Disulfiram ameliorates nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism

Yuanyuan Lei, Li Tang, Qiao Chen, Lingyi Wu, Wei He, Dianji Tu, Sumin Wang, Yuyang Chen, Shuang Liu, Zhuo Xie, Hong Wei (), Shiming Yang () and Bo Tang ()
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Yuanyuan Lei: Army Medical University
Li Tang: Army Medical University
Qiao Chen: Army Medical University
Lingyi Wu: Army Medical University
Wei He: Army Medical University
Dianji Tu: Army Medical University
Sumin Wang: Army Medical University
Yuyang Chen: Army Medical University
Shuang Liu: Army Medical University
Zhuo Xie: Army Medical University
Hong Wei: Jinfeng Laboratory
Shiming Yang: Army Medical University
Bo Tang: Army Medical University

Nature Communications, 2022, vol. 13, issue 1, 1-16

Abstract: Abstract Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, we investigate the potential for repurposing disulfiram (DSF), a drug commonly used to treat chronic alcoholism, for NASH. Using a mouse model, we show that DSF ameliorates NASH in a gut microbiota-dependent manner. DSF modulates the gut microbiota and directly inhibits the growth of Clostridium. Administration of Clostridium abolishes the ameliorating effects of DSF on NASH. Mechanistically, DSF reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis, which in turn activates hepatic farnesoid X receptor signaling to ameliorate NASH. To assess the effect of DSF on human gut microbiota, we performed a self-controlled clinical trial (ChiCTR2100048035), including 23 healthy volunteers who received 250 mg-qd DSF for 7 days. The primary objective outcomes were to assess the effects of the intervention on the diversity, composition and functional profile of gut microbiota. The pilot study shows that DSF also reduces Clostridium-mediated 7α-dehydroxylation activity. All volunteers tolerated DSF well and there were no serious adverse events in the 7-day follow-up period. Transferring fecal microbiota obtained from DSF-treated humans into germ-free mice ameliorates NASH. Collectively, the observations of similar ameliorating effects of DSF on mice and humans suggest that DSF ameliorates NASH by modulating the gut microbiota and bile acid metabolism.

Date: 2022
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DOI: 10.1038/s41467-022-34671-1

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