Compositions containing combinations of bioactive molecules derived from microbiota for treatment of disease

Abstract

Compositions consisting of bioactive molecules derived from the microbiota of a mammal are provided herein. When administered orally with a colonic delivery system, the compositions are useful for the prophylaxis and treatment of diseases, in particular inflammatory, autoimmune and infectious diseases. The compositions comprise combinations of small molecules and bacterial antigens formulated in colonic delivery systems. Use of the compositions results in any or all of: induction of immune tolerance; strengthening of the gut mucosal barrier integrity; reduction of inflammation; and amelioration of a disease state caused by inflammation, an autoimmune reaction or an infectious agent.

1 . A composition having an effect of inducing tolerance, strengthening gut barrier integrity, and reducing inflammation, the composition comprising: (a) one or more short-chain fatty acid or short-chain fatty acid derivative; (b) at least one GPR109 ligand; (c) at least one GPR43 ligand; (d) at least one histone-deacetylase (HDAC) inhibitor; (e) one or more antigen derived from bacteria belonging to  Clostridium  Cluster IV,  Clostridium  Cluster XIVa, or  Clostridium  Cluster XVIII; (f) a flagellin polypeptide; or (g) a combination of at least one of (a)-(d) and one of (e)-(f). 
     
     
         2 . The composition of  claim 1 , wherein (a) is selected from the group consisting of butyrate, isobutyrate, proprionate, acetate, tributyrin, pivaloyloxymethyl butyrate, and monoacetone glucose 3-butyrate. 
     
     
         3 . The composition of  claim 1 , wherein (a) is butyrate. 
     
     
         4 . The composition of  claim 1 , wherein (a) is a mixture of salts of butyrate, isobutyrate, propionate, and acetate. 
     
     
         5 . The composition of  claim 1 , wherein (f) is selected from the group consisting of flagellin, a flagellin-like sequence, a flagellin component, CBirl, Fla-X, FliC, FliD, FlgK, FlgC and FlgE. 
     
     
         6 . The composition of  claim 1 , wherein (f) is flagellin. 
     
     
         7 . The composition of  claim 1 , wherein the bacteria of (e) comprise a combination of bacteria from Clostridium Cluster IV and bacteria from  Clostridium  Cluster XIVa, or bacteria from  Clostridium  Cluster IV and bacteria from  Clostridium  Cluster XVIII, or bacteria from  Clostridium  Cluster XIVa and bacteria from  Clostridium  Cluster XVIII, or bacteria from  Clostridium  Cluster IV, bacteria from  Clostridium  Cluster XIVa, and bacteria from  Clostridium  Cluster XVIII. 
     
     
         8 . A composition having an effect of inducing tolerance, strengthening gut barrier integrity, and reducing inflammation, the composition comprising butyrate and flagellin. 
     
     
         9 . A composition having an effect of inducing tolerance, strengthening gut barrier integrity, and reducing inflammation, the composition comprising a mixture of salts of butyrate, isobutyrate, propionate, and acetate, and flagellin. 
     
     
         10 . The composition of  claim 1 , further comprising a delivery system that directs the composition preferentially to the colonic mucosa. 
     
     
         11 . A pharmaceutical composition comprising the composition according to  claim 1  and a pharmaceutically acceptable component. 
     
     
         12 . A method of inducing tolerance, strengthening gut barrier integrity, and reducing inflammation in an individual in need thereof, comprising administering, to the individual, the pharmaceutical composition of  claim 11 . 
     
     
         13 . A method of treating, aiding in treating, reducing the severity of, or preventing at least one disease selected from an autoimmune disease, an inflammatory disease, an allergic disease, and an infectious disease in an individual in need thereof, the method comprising administering the pharmaceutical composition of  claim 11  to the individual. 
     
     
         14 . The method of  claim 13 , wherein the administration is with a colonic delivery system. 
     
     
         15 . (canceled) 
     
     
         16 . A method of determining activation of a T-cell specific to an antigen expressed by bacteria belonging to  Clostridium  Cluster IV,  Clostridium  Cluster XIVa, or  Clostridium  Cluster XVIII, said method comprising the steps of (a) providing a sample from a subject suspected of comprising cells that recognize said antigen; (b) contacting the sample with complexes of MHC Class II tetramers containing an epitope of said antigen; and (c) determining if binding occurs between the cells of the sample and the MHC Class II tetramers containing the epitope.