Methods and compositions for reducing vancomycin-resistant enterococci infection or colonization

Abstract

The present invention relates to methods and compositions for reducing the risk and severity of vancomycin-resistant Enterococci infection or colonization. It is based, at least in part, on the discovery that a restricted fraction of the gut microbiota, including the bacteria Clostridium scindens and/or the bacteria Blautia producta contribute substantially to resistance against vancomycin-resistant Enterococci infection or colonization. Without being bound by any particular theory, it is believed that this is achieved through the biosynthesis of secondary bile acids in the case of Clostridium scindens.

We claim: 
     
         1 . A method for reducing the risk of vancomycin-resistant Enterococci (VRE) infection or VRE colonization in a subject, and/or increasing resistance to VRE infection or VRE colonization in the subject, and/or reducing the severity of VRE infection in the subject, and/or reducing the amount of VRE colonizing the subject, comprising administering, to the subject in need of such treatment, a therapeutically effective amount of a composition comprising at least one of a  Clostridium scindens  bacteria and/or a  Blautia producta  bacteria in a formulation suitable for administration to the subject. 
     
     
         2 . The method of  claim 1 , wherein the composition comprises both the  Clostridium scindens  bacteria and the  Blautia producta  bacteria. 
     
     
         3 . The method of  claim 1  or  claim 2 , wherein the composition further comprises one or more additional species of bacteria selected from the group consisting of a member of the Bacteroidetes phylum and a member of the Firmicutes phylum. 
     
     
         4 . The method of  claim 3 , wherein the additional species of bacteria that is a member of the Firmicutes phylum is a member of the Lachnospiraceae family. 
     
     
         5 . The method of  claim 1  or  claim 2 , wherein the composition further comprises one or more additional species of bacteria selected from the group consisting of a  Barnesiella intestihominis, Blautia hansenii, Pseudoflavonifractor capillosus, Clostridium hiranonis, Clostridium hylemonae, Clostridium perfringens, Clostridium sordellii, Proteocatella sphenisci , Lachnospiraceae 5_1_57FAA, Clostridiales VE202-05 and Clostridiales VE202-26. 
     
     
         6 . The method of  claim 1  or  claim 2 , wherein the composition further comprises the  Clostridium scindens  bacteria and a  Blautia hansenii  bacteria. 
     
     
         7 . The method of  claim 1  or  claim 2  wherein the composition further comprises the  Blautia producta  bacteria and a  Clostridium bolteae  bacteria. 
     
     
         8 . The method of  claim 1  or  claim 2 , wherein the composition further comprises one or more additional species of bacteria selected from the group consisting of  Parabacteroides distasonis, Bacteroides sartorii, Clostridium innocuum, Akkermansia muciniphila, Clostridium bolteae, Blautia  unclassified, and  Eubacterium dolichum.    
     
     
         9 . The method of any one of  claims 1 - 8 , wherein the one or more recombinant bacteria can express one or more of a recombinant enzyme that can convert a primary bile acid to a secondary bile acid, synthesize a recombinant antibiotic resistance molecule, express a recombinant protease, and express a recombinant glycosidase. 
     
     
         10 . The method of  claim 9 , wherein the recombinant enzyme that can convert a primary bile acid to a secondary bile acid is a bile acid hydroxysterol dehydrogenase enzyme. 
     
     
         11 . The method of any one of  claims 1 - 10  comprising administering at least one bacteria as an isolated viable bacteria. 
     
     
         12 . The method of any one of  claims 1 - 10  comprising administering at least one bacteria as an isolated spore thereof. 
     
     
         13 . The method of any one of  claims 1 - 12  wherein the composition is formulated for oral, nasogastric, or rectal administration. 
     
     
         14 . The method of  claim 13 , wherein the composition further comprises a probiotic bacteria, probiotic yeast, or a combination thereof. 
     
     
         15 . The method of  claim 13 , wherein the composition is a liquid, suspension, dried powder, tablet, capsule or food product. 
     
     
         16 . The method of any one of  claims 1 - 15 , further comprising administering to the subject, an antibiotic, an immunotherapeutic agent, an herbal remedy, a probiotic bacteria, a probiotic yeast, or a combination thereof. 
     
     
         17 . The method of any one of  claims 1 - 16 , wherein the therapeutically effective amount ameliorates at least one symptom of VRE infection selected from the group consisting of abdominal tenderness, abdominal pain, abdominal cramping, sepsis, endocarditis, meningitis, headache, stiff neck, confusion, back pain, pneumonia, fever, chills, diarrhea, urinary tract infection, endocarditis, elevated white blood cell count, decreased serum albumin. 
     
     
         18 . The method of any one of  claims 1 - 17 , wherein the therapeutically effective amount inhibits proliferation of VRE in the gastrointestinal tract of the subject. 
     
     
         19 . The method of any one of  claims 1 - 18 , further comprising evaluating the VRE infection or VRE colonization in the subject by culturing a sample from the subject. 
     
     
         20 . The method of any one of  claims 1 - 19 , further comprising evaluating the VRE infection or VRE colonization in the subject by detecting a VRE biomarker in a sample from the subject. 
     
     
         21 . A therapeutic composition for treating vancomycin-resistant Enterococci (VRE) infection, the composition comprising at least one of an isolated  Clostridium scindens  bacteria and/or an isolated  Blautia producta  bacteria in a formulation suitable for administration to a subject. 
     
     
         22 . The composition of  claim 21 , comprising both the  Clostridium scindens  therapeutic bacteria and the  Blautia producta  therapeutic bacteria. 
     
     
         23 . The composition of  claim 21  or  claim 22 , further comprising one or more additional species of bacteria selected from the group consisting of a member of the Bacteroidetes phylum and a member of the Firmicutes phylum. 
     
     
         24 . The composition of  claim 23 , wherein the additional species of bacteria that is a member of the Firmicutes phylum is a member of the Lachnospiraceae family. 
     
     
         25 . The composition of  claim 21  or  claim 22  further comprising one or more additional species of bacteria selected from the group consisting of a  Barnesiella intestihominis, Blautia hansenii, Pseudoflavonifractor capillosus, Clostridium hiranonis, Clostridium hylemonae, Clostridium perfringens, Clostridium sordellii, Proteocatella sphenisci , Lachnospiraceae 5_1_57FAA, Clostridiales VE202-05 and Clostridiales VE202-26. 
     
     
         26 . The composition of  claim 21  or  claim 22 , further comprising the  Clostridium scindens  bacteria and a  Blautia hansenii  bacteria. 
     
     
         27 . The composition of  claim 21  or  claim 22 , further comprising the  Blautia producta  bacteria and  Clostridium bolteae  bacteria. 
     
     
         28 . The composition of  claim 21  or  claim 22  further comprising one or more additional species of bacteria selected from the group consisting of  Parabacteroides distasonis, Bacteroides sartorii, Clostridium innocuum, Akkermansia muciniphila, Clostridium bolteae, Blautia  unclassified, and  Eubacterium dolichum.    
     
     
         29 . The composition of any one of  claims 21 - 28 , wherein bacteria of the composition can express an enzyme that can convert a primary bile acid to a secondary bile acid, synthesize an antibiotic resistance molecule, express a protease, and express a glycosidase. 
     
     
         30 . The composition of any one of  claims 21 - 28 , wherein the one or more recombinant bacteria can express one or more of a recombinant enzyme that can convert a primary bile acid to a secondary bile acid, synthesize a recombinant antibiotic resistance molecule, express a recombinant protease, and express a recombinant glycosidase. 
     
     
         31 . The composition of  claim 30 , wherein the recombinant enzyme that converts a primary bile acid to a secondary bile acid is a bile acid hydroxysterol dehydrogenase enzyme. 
     
     
         32 . The composition of any one of  claims 21 - 31  wherein at least one isolated bacteria is an isolated spore thereof. 
     
     
         33 . The composition of any one of  claims 21 - 32  wherein the composition is formulated for oral, nasogastric, or rectal administration. 
     
     
         34 . The composition of  claim 33 , wherein the composition further comprises a probiotic bacteria, probiotic yeast, or a combination thereof. 
     
     
         35 . The composition of  claim 33 , wherein the composition is a liquid, suspension, dried powder, tablet, capsule or food product.