Disulfiram ameliorates NASH. Disulfiram is a potential gut microbiota-dependent drug to ameliorate NASH

Nonalcoholic steatohepatitis (NASH) has poor prognosis and is lack of approved pharmacological therapies. A promising approach to meet the need for develop NASH treatment is drug repurposing. Here we highlight the potential for repurposing disulfiram (DSF), an old drug for chronic alcoholism that has been shown to be effective against metabolic disorders in mice models. We found that DSF showed potential protective effects on NASH in a gut microbiota-dependent manner. DSF significantly modulated the gut microbial diversity and inhibited the growth of Clostridium. Mechanically, DSF reduced Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis, which in turn activated the hepatic farnesoid X receptor (FXR) signaling to ameliorate NASH. Then, we conducted a self-control clinical trial which confirmed that DSF was potential to improve lipid metabolism and modulate gut microbiota in humans. Finally, transfer of gut microbiota-derived from DSF-treated humans protected germ-free (GF) mice from NASH. In this study, the observation of similar protective effects of DSF in both mice and humans suggest that DSF is a novel potential gut microbiota-dependent drug for NASH.