PROBIOTIC AND PREBIOTIC COMPOSITIONS, AND METHODS OF USE THEREOF FOR TREATMENT AND PREVENTION OF GRAFT VERSUS HOST DISEASE
Probiotic compositions containing non-pathogenic microbial entities, e.g., bacterial or fungal 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 transplant disorders, e.g., graft-versus-host disease (GVHD), in a subject are also provided.
1 . A method of increasing the duration of survival of a subject receiving a bone marrow transplant, comprising administering to the subject a probiotic composition comprising an isolated bacterial population, such that the duration of survival of the subject is increased.
2 . The method of claim 1 , wherein the bacterial population is a human-derived bacterial population.
3 . The method of claim 1 , wherein administration of the probiotic composition reduces the likelihood that the subject will develop sepsis following the bone marrow transplant.
4 . The method of claim 1 , wherein administration of the probiotic composition reduces the likelihood that the subject will develop graft versus host disease (GVHD) following the bone marrow transplant.
5 . The method of claim 1 , wherein the probiotic composition is administered to the subject prior to receiving the bone marrow transplant.
6 . The method of claim 1 , wherein the probiotic composition is administered to the subject after receiving the bone marrow transplant.
7 . The method of claim 1 , wherein the probiotic composition is administered to the subject concurrently with the bone marrow transplant.
8 . The method of claim 1 , wherein the probiotic composition reduces intestinal permeability in the subject.
9 . The method of claim 8 , wherein the probiotic composition comprises a bacterial population that produces short chain fatty acids.
10 . The method of claim 9 , wherein the bacterial population produces a short chain fatty acid selected from the group consisting of butyrate, acetate, propionate, valerate, and combinations thereof.
11 . The method of claim 1 , wherein the probiotic composition reduces inflammation in the gastrointestinal tract of the subject.
12 . The method of claim 1 , wherein the probiotic composition comprises an anti-inflammatory bacterial population.
13 . The method of claim 12 , 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).
14 . The method of claim 13 , 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.
15 . The method of claim 13 , 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.
16 . The method of claim 12 , wherein the anti-inflammatory bacterial population produces short chain fatty acids.
17 . The method of claim 1 , wherein the isolated bacterial population comprises one or more bacterial species of the order Clostridiales.
18 . The method of claim 17 , wherein the bacterial species is from the genus Blautia, Clostridium , or Ruminococcus.
19 . The method of claim 1 , wherein the bacterial population comprises a single bacterial species set forth in Table 1.
20 . The method of claim 1 , wherein the bacterial population comprises two or more bacterial species set forth in Table 1.
21 . The method of claim 1 , 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.
22 . The method of claim 1 , 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.
23 . The method of claim 1 , wherein the subject has a disorder selected from the group consisting of a hematopoietic neoplastic disorder, leukemia, lymphoma, and multiple myeloma.
24 . The method of claim 23 , wherein the probiotic composition does not significantly reduce or eliminate the graft versus tumor (GVT) effect of the bone marrow transplant.
25 . The method of claim 1 , wherein the subject has an autoimmune disorder.
26 . The method of claim 25 , wherein the autoimmune disorder is selected from the group consisting of lupus, multiple sclerosis, systemic sclerosis, Crohn's disease, type I diabetes, and juvenile idiopathic arthritis.
27 . The method of claim 1 , wherein the subject has sickle cell disease or sickle cell anemia.
28 . The method of claim 1 , further comprising administering a prebiotic to the subject.
29 . The method of claim 28 , 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.
30 . The method of claim 28 , 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.
31 . The method of claim 28 , 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.
32 . The method of claim 28 , wherein the prebiotic comprises a disaccharide selected from the group consisting of xylobiose, sucrose, maltose, lactose, lactulose, trehalose, cellobiose, and combinations thereof.
33 . The method of claim 28 , wherein the prebiotic comprises a polysaccharide, wherein the polysaccharide is xylooligosaccharide.
34 . (canceled)
35 . A method of increasing the duration of survival of a subject receiving a bone marrow transplant, comprising administering to the subject a probiotic composition comprising an isolated population of anti-inflammatory bacteria 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, in an amount effective to reduce inflammation in the gastrointestinal tract of the subject, such that the duration of survival of the subject is increased.
36 - 61 . (canceled)
62 . A method of preventing or treating graft versus host disease (GVHD) in a subject receiving a transplant, comprising administering to the subject a probiotic composition comprising an isolated bacterial population, such that GVHD is prevented or treated.
63 . (canceled)
64 . The method of claim 62 , wherein the subject is receiving a hematopoietic stem cell transplant.
65 . The method of claim 62 , wherein the subject is receiving a bone marrow transplant.
66 . The method of claim 62 , wherein the subject is receiving a solid organ transplant.
67 . The method of claim 66 , wherein the solid organ transplant is selected from the group consisting of a kidney transplant, a heart transplant, a lung transplant, a skin transplant, a liver transplant, a pancreas transplant, an intestinal transplant, an endocrine gland transplant, a bladder transplant, and a skeletal muscle transplant.
68 - 87 . (canceled)
88 . The method of claim 62 , further comprising administering a prebiotic to the subject.
89 - 94 . (canceled)
95 . A method of reducing inflammation in the gastrointestinal tract of a subject receiving a transplant, comprising administering to the subject a probiotic composition comprising an isolated, anti-inflammatory bacterial population and a pharmaceutically acceptable excipient, such that inflammation in the gastrointestinal tract of the subject receiving the transplant is reduced.
96 - 105 . (canceled)
106 . The method of claim 95 , further comprising administering a prebiotic to the subject.
107 - 112 . (canceled)
113 . A method of reducing intestinal permeability in a subject receiving a transplant, comprising administering to the subject a probiotic composition comprising an isolated bacterial population and a pharmaceutically acceptable excipient, such that the intestinal permeability of the subject of the subject receiving the transplant is reduced.
114 - 123 . (canceled)