BioCentury
ARTICLE | Distillery Therapeutics

Gastrointestinal

August 23, 2018 3:53 PM UTC

Cell culture and mouse studies suggest deoxycholate-mediated PGE2 inhibition or agonism of FXR could help treat colonic injury. In a mouse model of colonic mucosal biopsy injury, PGE2 levels were higher during the barrier reestablishment phase of wound repair than the wound channel formation and crypt regeneration phases. Screening of intestinal bacterial metabolites in a colonic mesenchymal stem cell-based assay identified deoxycholate as an inhibitor of PGE2 production. In a mouse model of colonic mucosal biopsy injury with vancomycin-induced defects in crypt regeneration, deoxycholate delivered to the colonic lumen via rectal enema increased crypt proliferation and regeneration compared with vehicle. Also in the model, the FXR agonist chenodeoxycholic acid or oral gavage with the deoxycholate-producing bacteria Clostridium scindens increased crypt regeneration compared with vehicle or C. clostridioforme, which does not produce deoxycholate. Next steps could include testing deoxycholate analogs or C. scindens in additional models of colonic injury.

Intercept Pharmaceuticals Inc. and Sumitomo Dainippon Pharma Co. Ltd. market the FXR agonist Ocaliva obeticholic acid for cirrhosis and have the compound in Phase III testing for non-alcoholic steatohepatitis (NASH) and Phase II testing for liver disease...