Patent Description:
The clinical efficacy of immune checkpoint inhibitors in several cancer types has demonstrated the importance of targeting this regulatory axis for cancer treatment (<NPL>). However, most of the successes have been obtained with inhibitors that target only a few immune checkpoint receptors and ligands and are effective in a subset of tumor types (<NPL>). Thus, a greater understanding of the mechanisms underlying the selectivity of the tumor response, the control of immune checkpoint components, and the emergence of tumors resistant to this therapy is needed (<NPL>).

<CIT> discloses Oscillibacter valericigenes in preventing and treating immune-mediated diseases.

Botticelli et al. discloses the involvement of the immune checkpoint inhibitors PD1 and PDL-<NUM> in the cross talk between gut microbiota and immune fitness and how gut microbiota impacts on the efficacy of anti-PD-<NUM> and anti-PDL-<NUM> treatments in cancer (<NPL>).

discloses that probiotics shifted gut microbiota community towards certain beneficial bacteria, including Prevotella and Oscillibacter, which in turn influenced the level of the anti-inflammatory metabolites in the gut (<NPL>).

Taper et al. discloses prebiotics inulin and oligofructose as possible adjuvant cancer therapy (<NPL>).

Vetizou et al. discloses that the anticancer immunotherapy by CTLA-<NUM> blockade relies on the gut microbiota (<NPL>).

<CIT> discloses a yeast-based immunotherapeutic composition comprising mucin for the prevention and treatment of cancers.

<CIT> discloses VSTM5 polypeptides, including mucin <NUM>, for use in treating cancer. Brown et al. discloses the use of vemurafenib in patients with metastatic melanoma containing the V600 BRAF gene mutation (<NPL>).

The invention is based, at least in part, on the discovery of an unexpected role for the ubiquitin ligase, RNF5, in regulating the gut microbiota composition and influencing the immune checkpoint response to tumors. RNF5 deficient animals exhibited significant inhibition of tumor development combined with an altered gut microbiota composition. Treatment of wild-type animals with selected prebiotics resulted in inhibition of tumor growth and an altered gut microbiota similar to that observed in RNF5 deficient animals.

The present invention provides a composition comprising a therapeutically effective amount of one or more bacteria for use in treating a cancer in a human subject in need thereof, wherein the composition is to be administered to the human subject and the one or more bacteria are selected from the group consisting of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium, wherein.

In some embodiments, the BRAF inhibitor is vemurafenib or dabrafenib.

In some embodiments, the MEK inhibitor is trametinib, cobimetinib, binimetinib, selumetinib, PD-<NUM>, CI-<NUM>, or TAK-<NUM>.

In some embodiments, the human subject is identified as having the V600E, R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, and/or A727V mutation in the BRAF gene prior to treatment.

Disclosed herein but not claimed is a method of treating a cancer in a human subject in need thereof by administering to the human subject a composition comprising a therapeutically effective amount of one or more bacteria selected from the group consisting of Bacteroides acidifaciens, Bacteroides xylanisolvens, B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza.

Also disclosed herein but not claimed is the use of one or more bacteria selected from the group consisting of Bacteroides acidifaciens, Bacteroides xylanisolvens, B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza for the preparation of a medicament for treatment of a cancer in a human subject.

Also disclosed herein but not claimed is a composition comprising a therapeutically effective amount of one or more bacteria selected from the group consisting of Bacteroides acidifaciens, Bacteroides xylanisolvens, B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza for use in treatment of a cancer in a human subject.

Disclosed herein but not claimed is a method of treating a cancer in a human subject in need thereof by administering to the human subject a composition comprising a therapeutically effective amount of one or more prebiotics that promote the growth of one or more bacteria selected from the group consisting of Bacteroides acidifaciens, Bacteroides xylanisolvens, B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza.

Also disclosed herein but not claimed is the use of one or more prebiotics that promote the growth of one or more bacteria selected from the group consisting of Bacteroides acidifaciens, Bacteroides xylanisolvens, B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza for the preparation of a medicament for treatment of a cancer in a human subject.

A composition for the inventive use as defined in the claims may further comprise a therapeutically effective amount of one or more prebiotics that promote the growth of one or more bacteria selected from the group consisting of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium.

Also disclosed herein but not claimed is a composition comprising a therapeutically effective amount of one or more prebiotics that promote the growth of one or more bacteria selected from the group consisting of Bacteroides acidifaciens, Bacteroides xylanisolvens, B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza for use in treatment of a cancer in a human subject. The inventive use as defined in the claims may comprise administering to the human subject in combination: (<NUM>) a therapeutically effective amount of one or more bacteria selected from the group consisting of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium; and (<NUM>) a therapeutically effective amount of one or more prebiotics that promote the growth of one or more bacteria selected from the group consisting of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium.

Disclosed herein but not claimed is a method of treating a cancer in a human subject in need thereof by administering to the human subject in combination: (<NUM>) a therapeutically effective amount of one or more bacteria selected from the group consisting of Bacteroides acidifaciens, Bacteroides xylanisolvens, B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza; and (<NUM>) a therapeutically effective amount of one or more prebiotics that promote the growth of one or more bacteria selected from the group consisting of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza.

A composition for the inventive use as defined in the claims may comprise the combination of (<NUM>) a therapeutically effective amount of one or more bacteria selected from the group consisting of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium; and (<NUM>) a therapeutically effective amount of one or more prebiotics that promote the growth of one or more bacteria selected from the group consisting of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium for simultaneous, separate, or sequential administration to a human subject.

Also disclosed herein but not claimed is the combination of (<NUM>) a therapeutically effective amount of one or more bacteria selected from the group consisting of Bacteroides acidifaciens, Bacteroides xylanisolvens, B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza; and (<NUM>) a therapeutically effective amount of one or more prebiotics that promote the growth of one or more bacteria selected from the group consisting of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza for simultaneous, separate, or sequential administration to a human subject for treatment of a cancer.

The one or more prebiotics may be selected from the group consisting of a mucin, inulin, N-acetyl-D-glucosamine, N-acetyl-D-mannosamine, glucose-<NUM>-phosphate, D-fructose, a galactomannan, N-acetyl mannosamine, N-acetylgalactosamine, N-acetylneuraminic acid, N-acetyl glucosamine, galactose, fucose, mannose, human milk oligosaccharides, guar gum, dextrin, α-cellulose, β-D glucan, pectin, corn starch, and potato starch.

The one or more prebiotics may include porcine gastric mucin.

The one or more prebiotics may include N-acetyl-D-glucosamine and N-acetyl-D-mannosamine.

The one or more prebiotics may include glucose-<NUM>-phosphate and D-fructose.

The inventive use as defined in the claims includes administering to the human subject an additional anti-cancer agent.

In some embodiments of the inventive use the anti-cancer agent is a BRAF inhibitor, such as vemurafenib or dabrafenib.

In some embodiments of the inventive use the anti-cancer agent is a MEK inhibitor, such as trametinib, cobimetinib, binimetinib, selumetinib, PD-<NUM>, CI-<NUM>, or TAK-<NUM>.

According to the invention, where a BRAF inhibitor is to be administered, the human subject is identified as having a mutation in the BRAF gene prior to treatment. In some embodimenst, the human subject is identified as having the V600E, R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T598I, V599D, V599E, V599K, V599R, V600K, and/or A727V mutation in the BRAF gene prior to treatment.

According to the invention, where a MEK inhibitor is to be administered, the human subject is identified as having a mutation in the NRAS gene prior to treatment.

The gut microbiome of the human subject may be evaluated prior to the initiation of treatment. The cancer of the inventive use is melanoma.

The composition for the inventive use may be administered orally.

Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the exemplary methods and materials are described below.

In case of conflict, the claims will control.

The following are examples of the practice of the invention.

The accompanying Examples demonstrate an unexpected role for the ubiquitin ligase, RNF5, in regulating the gut microbiota composition and the immune response to tumors. Growth of mouse melanoma cells in vivo is attenuated, while tumor infiltration of CD4+/CD8+ T cells and dendritic cells is increased, in Rnf5-/-mice, resembling changes seen upon immune checkpoint therapy. This phenotype was immune system intrinsic and linked to increased ER stress, intestinal inflammation and mucin production by intestinal epithelial cells. Notably, co-housing of Rnf5-/- and wild-type mice largely abolished these phenotypes, pointing to a microbiota-dependent immune checkpoint activity. Mucin- or inulin-fed wild-type mice phenocopied Rnf5-/- mice, exhibiting increased tumor infiltration of immune cells and reduced tumor growth, pointing to prebiotics that may resemble anti-CTLA-<NUM> therapy.

The bacterial compositions as degined in the claims are for use in treating cancer in human subject in need thereof, wherein a therapeutically effective amount of a bacterial composition is to be administered to a human subject that has cancer, wherein (i) the human subject is identified as having a mutation in the Neuroblastoma RAS (NRAS) gene and poor responsiveness to treatment with a Mitogen-activated protein kinase (MEK) inhibitor prior to administration of the composition and wherein the composition is to be administered to the human subject in combination with a MEK inhibitor; or (ii) the human subject is identified as having a mutation in the Serine/threonine-protein kinase B-raf (BRAF) gene and poor responsiveness to treatment with a BRAF inhibitor prior to administration of the composition and wherein the composition is to be administered to the human subject in combination with a BRAF inhibitor, wherein the cancer is melanoma.

A bacterial composition of the inventive use comprises a therapeutically effective amount of one or more bacteria selected from the group consisting of: Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium.

A bacterial composition can be administered to a subject as, for example, a medical food, a nutraceutical, or a nutritional supplement, or a component of a medical food, a nutraceutical, or a nutritional supplement.

A bacterial composition can be administered to a subject, for example, orally or rectally (e.g., into at least one of the terminal ileum and right colon).

A bacterial composition for the inventive use may contain a single species of bacteria selected from the group consisting of: Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium.

A bacterial composition for the inventive use may contain two or more species of bacteria selected from the group consisting of: Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or more species of bacteria selected from the group consisting of: Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium.

The bacterial composition for the inventive use may contain <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> species of bacteria selected from the group consisting of: Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium.

A bacterial composition for the inventive use may contain Oscillibacter valericigenes and at least one of Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, or Bacteroides rodentium. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria.

A bacterial composition for the inventive use may contain Acetatifactor muris and at least one of Oscillibacter valericigenes, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, or Bacteroides rodentium. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria.

A bacterial composition for the inventive use may contain Alistipes putredinis and at least one of Oscillibacter valericigenes, Acetatifactor muris, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, or Bacteroides rodentium. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria.

A bacterial composition for the inventive use may contain Alistipes finegoldii and at least one of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, or Bacteroides rodentium. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria.

A bacterial composition for the inventive use may contain Clostridium clostridioforme and at least one of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, or Bacteroides rodentium. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria.

A bacterial composition for the inventive use may contain Lactobacillus animalis and at least one of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, or Bacteroides rodentium. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria.

A bacterial composition for the inventive use may contain Lactobacillus murinus and at least one of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, or Bacteroides rodentium. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria.

A bacterial composition for the inventive use may contain Bacteroides massiliensis and at least one of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, or Bacteroides rodentium. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria.

A bacterial composition for the inventive use may contain Bacteroides sartorii and at least one of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, or Bacteroides rodentium. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria.

A bacterial composition for the inventive use may contain Muribaculum intestinale and at least one of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Parasutterella excrementihominis, Clostridium methylpentosum, or Bacteroides rodentium. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria.

A bacterial composition for the inventive use may contain Parasutterella excrementihominis and at least one of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Clostridium methylpentosum, or Bacteroides rodentium. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria.

A bacterial composition for the inventive use may contain Clostridium methylpentosum and at least one of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, or Bacteroides rodentium. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria.

A bacterial composition for the inventive use may contain Bacteroides rodentium and at least one of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, or Clostridium methylpentosum. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. The bacterial composition for the inventive use may contain no more than <NUM> species of bacteria. Disclosed herein but not claimed is a bacterial composition that contains Bacteroides acidifaciens and at least one of Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. Disclosed herein but not claimed is a bacterial composition that contains Bacteroides xylanisolvens and at least one of Bacteroides acidifaciens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. Disclosed herein but not claimed is bacterial composition that contains Bacteroides chinchilla (B. sartorii) and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. Disclosed herein but not claimed is a bacterial composition that contains B. thetaiotaomicron and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. Disclosed herein but not claimed is a bacterial composition that contains B. fragilis and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. bacterial composition may contain no more than <NUM> species of bacteria. Disclosed herein but not claimed is a bacterial composition that contains Dysgonomonas wimpennyi and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. bacterial composition may contain no more than <NUM> species of bacteria. Disclosed herein but not claimed is a bacterial composition that contains Parabacteroides merdae and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The may bacterial composition containe no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains Flavobacterium and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may containe no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains Staphylococcus spp. and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains Staphylococcus sciuri and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains Staphylococcus xylosus and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains Helicobacter ganmani and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains Helicobacter hepaticus and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains Enterobacter hormaechei and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. Disclosed herein but not claimed is a bacterial composition that contains Porphyromonas canis and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains Porphyromonas gingivicanis and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contains no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains Rickenella microfusus and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains Olivibacter spp and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains P. goldsteinii and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may containe no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains P. koreensis and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, Pedobacter spp. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains Pedobacter spp. and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, O. sinus, Blautia hansenii, or Lachnospira pectinoschiza. The bacterial composition may containe no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains O. sinus and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. , Blautia hansenii, or Lachnospira pectinoschiza. The may bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is that a bacterial composition contains Blautia hansenii and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, or Lachnospira pectinoschiza. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria. The bacterial composition may containe no more than <NUM> species of bacteria. The bacterial composition may contain no more than <NUM> species of bacteria.

Disclosed herein but not claimed is a bacterial composition that contains Lachnospira pectinoschiza and at least one of Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, or Blautia hansenii. The bacterial composition may containe no more than <NUM> species of bacteria. The bacterial composition may containe no more than <NUM> species of bacteria.

The bacterial composition may contains <NUM> million to <NUM> billion colony-forming units (CFU). The bacterial composition may contain <NUM> million to <NUM> billion CFU. The bacterial composition may contain <NUM> million to <NUM> billion CFU.

A bacterial composition can be prepared in a variety of forms, such as capsules, tablets, suppositories, food, or drink. Optionally, the bacterial composition can include a pharmaceutically acceptable excipient, such as microcrystalline cellulose, mannitol, glucose, defatted milk powder, polyvinylpyrrolidone, starch, and combinations thereof.

The bacterial composition can be prepared as a capsule containing a bacterial species or combination of bacterial species described herein. The capsule can be a hollow capsule formed from substances such as, e.g., gelatin, cellulose, or carbohydrate. The bacterial composition can be formulated such that the bacteria is not exposed to conditions prevalent in the gastrointestinal tract before the colon, e.g., high acidity and digestive enzymes present in the stomach and/or intestine. The capsule can be made from aqueous solutions of gelling agents such as animal protein (e.g., gelatin), plant polysaccharides or derivatives such as carrageenans and modified forms of starch and cellulose. Other ingredients may be added to a gelling agent solution such as plasticizers (e.g., glycerin and or sorbitol), coloring agents, preservatives, disintegrants, flavoring, rice or other starch, glycerin, caramel color, titanium dioxide lubricants, and/or a surface treatment.

The bacterial composition can be prepared as a tablet containing a bacterial species or combination of bacterial species described herein. The tablet can include bacteria and one or more tableting agents, such as dibasic calcium phosphate, stearic acid, croscarmellose, silica, cellulose, and/or a cellulose coating.

The bacterial composition can be prepared as a suppository containing a bacterial species or combination of bacterial species described herein. The suppository can include bacteria and one or more carriers, such as polyethylene glycol, acacia, acetylated monoglycerides, carnuba wax, cellulose acetate phthalate, com starch, dibutyl phthalate, docusate sodium, gelatin, glycerin, iron oxides, kaolin, lactose, magnesium stearate, methyl paraben, pharmaceutical glaze, povidone, propyl paraben, sodium benzoate, sorbitan monoleate, sucrose talc, titanium dioxide, white wax, and/or coloring agents.

The bacterial composition can be prepared as a food or drink, or an additive to a food or drink, containing a bacterial species or combination of bacterial species described herein.

A bacterial composition for the inventive use may contain or may be administered in conjunction with a prebiotic described herein.

A prebiotic composition described but not claimed herein may contain a therapeutically effective amount of one or more prebiotics that promote the growth of one or more bacteria selected from the group consisting of: (a) Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium; or (b) Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza.

The prebiotic composition may contain one or more prebiotics selected from the group consisting of a mucin (e.g., porcine gastric mucin), inulin, N-acetyl-D-glucosamine, N-acetyl-D-mannosamine, glucose-<NUM>-phosphate, D-fructose, a galactomannan, N-acetyl mannosamine, N-acetylgalactosamine, N-acetylneuraminic acid, N-acetyl glucosamine, galactose, fucose, mannose, human milk oligosaccharides, guar gum, dextrin, α-cellulose, β-D glucan, pectin, com starch, and potato starch.

The prebiotic composition may contain N-acetyl-D-glucosamine and N-acetyl-D-mannosamine.

The prebiotic composition may contain glucose-<NUM>-phosphate and D-fructose.

A prebiotic composition can be administered to a subject as, for example, a medical food, a nutraceutical, or a nutritional supplement, or a component of a medical food, a nutraceutical, or a nutritional supplement.

A prebiotic composition can be administered to a subject, for example, orally or rectally (e.g., into at least one of the terminal ileum and right colon).

A prebiotic composition may contain a single prebiotic that promotes the growth of one or more bacteria selected from the group consisting of: (a) Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium; or (b) Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza.

A prebiotic composition may contain two or more prebiotics that promote the growth of one or more bacteria selected from the group consisting of: (a) Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium; or (b) Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza, e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or more prebiotics that promote the growth of one or more bacteria selected from the group consisting of: (a) Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium; or (b) Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza. The prebiotic composition may contain no more than <NUM> prebiotics that promote the growth of one or more bacteria selected from the group consisting of: (a) Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium; or (b) Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza, e.g., <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, <NUM>, or <NUM> prebiotic that promotes the growth of one or more bacteria selected from the group consisting of: (a) Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium; or (b) Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza.

The prebiotic composition may comprise <NUM> to <NUM> of prebiotic. The prebiotic composition may comprise <NUM> to <NUM> of prebiotic. The prebiotic composition may comprise <NUM> to <NUM> of prebiotic. The prebiotic composition may comprise <NUM> to <NUM> of prebiotic. The prebiotic composition may comprise <NUM> to <NUM> of prebiotic. The prebiotic composition may comprise <NUM> to <NUM> of prebiotic. The prebiotic composition may comprise <NUM> to <NUM> of prebiotic. The prebiotic composition may comprise <NUM> to <NUM> of prebiotic.

A prebiotic composition can be prepared in a variety of forms, such as capsules, tablets, suppositories, food, or drink. Optionally, the prebiotic composition can include a pharmaceutically acceptable excipient, such as microcrystalline cellulose, mannitol, glucose, defatted milk powder, polyvinylpyrrolidone, starch, and combinations thereof.

The prebiotic composition can be prepared as a capsule containing a prebiotic or combination of prebiotics described herein. The capsule can be a hollow capsule formed from substances such as, e.g., gelatin, cellulose, or carbohydrate. The prebiotic composition can be formulated such that the prebiotic is not exposed to conditions prevalent in the gastrointestinal tract before the colon, e.g., high acidity and digestive enzymes present in the stomach and/or intestine. The capsule can be made from aqueous solutions of gelling agents such as animal protein (e.g., gelatin), plant polysaccharides or derivatives such as carrageenans and modified forms of starch and cellulose. Other ingredients may be added to a gelling agent solution such as plasticizers (e.g., glycerin and or sorbitol), coloring agents, preservatives, disintegrants, flavoring, rice or other starch, glycerin, caramel color, titanium dioxide lubricants, and/or a surface treatment.

The prebiotic composition can be prepared as a tablet containing a prebiotic or combination of prebiotics described herein. The tablet can include a prebiotic and one or more tableting agents, such as dibasic calcium phosphate, stearic acid, croscarmellose, silica, cellulose, and/or a cellulose coating.

The prebiotic composition can be prepared as a suppository containing a prebiotic or combination of prebiotics described herein. The suppository can include a prebiotic and one or more carriers, such as polyethylene glycol, acacia, acetylated monoglycerides, carnuba wax, cellulose acetate phthalate, corn starch, dibutyl phthalate, docusate sodium, gelatin, glycerin, iron oxides, kaolin, lactose, magnesium stearate, methyl paraben, pharmaceutical glaze, povidone, propyl paraben, sodium benzoate, sorbitan monoleate, sucrose talc, titanium dioxide, white wax, and/or coloring agents.

The prebiotic composition can be prepared as a food or drink, or an additive to a food or drink, containing a prebiotic or combination of prebiotics described herein.

A prebiotic composition may contain or may be administered in conjunction with a bacterial species described herein.

The bacterial species and prebiotics described herein can be administered together as a combination treatment.

The subject may be administered <NUM> million to <NUM> billion CFU of bacteria and <NUM> to <NUM> of prebiotic. The subject may be administered <NUM> million to <NUM> billion CFU of bacteria and <NUM> to <NUM> of prebiotic.

The may be The subject may be administered <NUM> million to <NUM> billion CFU of bacteria and <NUM> to <NUM> of prebiotic.

The bacterial species for the inventive use as defined in the claims are to be administered together with.

a BRAF inhibitor, or a MEK inhibitor. A composition for the inventive use as defined in the claims containing a therapeutically effective amount of one or more bacteria selected from the group consisting of: Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium may be administered in combination with an immune checkpoint activator. In one example, the immune checkpoint activator may be an agonist of costimulation by CD27 (e.g., an agonist antibody that binds to CD27). In one example, the immune checkpoint activator may be an agonist of costimulation by CD40 (e.g., an agonist antibody that binds to CD40). In one example, the immune checkpoint activator may be an agonist of costimulation by OX40 (e.g., an agonist antibody that binds to OX40). In one example, the immune checkpoint activator may be an agonist of costimulation by GITR (e.g., an agonist antibody that binds to GITR). In one example, the immune checkpoint activator may be an agonist of costimulation by CD137 (e.g., an agonist antibody that binds to CD137). In one example, the immune checkpoint activator may be an agonist of costimulation by CD28 (e.g., an agonist antibody that binds to CD28). In one example, the immune checkpoint activator may be an agonist of costimulation by ICOS (e.g., an agonist antibody that binds to ICOS). In some of these examples, the human subject may be identified as having poor responsiveness to treatment with the immune checkpoint activator prior to initiating administration of the one or more bacteria.

A composition for the inventive use as defined in the claims containing a therapeutically effective amount of one or more bacteria selected from the group consisting of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium may be administered in combination with an immune checkpoint inhibitor. In one example, the immune checkpoint inhibitor may be an antagonist of PD-<NUM> (e.g., an antagonist antibody that binds to PD-<NUM>). In one example, the immune checkpoint inhibitor may be an antagonist of PD-L1 (e.g., an antagonist antibody that binds to PD-L1). In one example, the immune checkpoint inhibitor may be an antagonist of CTLA-<NUM> (e.g., an antagonist antibody that binds to CTLA-<NUM>). In one example, the immune checkpoint inhibitor may be an antagonist of A2AR (e.g., an antagonist antibody that binds to A2AR). In one example, the immune checkpoint inhibitor may be an antagonist of B7-H3 (e.g., an antagonist antibody that binds to B7-H3). In one example, the immune checkpoint inhibitor may be an antagonist of B7-H4 (e.g., an antagonist antibody that binds to B7-H4). In one example, the immune checkpoint inhibitor may be an antagonist of BTLA (e.g., an antagonist antibody that binds to BTLA). In one example, the immune checkpoint inhibitor may be an antagonist of IDO (e.g., an antagonist antibody that binds to IDO). In one example, the immune checkpoint inhibitor may be an antagonist of KIR (e.g., an antagonist antibody that binds to KIR). In one example, the immune checkpoint inhibitor may be an antagonist of LAG3 (e.g., an antagonist antibody that binds to LAG3). In one example, the immune checkpoint inhibitor may be an antagonist of TIM-<NUM> (e.g., an antagonist antibody that binds to TIM-<NUM>). In one example, the immune checkpoint inhibitor may be an antagonist of VISTA (e.g., an antagonist antibody that binds to VISTA). In one example, the immune checkpoint inhibitor may be an antagonist of CD160 (e.g., an antagonist antibody that binds to CD160). In one example, the immune checkpoint inhibitor may be an antagonist of TIGIT (e.g., an antagonist antibody that binds to TIGIT). In one example, the immune checkpoint inhibitor may be an antagonist of PSGL-<NUM> (e.g., an antagonist antibody that binds to PSGL-<NUM>). In some of these examples, the human subject may be identified as having poor responsiveness to treatment with the immune checkpoint inhibitor prior to initiating administration of the one or more bacteria.

A composition for the inventive use as defined in the claims containing a therapeutically effective amount of one or more bacteria selected from the group consisting of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium may be administered in combination with an immune checkpoint regulator. In one example, the immune checkpoint regulator may be CDX-<NUM>. In one example, the immune checkpoint regulator may be TGN1412. In one example, the immune checkpoint regulator may be NKTR-<NUM>. In one example, the immune checkpoint regulator may be MEDI0562. In one example, the immune checkpoint regulator may be MEDI6469. In one example, the immune checkpoint regulator may be MEDI6383. In one example, the immune checkpoint regulator may be JTX-<NUM>. In one example, the immune checkpoint regulator may be Keytruda (pembrolizumab). In one example, the immune checkpoint regulator may be Opdivo (nivolumab). In one example, the immune checkpoint regulator may be Yervoy (ipilimumab). In one example, the immune checkpoint regulator may be tremelimumab. In one example, the immune checkpoint regulator may be Tecentriq (atezolizumab). In one example, the immune checkpoint regulator may be MGA271. In one example, the immune checkpoint regulator may be indoximod. In one example, the immune checkpoint regulator may be Epacadostat. In one example, the immune checkpoint regulator may be lirilumab. In one example, the immune checkpoint regulator may be BMS-<NUM>. In one example, the immune checkpoint regulator may be MPDL3280A. In one example, the immune checkpoint regulator may be avelumab. In one example, the immune checkpoint regulator may be durvalumab. In one example, the immune checkpoint regulator may be MEDI4736. In one example, the immune checkpoint regulator may be MEDI4737. In one example, the immune checkpoint regulator may be TRX518. In one example, the immune checkpoint regulator may be MK-<NUM>. In one example, the immune checkpoint regulator may be urelumab (BMS-<NUM>). In one example, the immune checkpoint regulator may be PF-<NUM> (PF-<NUM>). In some of these examples, the human subject may be dentified as having poor responsiveness to treatment with the immune checkpoint regulator prior to initiating administration of the one or more bacteria.

A composition for the inventive use as defined in the claims containing a therapeutically effective amount of one or more prebiotics that promote the growth of one or more bacteria selected from the group consisting of (a) Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium or (b) Bacteroides acidifaciens, Bacteroides xylanisolvens, Bacteroides chinchilla (B. sartorii), B. thetaiotaomicron, B. fragilis, Dysgonomonas wimpennyi, Parabacteroides merdae, Flavobacterium, Staphylococcus spp. , Staphylococcus sciuri, Staphylococcus xylosus, Helicobacter ganmani, Helicobacter hepaticus, Enterobacter hormaechei, Porphyromonas canis, Porphyromonas gingivicanis, Rickenella microfusus, Olivibacter spp, P. goldsteinii, P. koreensis, Pedobacter spp. sinus, Blautia hansenii, and Lachnospira pectinoschiza may be administered in combination with an immune checkpoint regulator. In one example, the immune checkpoint regulator may be CDX-<NUM>. In one example, the immune checkpoint regulator may be TGN1412. In one example, the immune checkpoint regulator may be NKTR-<NUM>. In one example, the immune checkpoint regulator may be MEDI0562. In one example, the immune checkpoint regulator may be MEDI6469. In one example, the immune checkpoint regulator may be MEDI6383. In one example, the immune checkpoint regulator may be JTX-<NUM>. In one example, the immune checkpoint regulator may be Keytruda (pembrolizumab). In one example, the immune checkpoint regulator may be Opdivo (nivolumab). In one example, the immune checkpoint regulator may be Yervoy (ipilimumab). In one example, the immune checkpoint regulator may be tremelimumab. In one example, the immune checkpoint regulator may be Tecentriq (atezolizumab). In one example, the immune checkpoint regulator may be MGA271. In one example, the immune checkpoint regulator may be indoximod. In one example, the immune checkpoint regulator may be Epacadostat. In one example, the immune checkpoint regulator may be lirilumab. In one example, the immune checkpoint regulator may be BMS-<NUM>. In one example, the immune checkpoint regulator may be MPDL3280A. In one example, the immune checkpoint regulator may be avelumab. In one example, the immune checkpoint regulator may be durvalumab. In one example, the immune checkpoint regulator may be MEDI4736. In one example, the immune checkpoint regulator may be MEDI4737. In one example, the immune checkpoint regulator may be TRX518. In one example, the immune checkpoint regulator may be MK-<NUM>. In one example, the immune checkpoint regulator may be urelumab (BMS-<NUM>). In one example, the immune checkpoint regulator may be PF-<NUM> (PF-<NUM>). In some of these examples, the human subject may be identified as having poor responsiveness to treatment with the immune checkpoint regulator prior to initiating administration of the one or more prebiotics.

In some embodiments, a composition for the inventinve use as defined in the claims comprising therapeutically effective amount of one or more bacteria selected from the group consisting of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium is to be administered in combination with a BRAF inhibitor. In one embodiment, the BRAF inhibitor is vemurafenib. In one embodiment, the The composition as defined in the claims in combination with the BRAF inhibitor BRAF inhibitor is dabrafenib. The composition as defined in the claims in combination with the BRAF inhibitor is used to treat melanoma in the human subject. The human subject is identified as having a mutation in the BRAF gene prior to the combination treatment. In some embodiments the human subject is identified as having the V600E, R461I, I462S, G463E, G463V, G465A, G465E, G465V, G468A, G468E, N580S, E585K, D593V, F594L, G595R, L596V, T5981, V599D, V599E, V599K, V599R, V600K, and/or A727V mutation in the BRAF gene prior to the combination treatment. The human subject is identified as having poor responsiveness to treatment with the BRAF inhibitor prior to initiating administration of the composition defined in the claims.

In some embodiments, a composition for the inventive use as defined in the claims comprising a therapeutically effective amount of one or more bacteria selected from the group consisting of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium is to be administered in combination with a MEK inhibitor. In one embodiment, the MEK inhibitor is trametinib. In one embodiment, the MEK inhibitor is cobimetinib. In one embodiment, the MEK inhibitor is binimetinib. In one embodiment, the MEK inhibitor is selumetinib. In one embodiment, the MEK inhibitor is PD-<NUM>. In one embodiment, the MEK inhibitor is CI-<NUM>. In one embodiment, the MEK inhibitor is TAK-<NUM>. The composition as defined in the claims in combination with the MEK inhibitor is used to treat melanoma in the human subject. The human subject is identified as having a mutation in the NRAS gene prior to the combination treatment. The human subject is identified as having poor responsiveness to treatment with the MEK inhibitor prior to initiating administration of the composition.

To determine whether RING finger protein <NUM>-/- (Rnf5-/-) mice exhibit altered immune checkpoint function, the growth of mouse melanoma cell lines was evaluated in syngeneic Rnf5-/- C57BL/<NUM> mice. Tumors arising from B16F10, or from YUMM1. <NUM>, YUMM1. <NUM> or YUMM1. <NUM>, BrafV600E::Pten-/-::Cdkn2a-/- cell lines, or YUMM1. <NUM> expressing shRNF5, grew more slowly and were significantly smaller in Rnf5-/- mice than in wild-type (WT) mice obtained from crosses of Rnf5 heterozygotes (<FIG>). Analysis of tumor-infiltrating cells isolated at <NUM> and <NUM> days after cell injection showed markedly higher CD44 effector (CD44hi) CD8+ and CD4+ T cells and CD45+ cells in the in tumors from Rnf5--l- mice compared to WT mice (<FIG>). Tumor-infiltrating CD4+ and CD8+ lymphocytes (TILs) from Rnf5-/- mice displayed greater effector function, as indicated by IFN-γ, TNF-α and IL-<NUM> expression (<FIG>), suggesting that increased recruitment and TIL effector function underlies the more potent anti-tumor response of Rnf5-/- mice. The inhibitory checkpoint receptors PD-<NUM>, TIM-<NUM>, and LAG-<NUM> were upregulated on Rnf-<NUM>-/-CD8+ T cells, and PD-L1 expression was upregulated on Rnf5-/- macrophages and dendritic cells (DCs), implying that the stimulated immune status of these mice overcomes checkpoint-mediated inhibition of the anti-tumor response. In support of this, expression of MHC class II and immunostimulatory CD80 and CD86 molecules were higher on tumor infiltrating macrophages from Rnf5-/- mice compared to WT mice; the total number of DCs was higher in tumors from Rnf5-/- mice including myeloid (mDCs) as well as plasmacytoid (pDCs) and CD8alpha+ conventional DCs (<FIG>). Rnf5-/- DCs also expressed higher levels of MHC class II as well as the costimulatory molecules CD40, CD80, and CD86 (<FIG>). These data indicate a clear shift to a proinflammatory tumor microenvironment in Rnf5-/- mice.

To determine whether the observed "immune checkpoint" phenotype of Rnf5-/-mice was due to RNF5 deficiency in cells from the hematopoietic or stromal compartment, tumor growth was examined in bone marrow chimeras created by injecting WT or Rnf5-/-bone marrow cells into lethally irradiated WT or Rnf5-/- animals. Tumor growth in WT→Rnf5-/- and Rnf5-/-→WT chimeras was comparable to that in WT→WT mice, indicating that the absence of RNF5 in both hematopoietic and non-hematopoietic cells is required for the anti-tumor response of Rnf5-/- mice (<FIG>). Moreover, depletion of either CD4+ (<FIG>) or CD8+ (<FIG>) T cells, but not blockade of PD-<NUM>, abrogated the ability of Rnf5-/- mice to inhibit melanoma tumor growth. Collectively, these results point to a critical role for RNF5 in the CD4+ and CD8+ T cell-dependent anti-tumor immune response.

The fecal microbiota of Rnf5-/- and WT mice were analyzed. In an initial analysis, the microbial profiles highlighted several differences prior, and more significantly, following tumor cell injection involving distinct taxonomic groups. Of those, increased relative abundance of several bacterial taxa (including Bacteroides spp. acidifaciens, B. chinchilla, B. xylanisolvens, Parabacteroides merdae, Porphyromonas canis, Rickenella microfusus) and decreased abundance of others (including unclassified Bifidobacterium spp. choerinum, Odoribacter denticanis, Parabacteroides goldsteinii, unclassified Olivibacter, Parapedobacter koreensis) typified the microbiome of Rnf5-/- mice bearing tumors, compared with the WT genotype.

The fecal microbiota of Rnf5-/- and WT mice were further analyzed. Marked differences in the microbial profiles were observed, highlighting differences in community structure depicted in principle component analysis that distinctly segregated Rnf5-/- from WT microbiota. Analysis of microbiota allowed the identification of <NUM> phylotypes that distinguished Rnf5-/- and WT microbiota in tumor bearing mice (<FIG>). These phylotypes are dominated by a few taxonomic groups, the largest of which fall into the Clostridium cluster (<NUM>%). All but four of these may be assigned to Clostrium cluster IV or XIVa, known to be capable of producing butyrate that may influence Foxp3+Treg cells expansion. A relatively large portion of the distinguishing taxa are related to Muribaculm intestinale (<NUM>%) that are phylogenetically similar to the better described Barnesiella.

From these studies, the following bacterial strains were identified as being associated with inhibition of tumor growth: Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium.

These observations prompted us to ask whether the gut microbiome might play a direct role in the immune checkpoint phenotype of Rnf5-/- mice. Treatment of mice with an antibiotic cocktail for two weeks, which is expected to eliminate most gut bacteria, increased the tumor growth rate in Rnf5-/- mice compared with untreated controls, suggesting that the gut microbiome influences tumor growth (<FIG>). Co-housing of Rnf5-/- and WT mice prior to tumor cell injection led to a convergence of the gut microbiota, such that Rnf5-/-was more similar to that of WT mice than Rnf5-/- mice housed alone.

Significantly, co-housing largely eliminated the Rnf5-/- suppression of tumor growth by Rnf5-/- mice (<FIG>), concomitant with a reduction in CD44hiCD4+, CD44hiCD8+ T cells and CD45+ cells, and cytokine production (<FIG>) and numbers of DCs and DC subsets (<FIG>) and MHC class II expression on DCs. Finally, the differences in PD-<NUM> and LAG-<NUM> expression between TILs from Rnf5-/- and WT mice were eliminated following co-housing. Collectively, these data support a role for cross-talk between the gut microbiota and immune system in the suppression of tumor growth in Rnf5-/- mice.

Differences in immunoregulatory gene expression between TILs from WT and Rnf5-/-mice were mapped by performing NanoString analysis of <NUM> genes expressed by <NUM> different immune cell types. This analysis identified marked changes in key immune regulatory networks associated with T, NK, DC and macrophage cell function. Interestingly, changes in the expression of chemokines and genes related to antigen presentation and DC function networks pointed to the possible role of Toll like receptors (TLRs) in the phenotype of Rnf5-/- mice. Changes in gene expression identified in the NanoString analysis were confirmed by qPCR analysis of cDNA derived from tumors grown in WT and Rnf5-/- mice.

Consistent with the elevated levels of TILs in Rnf5-/- mice, cytokine analysis identified higher levels of TNF-α and IFN-β in the sera of naive Rnf5-/- mice (<FIG>); however, these mice exhibited reduced levels of TNF-α, IL-<NUM>, IL-<NUM>, and IL-1α compared with WT mice after tumor cell inoculation (<FIG>). These findings are consistent with reports that high IL-<NUM>, TNF-α and IL-<NUM> levels are associated with poor clinical outcome, while lower IL1-α levels are associated with attenuated tumor growth. These findings further support the role of intrinsic inflammation in the anti-tumor response seen in the Rnf5-/- mice.

To provide independent support for the role of tumor specific T cells in the anti-tumor response of Rnf5-/- mice, OVA-specific OT-I transgenic CD8+ T cells were transferred into WT or Rnf5-/- recipient mice, and then injected the animals subcutaneously with OVA-expressing B16F10 melanoma cells. Analysis of tumor draining and non-draining lymph nodes showed that OT-I CD8+ T cells were more abundant in the tumor draining lymph nodes of Rnf5-/- mice compared with WT mice, despite their comparable proliferation, whereas no differences were observed in the non-draining lymph nodes (<FIG>).

To understand the mechanism by which altered function of Rnf5-/- mice might influence the anti-tumor immune response, changes in the intestinal epithelial cells (IECs) were examined, which cells play critical roles in both innate and adaptive immunity. A significant decrease in the villi length and increase in the depth of crypts was observed in tumor-bearing Rnf5-/- mice, compared with WT mice (<FIG>), both of which are associated with increased inflammation, which was reflected in the production of a number of inflammatory cytokines (<FIG>). Notably, co-housing of Rnf5-/- and WT mice partially restored villi length to that seen in Rnf5-/- alone animals, suggesting a direct link between the gut microbiota and intestinal structure. IECs from the Rnf5-/- mice exhibited increased expression of ER stress marker BIP (<FIG>), which was expected given the role of RNF5 in ER associated degradation. Furthermore, co-housed Rnf5-/- and WT mice partially restored BIP expression to that seen in Rnf5-/- alone mice. Consistent with this, organoids prepared from the IEC of tumor-bearing Rnf5-/- mice also exhibited a higher level of ER stress, increased apoptosis, and were fewer in number than WT IEC-derived organoids. These data point to a possible role of ER stress in key phenotypes seen in the Rnf5-/- mice, which were previously linked with altered immune response. However, treatment of Rnf5-/- mice with the chemical chaperone <NUM>-phenylbutyrate to alleviate ER stress did not affect tumor growth, probably due to its known antagonistic effect on immune cell function.

It was next investigated whether the intestinal alterations in Rnf5-/- mice affect immune cell recruitment and activity. Indeed, a significant increase in CD11c+ DCs was detected in the intestine of Rnf5-/- mice, compared with the WT mice. This finding is consistent with reports that CD11c+ DCs play a role in triggering immune responses that enhance immune checkpoint therapy. Although no difference in DC populations was observed in intestine-proximal lymphoid organs (Peyer's patches) in naïve WT and Rnf5-/-mice, DCs and pDC were significantly more abundant in Peyer's patches from tumor bearing Rnf5-/- mice, than the control WT littermates. These data demonstrate that Rnf5 controls dynamic changes in Peyer's patches-associated DCs, which are known to play key roles in the regulation of the immune response.

To probe these findings further, DCs from were isolated Peyer's patches of naive WT and Rnf5-/- mice and examined their in vitro response to several TLR agonists. Of note, DCs from Rnf5-/- mice produced higher levels of IL-1β in response to TLR7 stimulation, higher levels of IL-1β, IL-17A and IL-<NUM> in response to TLR9 stimulation, and lower levels of IL-<NUM> in response to both TLR7 and TLR9 stimulation, compared with WT DCs. Likewise, production of chemokines, including CCL5, CCL22, CXCL1, and CXCL5 was more effectively induced by TLR7 stimulation of Rnf5-/- DCs compared to WT DCs. The responses of Peyer's patch-derived DCs to TLR7 and TLR9 agonists are consistent with their expression in select organs / tissues.

The differences in the gut microbiota of Rnf5-/- and WT mice before and during tumor formation highlighted a functionally coherent group of species that define a food web enriched for species encoding extensive glycosyl hydrolase activities. Similar alterations in the relative abundance of Bifidobacterium, Bacteroides, Parabacteroides were also observed upon cultivation of human fecal samples in media featuring porcine gastric mucin, galactomannans and N-acetyl mannosamine as the sole carbohydrate source (<FIG>). These observations implied that altered availability of simple sugar moieties derived from complex carbohydrates may be a key feature of the Rnf5-/- phenotype. Consistent with this notion is the shift in relative abundance of fermentative species, including a reduction in members of Lachnospiraceae (Oribacterium spp. , Oscillispira) and Ruminococcaceae, that is coupled with increased abundance of species that may cross-feed on available sugars more effectively (i.e. Bacteroides spp. microfusus and Flavobacterium). To further assess this possibility, a metabolic model for the gut microbiota was constructed using <NUM> gut microbiota species that exhibit significant differences in WT and Rnf5-/- mice prior to and following tumor inoculation (<FIG>). This analysis allowed the prediction of a defined media capable of sustaining the observed abundance differences over time. In this media, galactose, N-acetyl-D-glucosamine and N-acetyl-D-mannosamine that are components of mucin and glucose-<NUM>-phosphate and D-fructose, which are products of inulin catabolism, are predicted to be consumed at a higher rate in Rnf5-/- microbiota, pointing to the possible importance of these substrates in accounting for the observed differences in the gut community (<FIG>). These findings, together with the elevated Mucin <NUM> expression in Rnf5-/- mice, suggested that mucin and/or inulin metabolism may drive the observed anti-tumor phenotypes.

The anti-tumor efficacy of mucin and inulin (see below), together with the strong conservation in taxa dynamics observed in the Rnf5-/- gut microbiota suggests that a key functional distinction between WT and Rnf5-/- microbiota also involves differential glycan and sugar metabolism. Both mucin and inulin suppressed large portions of Lactobacillus spp. , Ruminococaceae and Lachnospiriaceae highlighting major shifts in carbohydrate metabolism. The induction patterns of mucin and inulin fed WT and Rnf5-/-mice revealed an enrichment of Bacteroides spp. goldsteinii, P. koreensis, unclassified Pedobacter and O. sinus and reduced abundance for S. hydroxybenzoicus, Blautia spp. These patterns are highly concordant with those observed in Rnf5-/- microbiota. Spearman and Pearson correlation analysis confirmed that the relative abundance of B. acidifaciens, B. xylanisolvens, P. merdae, Flavobacterium correlated with reduced tumor growth and anti-tumorigenic TILs (Table <NUM>). Taken together, the analysis strongly supports that altered metabolism of complex carbohydrates acts as a driver of gut microbiota-elicited changes seen in the Rnf5-/-mice. Complex carbohydrates can be depolymerized in the endosomes of APCs that are then presented to CD4+ T cells by MHC-II molecules.

Mucin2 is prominently expressed by goblet cells and subsequently becomes heavily O-glycosylated where it plays a critical role in intestinal epithelial barrier function, but also serves as a continuous energy source for mucosal-associated bacterial populations. Mucin2 expression was found to be significantly higher in the jejunum, ileum, and colon of tumor-bearing Rnf5-/- mice compared with WT mice (<FIG>), but not in the naïve mice. Furthermore, possible differences were examined in the sugar composition of mucin2, that may influence the antigenicity of mucin2. Analysis of mucin prepared from the small intestine of tumor-bearing Rnf5-/- mice showed higher Galactose, N-acetylgalactosamine (GalNAC), N-acetylglucosamine (GlcNAC) and reduced sialic acid (N-acetylneuraminic acid, Neu5A) compared to WT littermates. Consistent with these findings, GalNAc glycosylation has been implicated in enhanced antigen uptake by DCs and CD4+ T-cell, enhancing humoral responses. Likewise, O-GlcNAc modification was implicated in productive T-cell activation and Neu5Ac was associated with IL-<NUM> and IL-<NUM> expression and tumor promotion. Indeed, lower IL-<NUM> was detected in the serum of tumor-bearing Rnf5-/-mice, compared with WT littermates (<FIG>). Moreover, higher Fucose and GalNAc levels were observed in the small intestine and colon of naive Rnf5-/- mice, compared with the WT littermates. Microbiota-induced host-derived fucose signaling has been implicated in pathogenic intestinal colonization further supporting mucin glycosylation in microbial ecology. Indeed, mucin glycosylation correlates with distinct microbial communities. Consistent with these reports, our findings of altered mucin2 glycosylation, expression and the recruitment of CD11c+ DC in the intestine and the Peyer's patches, is likely to provide the basis for changes observed in tumors and in draining lymph nodes of the tumor bearing Rnf5-/- mice.

To determine whether differences in mucin2 glycosylation might drive the observed differences in the gut microbiota of Rnf5-/- mice, a computer simulation was performed to identify the media requirements (diet) required to maintain the observed abundances of taxa distinguishing Rnf5-/- and WT microbiota in tumor bearing mice. Using a metabolic model, microbial were generated communities using five select species to represent the families that distinguish Rnf5-/- and WT microbiota (Table <NUM>) to model the uptake and utilization of substrates by the communities. The results of the simulation identified substantial differences in the uptake of mucin components including: D-mannose, N-acetyl-D-glucosamine and galactose (Table <NUM>). Using a "leave one out" approach it was determined that the utilization of these products within the model were dependent on the presence of C. leptum and B. longum, but not of the other community members. These findings suggested that mucin metabolism by Rnf5-/- gut microbiota may be a driver of the anti-tumor phenotype.

To test this directly it was investigated whether administration of mucin to WT mice could phenocopy Rnf5-/- mice, in terms of tumor growth, immune response and gut microbiota composition. Strikingly, administration of porcine gastric mucin (<NUM>% in drinking water) to WT mice attenuated melanoma growth to the degree seen in Rnf5-/- mice, but did not further attenuate tumor growth in Ruf5-/- mice (<FIG>). Fecal cultivation experiments in vitro indicated that inulin as the sole carbohydrate source generated communities similar to that of gastric mucin, prompting us to test this prebiotic also in mice in vivo (SNP, unpublished results). Inulin fed mice (<NUM>% chow) also exhibited effective inhibition of melanoma growth (<FIG>). This prompted us to use machine learning to identify phylotypes that best distinguished WT (non-attenuated tumor growth) from Rnf5-/- and WT mice treated with mucin or inulin (attenuated tumor growth). This resulted in the identification of <NUM> phylotypes exhibiting consistent alterations in all tumor attenuated phenotypes (<FIG>). The immune status of mucin and inulin-fed WT mice also shifted to resemble that of Rnf5-/- mice. Thus, mucin administration increased the number of CD44hiCD4+, CD44hiCD8+ and CD45+ cells, enhanced TIL cytokine production, increased the number of tumor-associated total DCs and DC subsets. Inulin administration resulted in a similar tumor infiltrating immune cell phenotype. Notably, mucin and inulin also induced a shift in the transcription of immune-related genes to that seen in Rnf5-/- mice, albeit to a lower extent. Collectively, these data suggest that mucin catabolism or inulin/mucin treatment shapes the immune regulatory components of the anti-tumor response.

To determine whether TLR4, the receptor for bacterial lipopolysaccharides, might be involved in the mucin-induced anti-tumor immune phenotype, the growth of mouse melanoma SW1 cells was examined in Tlr4-/- C3H/HeJ mice. Importantly, feeding of mucin or inulin to these mice failed to significantly attenuate melanoma growth (<FIG>), demonstrating a requirement for TLR4 in the mucin-induced anti-tumor response. Interestingly, mucin, but not inulin induced an increase in CD8+ T cells and TNF-α-producing tumor-infiltrating CD4+ T cells in these mice, indicating that these cells alone are insufficient to induce tumor regression.

Next, it was determined whether mucin or inulin are also able to impact growth of colon cancer cells, representative of a different tumor type. Growth of MC-<NUM> cells injected to WT mice was attenuated by inulin but not mucin (<FIG>). Further, increase in the infiltration of MHC-I and MHC-I on DC cells was noted following inulin administration. Significantly, intrinsic resistance of N-Ras mutant melanoma cells to MEK inhibitor (MEKi) was attenuated upon combined administration of inulin and MEKi (<FIG>). Corresponding increase in CD4, CD8, CD45 and DC, including pDC and mDC and MHC-I expression on DC, was identified in tumors subjected to the MEKi+inulin treatment.

Claim 1:
A composition comprising a therapeutically effective amount of one or more bacteria for use in treating a cancer in a human subject in need thereof, wherein the composition is to be administered to the human subject and the one or more bacteria are selected from the group consisting of Oscillibacter valericigenes, Acetatifactor muris, Alistipes putredinis, Alistipes finegoldii, Clostridium clostridioforme, Lactobacillus animalis, Lactobacillus murinus, Bacteroides massiliensis, Bacteroides sartorii, Muribaculum intestinale, Parasutterella excrementihominis, Clostridium methylpentosum, and Bacteroides rodentium,
wherein
(i) the human subject is identified as having a mutation in the Neuroblastoma RAS (NRAS) gene and poor responsiveness to treatment with a Mitogen-activated protein kinase (MEK) inhibitor prior to administration of the composition and wherein the composition is to be administered to the human subject in combination with a MEK inhibitor; or
(ii) the human subject is identified as having a mutation in the Serine/threonine-protein kinase B-raf (BRAF) gene and poor responsiveness to treatment with a BRAF inhibitor prior to administration of the composition and wherein the composition is to be administered to the human subject in combination with a BRAF inhibitor,
wherein the cancer is melanoma.