastiforme, Clostridium histolyticum, Clostridium indolis, Clostridium innocuum, Clostridium irregulare, Clostridium limosum, Clostridium malenominatum, Clostridium novyi, Clostridium oroticum, Clostridium paraputrificum, Clostridium perfringens, Clostridium piliforme, Clostridium putrefaciens, Clostridium putrificum, Clostridium ramosum, Clostridium sardiniense, Clostridium sartagoforme, Clostridium scindens, Clostridium septicum, Clostridium sordellii, Clostridium sphenoides, Clostridium spiroforme, Clostridium sporogenes, Clostridium subterminale, Clostridium symbiosum, Clostridium tertium, Clostridium tetani, Clostridium welchii, Clostridium villosum.

31. The method of either claim 29 or claim 30, further comprising administering at least one strain of viable non-pathogenic or attenuated pathogenic Bacteroides.

32. The method of claim 31, wherein said Bacteroides is selected from the group consisting of Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides fragilis-ryhm, Bacteroides gracilis, Bacteroides levii, Bacteroides macacae, Bacteroides merdae, Bacteroides ovatus, Bacteroides pneumosintes, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides splanchnicus, Bacteroides stercoris, Bacteroides tectum, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgatus.

33. A method according to any one of claims 29 to 32, further comprising administering one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas, Peptostreptococcus, species.

34. A method according to claim 33 wherein the one or more additional viable non-pathogenic or attenuated pathogenic microorganisms are Bacteroides fragilis ss. Vulgatus, Eubacterium aerofaciens, Bacteroides fragilis ss. Thetaiotaomicron, Peptostreptococcus productus II, Bacteroides fragilis ss. Distasonis, Fusobacterium prausnitzii, Coprococcus eutactus, Eubacterium aerofaciens III, Peptostreptococcus productus I, Ruminococcus bronii, Bifidobacterium adolescentis, Gemmiger formicilis, Bifidobacterium longum, Eubacterium siraeum, Ruminococcus torques, Eubacterium rectale III-H, Eubacterium rectale IV, Eubacterium eligens, Bacteroides eggerthii, Clostridium leptum, Bacteroides fragilis ss. A, Eubacterium biforme, Bifidobacterium infantis, Eubacterium rectale III-F, Coprococcus comes, Bacteroides capillosus, Ruminococcus albus, Eubacterium formicigenerans, Eubacterium hallii, Eubacterium ventriosum I, Fusobacterium russii, Ruminococcus obeum, Eubacterium rectale II, Clostridium ramosum I, Lactobacillus leichmanii, Ruminococcus cailidus, Butyrivibrio crossotus, Acidaminococcus fermentans, Eubacterium ventriosum, Bacteroides fragilis ss. fragilis, Bacteroides AR, Coprococcus catus, Eubacterium hadrum, Eubacterium cylindroides, Eubacterium ruminantium, Eubacterium CH-1, Staphylococcus epidermidis, Peptostreptococcus BL, Eubacterium limosum, Bacteroides praeacutus, Bacteroides L, Fusobacterium mortiferum I, Fusobacterium naviforme, Clostridium innocuum, Clostridium ramosum, Propionibacterium acnes, Ruminococcus flavefaciens, Ruminococcus AT, Peptococcus AU-1, Eubacterium AG, -AK, -AL, -AL-1, -AN; Bacteroides fragilis ss. ovatus, -ss. d, -ss. f; Bacteroides L-1, L-5; Fusobacterium nucleatum, Fusobacterium mortiferum, Escherichia coli, Streptococcus morbiliorum, Peptococcus magnus, Peptococcus G, -AU-2; Streptococcus intermedius, Ruminococcus lactaris, Ruminococcus CO Gemmiger X, Coprococcus BH, CC; Eubacterium tenue, Eubacterium ramulus, Eubacterium AE, -AG-H, -AG-M, -AJ, -BN-1; Bacteroides clostridiiformis ss. clostridliformis, Bacteroides coagulans, Bacteroides orails, Bacteroides rumlnicola ss. brevis, -ss. ruminicola, Bacteroides splanchnlcus, Desuifomonas pigra, Bacteroides L-4, -N-i; Fusobacterium H, Lactobacillus G, or Succinivibrio A.

35. A method according to any one of claims 29 to 34, further comprising administering fungi.

36. A method according to claim 35, wherein the fungi are Monilia.

37. The method according to any one of claims 29 to 36, further comprising administering at least one strain of viable non-pathogenic or attenuated pathogenic Bifidobacterium.

38. A method for the treatment and/or prophylaxis of a chronic disorder associated with the presence in the gastrointestinal tract of a mammalian host of abnormal or an abnormal distribution of microflora, which method comprises administering an effective amount of a composition comprising viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Clostridia, Bacteroides, Peptostreptococcus, Escherichia coli, Bifidobacterium, and Lactobacillus for a period of time sufficient to displace the existing microflora.

39. A method according to claim 38, further comprising administering one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas, Peptostreptococcus, species.

40. A method for the treatment and/or prophylaxis of a chronic disorder associated with the presence in the gastrointestinal tract of a mammalian host of abnormal or an abnormal distribution of microflora, which method comprises administering an effective amount of a composition comprising viable non-pathogenic or attenuated pathogenic Escherichia coli, at least one strain of viable non-pathogenic or attenuated pathogenic Bacteroides and at least one other viable non-pathogenic or attenuated pathogenic microorganism for a period of time sufficient to displace the existing microflora.

41. The method of claim 40, wherein the Bacteroides is selected form the group consisting of Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides. fragilis, Bacteroides fragilis-ryhm, Bacteroides gracilis, Bacteroides levii, Bacteroides macacae, Bacteroides merdae, Bacteroides ovatus, Bacteroides pneumosintes, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides splanchnicus, Bacteroides stercoris, Bacteroides tectum, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgatus.

42. A method according to claim 41, further comprising administering one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas, Peptostreptococcus, species.

43. The method according to any one of claims 40 to 42, wherein the other viable non-pathogenic or attenuated pathogenic microorganism is selected from the group consisting of Clostridia, Peptostreptococcus, Bifidobacterium, and Lactobacillus.

44. A method according to any one of claims 29 to 43, further comprising administering an acid suppressant.

45. A method according to any one of claims 29 to 44, further comprising administering an antacid.

46. A method according to any one of claims 29 to 45, further comprising administering an H2 antagonist.

47. A method according to any one of claims 29 to 46, further comprising administering a proton pump inhibitor.

48. The method according to any one of claims 29 to 47, wherein said microorganisms are spores.

49. The method according to any one of claims 29 to 47, wherein the composition is lyophilised, pulverised and powdered.

50. The method according to any one of claims 29 to 47, wherein the composition is a liquid culture.

51. The method according to any one of claims 29 to 50, wherein the composition is administered in the form of an enteric coated capsule, an enteric coated microcapsule, or a reconstituted powder.

52. A method according to any one of claims 29 to 51, wherein the composition is administered in the form of an enema.

53. The method according to any one of claims 29 to 51, wherein the composition is administered in the form of a food or drink.

54. The method according to claim 53, wherein said food is a dairy-based product, a soy-based product, or a derivative thereof.

55. The method according to either claim 53 or claim 54, wherein said food is yogurt.

56. The method according to any one of claims 29 to 55, wherein the period of time sufficient to displace the existing microflora is several days to several weeks.

57. The method according to any one of claims 29 to 56, wherein the mammalian host is human.

58. The method according to any one of claims 29 to 57, further comprising administration of an effective amount of at least one antibiotic prior to administering said composition.

59. The method according to claim 58, wherein said antibiotic is an anti-Clostridial antibiotic.

60. The method according to claim 59, wherein said anti-Clostridial antibiotic is selected from the group consisting of vancomycin, rifampicin, and nitroimidazole.

61. The method according to any one of claims 29 to 60, further comprising nasogastric and/or nasoduodenal washout prior to administering said composition.

62. The method according to any one of claims 29 to 60, wherein the composition is administered by ingestion or by parenteral infusion.

63. The method according to any one of claims 29 to 60, wherein administration is by enema, per-colonoscope, by intubation of the small bowel or orally.

64. The method according to any one of claims 29 to 63, wherein the chronic disorder is a gastrointestinal disorder, a rheumatic disorder, an immune mediated disorder, an auto-immune disorder, a neurological disorder, a regressive disorder, a liver disorder, a psychiatric disorder or a dermatological condition.

65. The method of claim 64, wherein said gastrointestinal disorder is irritable bowel syndrome or spastic colon.

66. The method of claim 64, wherein said gastrointestinal disorder is functional bowel disease (FBD), inflammatory bowel disease, chronic gut infection, or a viral gastrointestinal disorder.

67. The method of claim 66, wherein said functional bowel disease is constipation predominant FBD, pain predominant FBD, upper abdominal FBD (non ulcer dyspepsia), or gastro oesophageal reflux.

68. The method of claim 66, wherein said inflammatory bowel disease is Crohn's disease, ulcerative colitis, indeterminate colitis, collagenous colitis, microscopic colitis, chronic Clostridium difficile infection, pseudomembranous colitis, mucous colitis, antibiotic associated colitis, idiopathic or simple constipation, diverticular disease, AIDS enteropathy, small bowel bacterial overgrowth, coeliac disease, polyposis coli, colonic polyps, or chronic idiopathic pseudo obstructive syndrome.

69. The method of claim 66, wherein said chronic gut infection is a bacterial, viral, fungal or protozoal infection.

70. The method of claim 66, wherein said viral gastrointestinal disorder is viral gastroenteritis, Norwalk viral gastroenteritis, rotavirus gastroenteritis, AIDS related gastroenteritis.

71. The method of claim 64, wherein said rheumatic disorder is rheumatoid arthritis, non-rheumatoid arthritidies, non rheumatoid factor positive arthritis, ankylosing spondylitis, Reiter's syndrome, or Lyme Disease.

72. The method of claim 64, wherein said immune mediated disorder is glomerulonephritis, haemolytic uraemic syndrome, juvenile diabetes mellitus, mixed cryoglobulinaemia, polyarteritis, familial Mediterranean fever, amyloidosis, scleroderma, systemic lupus erythematosus, or Behcets syndrome.

73. The method of claim 64, wherein said auto-immune disorder is systemic Lupus, idiopathic thrombocytopenic purpura, Sjogren's syndrome, haemolytic uraemic syndrome, or scleroderma.

74. The method of claim 64, wherein said neurological disorder is chronic fatigue syndrome, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Guillain Barre syndrome, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), migraine or myasthenia gravis.

75. The method of claim 64, wherein said regressive disorder is Aspergers syndrome, Rett syndrome, attention deficit hyperactivity disorder (ADHD) or attention deficit disorder (ADD).

76. The method of claim 64, wherein said regressive disorder is autism.

77. The method of claim 64, wherein said disorder is sudden infant death syndrome (SIDS) or anorexia nervosa.

78. The method of claim 64, wherein said liver disorder is primary biliary cirrhosis, primary sclerosing cholangitis, fatty liver or cryptogenic cirrhosis.

79. The method of claim 64, wherein said psychiatric disorder is chronic depression, schizophrenia/psychotic disorders, or manic depressive illness.

80. The method of claim 64, wherein said dermatological condition is chronic urticaria, acne, dermatitis herpetiformis or a vasculitic disorder.

81. The method according to any one of claims 29 to 80, wherein each dose is at least about 10.sup.3 cells.

82. The method according to any one of claims 29 to 80, wherein each dose is in the range of about 10.sup.3 cells to about 10.sup.13 cells.

83. The method according to any one of claims 29 to 80, wherein each dose is in the range of about 10.sup.5 cells to about 10.sup.11 cells.

84. The method according to any one of claims 29 to 80, wherein each dose is in the range of about 10.sup.7 cells to about 10.sup.9 cells.

85. The method according to any one of claims 29 to 84, further comprising an initial treatment regimen of about 10.sup.10 cells per dose administered 3 to 6 times per day for a period sufficient to stabilise the gut flora.

86. The method according to claim 85, wherein the period sufficient to stabilise the gut flora is about 7 to about 10 days.

87. A method for the treatment and/or prophylaxis of a chronic disorder associated with the presence in the gastrointestinal tract of a mammalian host of abnormal or an abnormal distribution of microflora, which method comprises administering an effective amount of a composition according to any one of claims 1 to 28 for a period of time sufficient to displace the existing microflora.

88. A method according to claim 87, further comprising administering an acid suppressant.

89. A method according to claim 87 or claim 88, further comprising administering an antacid.

90. A method according to any one of claims 87 to 89, further comprising administering an H2 antagonist.

91. A method according to any one of claims 87 to 90, further comprising administering a proton pump inhibitor.

92. The method according to any one of claims 87 to 91, wherein said microorganisms are spores.

93. The method according to any one of claims 87 to 91, wherein the composition is lyophilised, pulverised and powdered.

94. The method according to any one of claims 87 to 91, wherein the composition is a liquid culture.

95. The method according to any one of claims 87 to 94, wherein the composition is administered in the form of an enteric coated capsule, an enteric coated microcapsule, or a reconstituted powder.

96. A method according to any one of claims 87 to 95, wherein the composition is administered in the form of an enema.

97. The method according to any one of claims 87 to 95, wherein the composition is administered in the form of a food or drink.

98. The method according to claim 97, wherein said food is a dairy-based product, a soy-based product, or a derivative thereof.

99. The method according to either claim 97 or claim 98, wherein said food is yogurt.

100. The method according to any one of claims 87 to 99, wherein the period of time sufficient to displace the existing microflora is several days to several weeks.

101. The method according to any one of claims 87 to 100, wherein the mammalian host is human.

102. The method according to any one of claims 87 to 101, further comprising administration of an effective amount of at least one antibiotic prior to administering said composition.

103. The method according to claim 102, wherein said antibiotic is an anti-Clostridial antibiotic.

104. The method according to claim 103, wherein said anti-Clostridial antibiotic is selected from the group consisting of vancomycin, rifampicin, and nitroimidazole.

105. The method according to any one of claims 87 to 104, further comprising nasogastric and/or nasoduodenal washout prior to administering said composition.

106. The method according to any one of claims 87 to 104, wherein the composition is administered by ingestion or by parenteral infusion.

107. The method according to any one of claims 87 to 104, wherein administration is by enema, per-colonoscope, by intubation of the small bowel or orally.

108. The method according to any one of claims 87 to 107, wherein the chronic disorder is a gastrointestinal disorder, a rheumatic disorder, an immune mediated disorder, an auto-immune disorder, a neurological disorder, a regressive disorder, a liver disorder, a psychiatric disorder or a dermatological condition.

109. The method of claim 108, wherein said gastrointestinal disorder is irritable bowel syndrome or spastic colon.

110. The method of claim 108, wherein said gastrointestinal disorder is functional bowel disease (FBD), inflammatory bowel disease, chronic gut infection, or a viral gastrointestinal disorder.

111. The method of claim 110, wherein said functional bowel disease is constipation predominant FBD, pain predominant FBD, upper abdominal FBD, non ulcer dyspepsia, or gastro oesophageal reflux.

112. The method of claim 110, wherein said inflammatory bowel disease is Crohn's disease, ulcerative colitis, indeterminate colitis, collagenous colitis, microscopic colitis, chronic Clostridium difficile infection, pseudomembranous colitis, mucous colitis, antibiotic associated colitis, idiopathic or simple constipation, diverticular disease, AIDS enteropathy, small bowel bacterial overgrowth, coeliac disease, polyposis coli, colonic polyps, or chronic idiopathic pseudo obstructive syndrome.

113. The method of claim 110, wherein said chronic gut infection is a bacterial, viral, fungal or protozoal infection.

114. The method of claim 110, wherein said viral gastrointestinal disorder is viral gastroenteritis, Norwalk viral gastroenteritis, rotavirus gastroenteritis, AIDS related gastroenteritis.

115. The method of claim 108, wherein said rheumatic disorder is rheumatoid arthritis, non-rheumatoid arthritidies, non rheumatoid factor positive arthritis, ankylosing spondylitis, Reiter's syndrome, or Lyme Disease.

116. The method of claim 108, wherein said immune mediated disorder is glomerulonephritis, haemolytic uraemic syndrome, juvenile diabetes mellitus, mixed cryoglobulinaemia, polyarteritis, familial Mediterranean fever, amyloidosis, scleroderma, systemic lupus erythematosus, or Behcets syndrome.

117. The method of claim 108, wherein said auto-immune disorder is systemic Lupus, idiopathic thrombocytopenic purpura, Sjogren's syndrome, haemolytic uraemic syndrome, or scleroderma.

118. The method of claim 108, wherein said neurological disorder is chronic fatigue syndrome, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Guillain Barre syndrome, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), migraine or myasthenia gravis.

119. The method of claim 108, wherein said regressive disorder is Aspergers syndrome, Rett syndrome, attention deficit hyperactivity disorder (ADHD) or attention deficit disorder (ADD).

120. The method of claim 108, wherein said regressive disorder is autism.

121. The method of claim 108, wherein said disorder is sudden infant death syndrome (SIDS), anorexia nervosa.

122. The method of claim 108, wherein said liver disorder is primary biliary cirrhosis, primary sclerosing cholangitis, fatty liver or cryptogenic cirrhosis.

123. The method of claim 108, wherein said psychiatric disorder is chronic depression, schizophrenia/psychotic disorders, or manic depressive illness.

124. The method of claim 108, wherein said dermatological condition is chronic urticaria, acne, dermatitis herpetiformis or a vasculitic disorder.

125. The method according to any one of claims 87 to 124, wherein each dose is at least about 10.sup.3 cells.

126. The method according to any one of claims 87 to 124, wherein each dose is in the range of about 10.sup.3 cells to about 10.sup.13 cells.

127. The method according to any one of claims 87 to 124, wherein each dose is in the range of about 10.sup.5 cells to about 10 cells.

128. The method according to any one of claims 87 to 124, wherein each dose is in the range of about 10.sup.7 cells to about 10.sup.9 cells.

129. The method according to any one of claims 87 to 128, further comprising an initial treatment regimen of about 10.sup.10 cells per dose administered 3 to 6 times per day for a period sufficient to stabilise the gut flora.

130. The method according to claim 129, wherein the period sufficient to stabilise the gut flora is about 7 to about 10 days.

131. Use of viable non-pathogenic or attenuated pathogenic Clostridia for the manufacture of a medicament for the treatment and/or prophylaxis of a chronic disorder associated with the presence in the gastrointestinal tract of a mammalian host of abnormal or an abnormal distribution of microflora.

132. The use of claim 131, wherein the Clostridia is selected from the group consisting of Clostridium absonum, Clostridium argentinense, Clostridium baratii, Clostridium bifermentans, Clostridium botulinum, Clostridium butyricum, Clostridium cadaveris, Clostridium carnis, Clostridium celatum, Clostridium chauvoei, Clostridium clostridioforme, Clostridium cochlearium, Clostridium difficile, Clostridium fallax, Clostridium felsineum, Clostridium ghonii, Clostridium glycolicum, Clostridium haemolyticum, Clostridium hastiforme, Clostridium histolyticum, Clostridium indolis, Clostridium innocuum, Clostridium irregulare, Clostridium limosum, Clostridium malenominatum, Clostridium novyi, Clostridium oroticum, Clostridium paraputrificum, Clostridium perfringens, Clostridium piliforme, Clostridium putrefaciens, Clostridium putrificum, Clostridium ramosum, Clostridium sardiniense, Clostridium sartagoforme, Clostridium scindens, Clostridium septicum, Clostridium sordeffii, Clostridium sphenoides, Clostridium spiroforme, Clostridium sporogenes, Clostridium subterminale, Clostridium symbiosum, Clostridium tedium, Clostridium tetani, Clostridium welchii, Clostridium villosum.

133. The use of either claim 131 or claim 132, further comprising at least one strain of viable non-pathogenic or attenuated pathogenic Bacteroides.

134. The use of claim 133, wherein said Bacteroides is selected from the group consisting of Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides fragilis, Bacteroides fragilis-ryhm, Bacteroides gracilis, Bacteroides levii, Bacteroides macacae, Bacteroides merdae, Bacteroides ovatus, Bacteroides pneumosintes, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides splanchnicus, Bacteroides stercoris, Bacteroides tectum, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgatus.

135. The use according to any one of claims 131 to 134, further comprising one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas, Peptostreptococcus, species.

136. The use according to claim 135 wherein the one or more additional viable non-pathogenic or attenuated pathogenic microorganisms are Bacteroides fragilis ss. Vulgatus, Eubacterium aerofaciens, Bacteroides fragilis ss. Thetaiotaomicron, Peptostreptococcus productus II, Bacteroides fragilis ss. Distasonis, Fusobacterium prausnitzii, Coprococcus eutactus, Eubacterium aerofaciens III, Peptostreptococcus productus I, Ruminococcus bronii, Bifidobacterium adolescentis, Gemmiger formicilis, Bifidobacterium longum, Eubacterium siraeum, Ruminococcus torques, Eubacterium rectale III-H, Eubacterium rectale IV, Eubacterium eligens, Bacteroides eggerthii, Clostridium leptum, Bacteroides fragilis ss. A, Eubacterium biforme, Bifidobacterium infantis, Eubacterium rectale III-F, Coprococcus comes, Bacteroides capillosus, Ruminococcus albus, Eubacterium formicigenerans, Eubacterium haffii, Eubacterium ventriosum I, Fusobacterium russii, Ruminococcus obeum, Eubacterium rectale II, Clostridium ramosum I, Lactobacillus leichmanii, Ruminococcus cailidus, Butyrivibrio crossotus, Acidaminococcus fermentans, Eubacterium ventriosum, Bacteroides fragilis ss. fragilis, Bacteroides AR, Coprococcus catus, Eubacterium hadrum, Eubacterium cylindroides, Eubacterium ruminantium, Eubacterium CH-1, Staphylococcus epidermidis, Peptostreptococcus BL, Eubacterium limosum, Bacteroides praeacutus, Bacteroides L, Fusobacterium mortiferum I, Fusobacterium naviforme, Clostridium innocuum, Clostridium ramosum, Propionibacterium acnes, Ruminococcus flavefaciens, Ruminococcus AT, Peptococcus AU-1, Eubacterium AG, -AK, -AL, -AL-1, -AN; Bacteroides fragilis ss. ovatus, -ss. d, -ss. f; Bacteroides L-1, L-5; Fusobacterium nucleatum, Fusobacterium mortiferum, Escherichia coli, Streptococcus morbiliorum, Peptococcus magnus, Peptococcus G, -AU-2; Streptococcus intermedius, Ruminococcus lactaris, Ruminococcus CO Gemmiger X, Coprococcus BH, CC; Eubacterium tenue, Eubacterium ramulus, Eubacterium AE, -AG-H, -AG-M, -AJ, -BN-1; Bacteroides clostridiiformis ss. clostridliformis, Bacteroides coagulans, Bacteroides orailis, Bacteroides ruminicola ss. brevis, -ss. ruminicola, Bacteroides splanchnlcus, Desuifomonas pigra, Bacteroides L-4, -N-i; Fusobacterium H, Lactobacillus G, or Succinivibrio A.

137. The use according to any one of claims 131 to 136, further comprising fungi.

138. The use according to claim 137, wherein the fungi are Monilia.

139. The use according to any one of claims 131 to 138, further comprising at least one strain of viable non-pathogenic or attenuated pathogenic Bifidobacterium.

140. Use of viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Clostridia, Bacteroides, Peptostreptococcus, Escherichia coli, Bifidobacterium, and Lactobacillus for the manufacture of a medicament for the treatment and/or prophylaxis of a chronic disorder associated with the presence in the gastrointestinal tract of a mammalian host of abnormal or an abnormal distribution of microflora.

141. The use according to claim 140, further comprising one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas, Peptostreptococcus, species.

142. Use of viable non-pathogenic or attenuated pathogenic Escherichia coli, at least one strain of viable non-pathogenic or attenuated pathogenic Bacteroides and at least one other viable non-pathogenic or attenuated pathogenic microorganism for the manufacture of a medicament for the treatment and/or prophylaxis of a chronic disorder associated with the presence in the gastrointestinal tract of a mammalian host of abnormal or an abnormal distribution of microflora.

143. The use of claim 142, wherein the Bacteroides is selected form the group consisting of Bacteroides caccae, Bacteroides capillosus, Bacteroides coagulans, Bacteroides distasonis, Bacteroides eggerthii, Bacteroides forsythus, Bacteroides. fragilis, Bacteroides fragilis Bacteroides gracilis, Bacteroides levii, Bacteroides macacae, Bacteroides merdae, Bacteroides ovatus, Bacteroides pneumosintes, Bacteroides putredinis, Bacteroides pyogenes, Bacteroides splanchnicus, Bacteroides stercoris, Bacteroides tectum, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides ureolyticus, Bacteroides vulgatus.

144. The use according to claim 142, further comprising one or more additional viable non-pathogenic or attenuated pathogenic microorganisms selected from the group consisting of Bacteroides, Eubacteria, Fusobacteria, Propionibacteria, Lactobacilli, anaerobic cocci, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas, Peptostreptococcus, species.

145. The use according to any one of claims 142 to 144, wherein the other viable non-pathogenic or attenuated pathogenic microorganism is selected from the group consisting of Clostridia, Peptostreptococcus, Bifidobacterium, and Lactobacillus.

146. The use according to any one of claims 131 to 145, further comprising an acid suppressant.

147. The use according to any one of claims 131 to 146, further comprising an antacid.

148. The use according to any one of claims 131 to 147, further comprising an H2 antagonist.

149. The use according to any one of claims 131 to 148, further comprising a proton pump inhibitor.

150. The use according to any one of claims 131 to 149, wherein said microorganisms are spores.

151. The use according to any one of claims 131 to 150, wherein the microorganisms are lyophilised, pulverised and powdered.

152. The use according to any one of claims 131 to 151, wherein the microorganism is a liquid culture.

153. The use according to any one of claims 131 to 152, wherein the medicament is an enteric coated capsule, an enteric coated microcapsule, or a reconstituted powder.

154. The use according to any one of claims 131 to 153, wherein the medicament is administered in the form of an enema.

155. The use according to any one of claims 131 to 154, wherein the medicament is administered in the form of a food or drink.

156. The use according to claim 155, wherein said food is a dairy-based product, a soy-based product, or a derivative thereof.

157. The use according to either claim 155 or claim 156, wherein said food is yogurt.

158. The use according to any one of claims 131 to 157, wherein the treatment and/or prophylaxis period is several days to several weeks.

159. The use according to any one of claims 131 to 158, wherein the mammalian host is human.

160. The use according to any one of claims 131 to 159, wherein the medicament is suitable for administration by ingestion or by parenteral infusion.

161. The use according to any one of claims 131 to 159, wherein the medicament is suitable for administration by enema, per-colonoscope, by intubation of the small bowel or orally.

162. The use according to any one of claims 131 to 161, wherein the chronic disorder is a gastrointestinal disorder, a rheumatic disorder, an immune mediated disorder, an auto-immune disorder, a neurological disorder, a regressive disorder, a liver disorder, a psychiatric disorder or a dermatological condition.

163. The use of claim 162, wherein said gastrointestinal disorder is irritable bowel syndrome or spastic colon.

164. The use of claim 163, wherein said gastrointestinal disorder is functional bowel disease (FBD), inflammatory bowel disease, chronic gut infection, or a viral gastrointestinal disorder.

165. The use of claim 164, wherein said functional bowel disease is constipation predominant FBD, pain predominant FBD, upper abdominal FBD (non ulcer dyspepsia), or gastro oesophageal reflux.

166. The use of claim 164, wherein said inflammatory bowel disease is Crohn's disease, ulcerative colitis, indeterminate colitis, collagenous colitis, microscopic colitis, chronic Clostridium difficile infection, pseudomembranous colitis, mucous colitis, antibiotic associated colitis, idiopathic or simple constipation, diverticular disease, AIDS enteropathy, small bowel bacterial overgrowth, coeliac disease, polyposis coli, colonic polyps, or chronic idiopathic pseudo obstructive syndrome.

167. The use of claim 164, wherein said chronic gut infection is a bacterial, viral, fungal or protozoal infection.

168. The use of claim 164, wherein said viral gastrointestinal disorder is viral gastroenteritis, Norwalk viral gastroenteritis, rotavirus gastroenteritis, AIDS related gastroenteritis.

169. The use of claim 162, wherein said rheumatic disorder is rheumatoid arthritis, non-rheumatoid arthritidies, non rheumatoid factor positive arthritis, ankylosing spondylitis, Reiter's syndrome, or Lyme Disease.

170. The use of claim 162, wherein said immune mediated disorder is glomerulonephritis, haemolytic uraemic syndrome, juvenile diabetes mellitus, mixed cryoglobulinaemia, polyarteritis, familial Mediterranean fever, amyloidosis, scleroderma, systemic lupus erythematosus, or Behcets syndrome.

171. The use of claim 162, wherein said auto-immune disorder is systemic Lupus, idiopathic thrombocytopenic purpura, Sjogren's syndrome, haemolytic uraemic syndrome, or scleroderma.

172. The use of claim 162, wherein said neurological disorder is chronic fatigue syndrome, Alzheimer's disease, multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Guillain Barre syndrome, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), migraine or myasthenia gravis.

173. The use of claim 162, wherein said regressive disorder is Aspergers syndrome, Rett syndrome, attention deficit hyperactivity disorder (ADHD) or attention deficit disorder (ADD).

174. The use of claim 162, wherein said regressive disorder is autism.

175. The use of claim 162, wherein said disorder is sudden infant death syndrome (SIDS) or anorexia nervosa.

176. The use of claim 162, wherein said liver disorder is primary biliary cirrhosis, primary sclerosing cholangitis, fatty liver or cryptogenic cirrhosis.

177. The use of claim 162, wherein said psychiatric disorder is chronic depression, schizophrenia/psychotic disorders, or manic depressive illness.

178. The use of claim 162, wherein said dermatological condition is chronic urticaria, acne, dermatitis herpetiformis or a vasculitic disorder.

179. The use according to any one of claims 131 to 178, wherein each dose of the medicament is at least about 10.sup.3 cells.

180. The use according to any one of claims 131 to 178, wherein each dose of the medicament is in the range of about 10.sup.3 cells to about 10.sup.13 cells.

181. The use according to any one of claims 131 to 178, wherein each dose of the medicament is in the range of about 10.sup.5 cells to about 10.sup.11 cells.

182. The use according to any one of claims 131 to 178, wherein each dose of the medicament is in the range of about 10.sup.7 cells to about 10.sup.9 cells.

Description

BEST METHOD OF PERFORMING THE INVENTION

[0077] In the practice of the invention a synthetic faecal composition of predetermined flora in the form of a liquid or dry powdered culture of Clostridia, Bacteroides, Peptostreptococcus, Escherichia coil, Bifidobacterium, and Lactobacillus, which composition does not include antibiotic resistant populations, is prepared as a liquid culture.

[0078] Typically the method of the invention is applicable to a patient suffering from a chronic disorder associated with the presence of abnormal microflora in the gastrointestinal tract such as irritable bowel syndrome.

[0079] In the practice of the invention a composition of predetermined flora in the form of a liquid culture of Clostridia, Bacteroides, Peptostreptococcus, Escherichia coli, Bifidobacterium, and Lactobacillus is ingested by the patient in an amount sufficient to replace and recolonise the dysbiotic flora of the gastrointestinal tract, and reverse the disease process. Alternatively fresh homologous faeces obtained from a disease screened donor are liquefied and mixed with unprocessed bran. The mixture is then homogenised anaerobically under CO.sub.2 cover and infused into the patient per colonoscope.

[0080] Cure or remission of symptoms is then monitored subjectively and by assessment of stool frequency or other appropriate criteria.

[0081] Using liquid cultures of Clostridia, Bacteroides, Peptostreptococcus, Escherichia coli, Bifidobacterium, and Lactobacillus the inventor has achieved total reversal of colitis, irritable bowel syndrome and constipation.

[0082] As indicated in the method of treatment aspect of the invention, a preparatory course of appropriate antibiotics may be used. For example, Septrin for chronic yersiniasis, Metronidazole for ulcerative colitis, anti-TB therapy in Crohn's disease, or Vancomycin in chronic Clostridium difficile infestations.

TABLE-US-00001 TABLE 1 % of flora .sup.b Organism(s) 11.8(0.90) Bacteroides fragilis ss. Vulgatus 9.9(0.83) Eubacterium aerofaciens 8.9(0.78) Bacteroides fragilis ss. Thetaiotaomicron 6.6(0.68) Peptostreptococcus productus II 6.0(0.64) Bacteroides fragilis ss. Distasonis 4.4(0.55) Fusobacterium prausnitzil 3.5(0.49) Coprococcus eutactus 3.0(0.45) Eubacterium aerofaciens III 2.8(0.44) Peptostreptococcus productus I 2.7(0.43) Ruminococcus bronii 2.6(0.43) Bifidobacterium adolescentis 2.2(0.39) Gemmiger formicilis, Bifidobacterium longum 2.1(0.38) Eubacterium siraeum 1.8(0.35) Ruminococcus torques 1.7(0.34) Eubacterium rectale III-H 1.6(0.33) Eubacterium rectale IV, Eubacterium eligens 1.5(0.32) Bacteroides eggerthii 1.4(0.31) Clostridium leptum 1.3(0.29) Bacteroides fragilis ss. A 1.2(0.29) Eubacterium biforme 0.91(0.25) Bifidobacterium infantis 0.84(0.24) Eubacterium rectale III-F 0.57(0.20) Coprococcus comes, Bacteroides capillosus 0.50(0.18) Ruminococcus albus, Eubacterium formicigenerans, Eubacterium hallii, Eubacterium ventriosum I, Fusobacterium russii 0.43(0.17) Ruminococcus obeum, Eubacterium rectale II, Clostridium ramosum I, Lactobacillus leichmanii 0.36(0.16) Ruminococcus caflidus, Butyrivibrio crossotus 0.30(0.14) Acidaminococcu fermentans, Eubacterium ventriosum, Bacteroides fragilis ss. fragilis, Bacteroides AR 0.23(0.12) Coprococcus catus, Eubacterium hadrum, Eubacterium cylindroides, Eubacterium ruminantium, Eubacterium CH-1, Staphylococcus epidermidis 0.17(0.10) Peptostreptococcus BL, Eubacterium limosum, Bacteroides praeacutus, Bacteroides L, Fusobacterium mortiferum I, Fusobacterium naviforme, Clostridium innocuum, Clostridium ramosum, Propionibacterium acnes, Ruminococcus flavefaciens 0.10(0.08) Ruminococcus AT, Peptococcus AU-1, Eubacterium AG, -AK, -AL, -AL-1, -AN; Bacteroides fragilis ss. ovatus, -ss. d, -ss. f; Bacteroides L-1, L-5; Fusobacterium nucleatum, Fusobacterium mortiferum, Escherichia coli, Streptococcus morbiliorum 0.05(0.05) Peptococcus magnus, Peptococcus G, -AU-2; Streptococcus intermedius, Ruminococcus lactaris, Ruminococcus CO Gemmiger X, Coprococcus BH, -CC; Eubacterium tenue, Eubacterium ramulus, Eubacterium AE, -AG-H, -AG-M, -AJ, -BN-1; Bacteroides clostridiiformis ss. clostridliformis, Bacteroides coagulans, Bacteroides orails, Bacteroides rumlnicola ss. brevis, -ss. ruminicola, Bacteroides splanchnlcus, Desuifomonas pigra, Bacteroides L-4, -N-i; Fusobacterium H, Lactobacillus G, Succinivibrio A .sup.b The percentage of the faecal population (the standard deviation of the estimate is given in parentheses).

[0083] The invention will now be further described with reference to the following non-limiting examples.

EXAMPLES

[0084] Formulations:

[0085] The probiotic therapeutic agents may be prepared in liquid culture anaerobically or aerobically (depending on bacterium cultured) in pure form. Alternatively the probiotics may be cultured on solid media and scraped into a liquid carrier. The resulting product may be spray-dried into a powder form and encapsulated or combined with excipients to be delivered in sachets.

[0086] Combinations of Clostridia, Escherichia coli, Bacteroides, and Peptostreptococcus with or without Lactobacilli, Bifidobacteria and Eubacteria may be used in varying disorders.

Example No 1-43 Year Old Female

[0087] Patient with long standing constipation not responsive to high-dose fibre usage together with prokinetics and standard anti-constipation treatments, was treated with increasing doses of orally administered bacterial mix (mixture composition included Clostridium innocuum, bifermentans, butyricum, together with Bacteroides fragilis, thetaiotaomicron and uniformis. Three strains of Escherichia coli were also included, as was Lactobacillus). This was ingested twice daily in the first two weeks and then daily thereafter. The patient was not given any pre-treatment purgative nor any antibiotics. However, she did take Ranitidine (an acid suppressant) three hours prior to ingestion of the bacterial mix. Two weeks after commencing the treatment the patients constipationwhich would prevent her from defecating for up to four daysreversed to increased frequency with reduction of bloating. Initially, gas production increased and there was burbulance and gurgling in the abdomen but after four weeks of treatment the patient was defecating on a daily basis with no sensation of incomplete emptying and an almost total absence of bloating. Following the treatment she remained virtually normal, defecating on a daily basis with 3 month follow up.

Example No 24 Year Old Male

[0088] Patient with 3 year history of diagnosis of autism associated with Irritable Bowel Syndrome characterised by constipation alternating with diarrhoea and flatulence, with foul motions, was treated with oral administration of bacterial mix consisting of Clostridium bifermentans, Clostridium innocuum, and Clostridium butyricum in combination with three strains of Escherichia coli, three strains of bacteroides and Peptostreptococcus productus. These were ingested following acid suppression with Ranitidine and were at first taken 3 times daily, reducing to twice daily and then once daily maintenance for eight weeks. The patient's autistic symptoms were reversed quite dramatically with word power increasing from 20 to 200 words (counted by teacher at special autistic school), he began to sleep through the night, and his IBS-type symptoms reverted to near-normality with less constipation, less diarrhoea and less foul flatulence. He developed eye contact, was able to speak sentences up to six words constructed to commands and he began to look, to the untrained eye, as a relatively normal child by about week 10.

Example 3 Male Child, 5 Years Old

[0089] Male child, 5 years of age with autism symptoms dating back to age of around 15 monthsbut diagnosed significantly later. The patient presented initially with gastrointestinal symptoms in association with classical autismfor treatment of the bowel symptoms. Although stool test did not indicate any specific pathogen the bowel symptoms resembled those of a chronic infection or adult Irritable Bowel Syndrome (IBS), ie intermittent diarrhoea, constipation, cramping, colicky pain, inability to sleep at night, occasional explosive diarrhoea and incontinence. The patient was treated with orthostatic lavage using sodium pico-sulfate followed by water to produce voluminous diarrhoea and to flush out the enteric contents. He was then given 125 mg Vancomycin three times daily orally followed by oral re-colonisation with bacteria at a concentration of 10.sup.9 through to 10.sup.10, suspended in yoghurtof strains which included bacteroides, Escherichia coli, and non pathogenic Clostridiaincluding Clostridium innocuum, bifermentans and ramosum. The response was quite noticeable, in the reversal of the abnormal stool function towards normality. The patient was also able to sleep through the night without any explosive diarrhoea and produced formed stools within five days of commencing the bacterial therapy. While the bacteriotherapy was continued the bowel symptoms were well controlled. Within 3-4 weeks of missing out the treatment for a week or two some of the symptoms would begin to recur. This suggested that the abnormal bacterial flora was suppressed rather than being cured with this treatment in this patient. The unexpected finding however, was a noticeable and marked reversal of symptoms of autism. Whereas previously repetitive movements were present with lack of eye contact, eye contact returned fairly rapidly together with cessation of repetitive movement and progressive increase of word power from around 20 words to around 600 words by the sixth month of treatment. The therapy continues now for more than 12 months with sustained reversal of autism and IBS symptoms.

Example 4 Male Child, 7 Years Old

[0090] A seven year old male patient was referred for treatment initially of bowel problems. He had developed autism between age 1 and 2 years characterised by lack of eye contact, repetitive movements, poorly developed cognitive abilities, vocabulary of fewer than 20 words The marked bowel symptoms were characterised by either constipation or large voluminous motions, sometimes diarrhoea and explosive stools. Stool examination was negative.

[0091] The patient was given a pre-treatment of Vancomycin 125 mg twice daily and at one week he was given an orthostatic lavage consisting of picosulfate preparation which flushed out his bowel. He was then given twice daily oral bacteriotherapy consisting of cultures containing living probiotics. These included several bacteroides species, Escherichia coli and non-pathogenic Clostridia such as Clostridium butyricum, Clostridium bifermentans and Clostridium innocuum.

[0092] Within two weeks the bowel symptoms reversed to normal defecation with soft, formed stoolonce or twice per day. Constipation disappeared, eye contact returned over the next six weeks and vocabulary and word use quite dramatically improved, to everyone's surprise. When followed for eight months over 600 words could be counted in the vocabulary with sentences of up to eight words being constructed where previously this was not possible. Some abstract thinking was noted by teachers at the special autism school. Parents in particular noted reduced aggression, greater co-operation, and general increasing ability to develop a more normal relationship with the child. Repetitive action also disappeared.

Example 5 Male Child, 6 Years Old

[0093] A male patient aged 6 was referred to the clinic for treatment of chronic diarrhoea and at times incontinence. The child had been autistic since the age of one year and three months. The diagnosis however was delayed. He had slow cognitive development and very limited vocabulary. There was virtually absent eye contact and at times violent and explosive behaviour. The greatest problem with management was that of control of defecation as the child developed a fascination with the stools which would then be spread over furniture and walls. This brought severe pressure upon the family with respect to difficulty with management. Stool test was collected and again was negative for any pathogen. The patient was given Vancomycin 250 mg twice daily for 10 days after which a polyethylene glycol orthostatic lavage achieved a large volume flush of the bowel. He was then given twice daily oral bacteriotherapy in a neutral yogurt as a carrier. Within one week the bowel function returned to virtual normality. However, the behavioural changes were just as rapid in reversing again characterised by fairly rapid reduction in aggressiveness and uncontrollable behaviour, sleeping through the night, increased eye contact, and progressively increased word power. The behaviour of spreading stools also disappeared, more as a behavioural change than learnt phenomenon. The patient was continued on medications for over a year and progressively improved in all parametersat times fluctuating in severity.