Small molecule modulators of bile acid metabolism to treat NAFLD/NASH

Liver diseases are growing worldwide health concerns and place significant burdens on healthcare systems. The prevalence of non-alcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and liver cirrhosis is rising. There is a large, unmet need for effective treatments for these conditions. There are currently no approved medications for NAFLD/NASH, and while off-label usage of type 2 diabetes medications has become common, evidence for benefits has been limited. Drugs in the pipeline target later stages of fibrosis and display modest effects. Our data indicate that conjugated bile acids, a large class of host-produced endogenous metabolites, protect against pathogenic intestinal permeability, an early feature of NAFLD/NASH that contributes to the development of liver inflammation and injury. Our goal is to use small molecule inhibitors of gut bacterial enzymes that chemically modify bile acids to modulate the in vivo pool of these metabolites. We will test whether these inhibitors shift the bile acid pool toward beneficial conjugated bile acids and away from damaging unconjugated bile acids and thereby present a novel treatment strategy for NAFLD/NASH.