PROBIOTIC AND PREBIOTIC COMPOSITIONS, AND METHODS OF USE THEREOF FOR TREATMENT OF GASTROINTESTINAL DISORDERS
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, e.g., gastrointestinal disorders, in a subject are also provided.
1 . A method of reconstituting, modulating, or creating a beneficial bacterial flora in the gastrointestinal tract of a subject, the method comprising administering to the subject a composition comprising at least one isolated population of bacterial cells and a first isolated prebiotic, thereby reconstituting, modulating or creating a beneficial bacterial flora in the gastrointestinal tract of the subject.
2 . The method of claim 1 , wherein the composition comprises at least two isolated populations of bacterial cells.
3 . The method of claim 1 , wherein the composition comprises 20 or fewer isolated populations of bacterial cells.
4 . (canceled)
5 . The method of claim 1 , wherein the composition comprises 10 or fewer isolated populations of bacterial cells.
6 . The method of claim 1 , wherein the composition comprises 5 or fewer isolated populations of bacterial cells.
7 . The method of claim 1 , wherein the composition comprises between about 12 and about 20 populations of bacterial cells.
8 . The method of claim 1 , wherein the composition comprises about 9 populations of bacterial cells.
9 . The method of claim 1 , wherein the composition comprises about 8 populations of bacterial cells.
10 . The method of claim 1 , wherein the composition comprises a single population of bacterial cells.
11 . The method of claim 1 , wherein at least one isolated population of bacterial cells is incapable of forming spores.
12 . (canceled)
13 . The method of claim 1 , wherein the composition further comprises at least one additional isolated prebiotic.
14 . The method of claim 1 , wherein the bacterial cells and first isolated prebiotic are capable of functionally interacting.
15 . The method of claim 1 , wherein the bacterial cells and first isolated prebiotic are formulated to functionally interact when co-localized in the gastrointestinal tract of a human subject.
16 . The method of claim 1 , wherein the bacterial cells engraft in the gastrointestinal tract of the subject.
17 . The method of claim 1 , wherein the bacterial cells comprise a bacterial cell of the order Clostridiales.
18 . The method of claim 17 , wherein the bacterial cells are of the genus Blautia, Clostridium , or Ruminococcus.
19 . The method of claim 1 , wherein the population of bacterial cells comprise anti-inflammatory bacterial cells.
20 . The method of claim 19 , wherein the anti-inflammatory bacterial cells decrease secretion of a pro-inflammatory cytokine and/or increase secretion of an anti-inflammatory cytokine by a population of human peripheral blood mononuclear cells (PBMCs).
21 . The method of claim 19 , wherein the anti-inflammatory bacterial cells decrease 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.
22 . The method of claim 19 , wherein the anti-inflammatory bacterial cells increase secretion of an anti-inflammatory cytokine selected from the group consisting of IL-10, IL-13, IL-4, IL-5, and combinations thereof.
23 . The method of claim 1 , wherein the bacterial cells belong to bacterial strain or species set forth in Table 1.
24 . The method of claim 1 , wherein the bacterial cells belong to a single bacterial strain or species set forth in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, or Table 1F.
25 . The method of claim 1 , wherein the first prebiotic comprises at least one polymer or monomer selected from the group consisting of arabinoxylan, xylose, soluble fiber dextran, soluble corn fiber, polydextrose, lactose, N-acetyl-lactosamine, glucose, and mixtures thereof.
26 . The method of claim 13 , wherein the additional prebiotic comprises at least one polymer or monomer 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 mixtures thereof.
27 . The method of claim 1 , wherein the prebiotic comprises a sugar selected from the group consisting of arabinose, fructose, fucose, lactose, galactose, glucose, mannose, D-xylose, xylitol, ribose, xylobiose, sucrose, maltose, lactose, lactulose, trehalose, cellobiose, xylooligosaccharide, and combinations thereof.
28 . The method of claim 1 , wherein the bacterial cells comprise a bacterial cell in vegetative form.
29 . The method of claim 1 , wherein the bacterial cells are purified from fecal matter.
30 . The method of claim 1 , wherein the bacterial cells are cultured from a bacterial stock and purified.
31 . The method of claim 1 , wherein each of the populations of bacterial cells are independently cultured and purified.
32 . The method of claim 1 , wherein the populations of bacterial cells are co-cultured and purified.
33 . The method of claim 1 , wherein the composition is administered orally or rectally.
34 . The method of claim 1 , wherein at least one population of bacterial cells comprises at least 1×10 4 colony forming units (CFUs).
35 . The method of claim 2 , wherein a first population of bacterial cells comprises at least 1×10 4 colony forming units (CFUs) and a second population of bacterial cells comprises at least 1×10 4 CFUs.
36 . The method of claim 1 , wherein at least one population of bacterial cells comprises at least 1×10 4 CFUs of an OTU comprising a 16S sequence selected from the group consisting of SEQ ID NO 1-2032.
37 . The method of claim 2 , wherein a first and second isolated population of bacterial cells independently comprise at least 1×10 4 CFUs of an OTU comprising a 16S sequence selected from the group consisting of SEQ ID NO 1-2032.
38 - 40 . (canceled)
41 . The method of claim 1 , wherein the composition further comprises a pharmaceutically acceptable excipient.
42 . The method of claim 1 , wherein the subject has a gastrointestinal dysbiosis.
43 . The method of claim 1 , wherein the subject is suffering from a gastrointestinal disorder.
44 . The method of claim 43 , wherein the gastrointestinal disorder is selected from the group consisting of antibiotic associated diarrhea, Clostridium difficile -induced diarrhea, irritable bowel syndrome (IBS), colonization with a pathogen or pathobiont, infection with a drug-resistant pathogen or pathobiont, colitis, constipation, and Crohn's Disease.
45 . The method of claim 1 , wherein the subject is an infant or toddler.
46 . The method of claim 1 , wherein administration is to a subject following colonoscopy or endoscopic large bowel examination.
47 . A method of treating or alleviating a gastrointestinal disorder in a subject in need thereof, the method comprising administering to the subject a composition comprising at least one isolated population of bacterial cells and a first isolated prebiotic, thereby treating or alleviating the gastrointestinal disorder in the subject.
48 . The method of claim 47 , wherein the gastrointestinal disorder is selected from the group consisting of antibiotic associated diarrhea, Clostridium difficile -induced diarrhea, irritable bowel syndrome (IBS), colonization with a pathogen or pathobiont, infection with a drug-resistant pathogen or pathobiont, colitis, constipation, and Crohn's Disease.
49 - 88 . (canceled)
89 . A composition comprising at least one isolated population of bacterial cells and a first isolated prebiotic.
90 . The composition of claim 89 , wherein the composition comprises at least two isolated populations of bacterial cells.
91 . The composition of claim 89 , wherein the composition comprises 20 or fewer isolated populations of bacterial cells.
92 . (canceled)
93 . The composition of claim 89 , wherein the composition comprises 10 or fewer isolated populations of bacterial cells.
94 . The composition of claim 89 , wherein the composition comprises 5 or fewer isolated populations of bacterial cells.
95 . The composition of claim 89 , wherein the composition comprises between about 12 and about 20 populations of bacterial cells.
96 . The composition of claim 89 , wherein the composition comprises about 9 populations of bacterial cells.
97 . The composition of claim 89 , wherein the composition comprises about 8 populations of bacterial cells.
98 . The composition of claim 89 , wherein the composition comprises a single population of bacterial cells.
99 . The composition of claim 89 , wherein at least one isolated population of bacterial cells is incapable of forming spores.
100 . (canceled)
101 . The composition of claim 89 , wherein the composition further comprises at least one additional isolated prebiotic.
102 . The composition of claim 89 , wherein the bacterial cells and first isolated prebiotic are capable of functionally interacting.
103 . The composition of claim 89 , wherein the bacterial cells and first isolated prebiotic are formulated to functionally interact when co-localized in the gastrointestinal tract of a human subject.
104 . The composition of claim 89 , wherein the bacterial cells are capable of engrafting in the gastrointestinal tract of a subject to whom the composition is administered.
105 . The composition of claim 89 , wherein the bacterial cells comprise a bacterial cell of the order Clostridiales.
106 . The composition of claim 105 , wherein the bacterial cells are of the genus Blautia, Clostridium , or Ruminococcus.
107 . The composition of claim 89 , wherein the bacterial cells are anti-inflammatory bacterial cells.
108 . The composition of claim 107 , wherein the anti-inflammatory bacterial cells decrease secretion of a pro-inflammatory cytokine and/or increase secretion of an anti-inflammatory cytokine by a population of human peripheral blood mononuclear cells (PBMCs).
109 . The composition of claim 107 , wherein the anti-inflammatory bacterial cells decrease 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.
110 . The composition of claim 107 , wherein the anti-inflammatory bacterial cells increase secretion of an anti-inflammatory cytokine selected from the group consisting of IL-10, IL-13, IL-4, IL-5, and combinations thereof.
111 . The composition of claim 89 , wherein the bacterial cells belong to bacterial strain or species set forth in Table 1.
112 . The composition of claim 89 , wherein the bacterial cells belong to a single bacterial strain or species set forth in Table 1A, Table 1B, Table 1C, Table 1D, Table 1E, or Table 1F.
113 . The composition of claim 89 , wherein the first prebiotic comprises at least one polymer or monomer selected from the group consisting of arabinoxylan, xylose, soluble fiber dextran, soluble corn fiber, polydextrose, lactose, N-acetyl-lactosamine, glucose, and mixtures thereof.
114 . The composition of claim 101 , wherein the additional prebiotic comprises at least one polymer or monomer 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 mixtures thereof.
115 . The composition of claim 89 , wherein the prebiotic comprises a sugar selected from the group consisting of arabinose, fructose, fucose, lactose, galactose, glucose, mannose, D-xylose, xylitol, ribose, xylobiose, sucrose, maltose, lactose, lactulose, trehalose, cellobiose, xylooligosaccharide, and combinations thereof.
116 - 121 . (canceled)
122 . The composition of claim 89 , wherein at least one population of bacterial cells comprises at least 1×10 4 colony forming units (CFUs).
123 . The composition of claim 90 , wherein a first population of bacterial cells comprises at least 1×10 4 colony forming units (CFUs) and a second population of bacterial cells comprises at least 1×10 4 CFUs.
124 . The composition of claim 89 , wherein at least one population of bacterial cells comprises at least 1×10 4 CFUs of an OTU comprising a 16S sequence selected from the group consisting of SEQ ID NO 1-2032.
125 . The composition of claim 90 , wherein a first and second isolated population of bacterial cells independently comprise at least 1×10 4 CFUs of an OTU comprising a 16S sequence selected from the group consisting of SEQ ID NO 1-2032.
126 - 128 . (canceled)
129 . The composition of claim 89 , wherein the composition is encapsulated and optionally further comprising an enteric coating.
130 . The composition of claim 89 , wherein the composition is formulated for oral or rectal administration.
131 . The composition of claim 89 , wherein the composition is formulated as a solid, liquid, gel or emulsion.
132 . A pharmaceutical composition comprising the composition of claim 89 , further comprising a pharmaceutically acceptable excipient suitable for administration to a mammalian subject in need thereof.
133 . The pharmaceutical composition of claim 132 , wherein the excipient is suitable for oral or rectal administration.