Disulfiram ameliorates nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism.
Disulfiram ameliorates nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism.
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DOI：
10.1038/s41467-022-34671-1
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发表时间：
2022-11-11
影响因子：
16.6
通讯作者：
Tang, Bo
中科院分区：
文献类型：
--
作者：
Lei, Yuanyuan;Tang, Li;Chen, Qiao;Wu, Lingyi;He, Wei;Tu, Dianji;Wang, Sumin;Chen, Yuyang;Liu, Shuang;Xie, Zhuo;Wei, Hong;Yang, Shiming;Tang, Bo
非酒精性脂肪性肝炎（NASH）与肠-肝轴有关。在这里，我们调查了双硫仑（DSF），一种常用于治疗慢性酒精中毒的药物，用于NASH的可能性。使用小鼠模型，我们表明DSF以肠道微生物群依赖性方式改善NASH。DSF调节肠道微生物群并直接抑制梭菌的生长。梭菌属的施用消除了DSF对NASH的改善作用。在机制上，DSF降低梭菌介导的7α-脱羟基活性以抑制次级胆汁酸生物合成，这反过来激活肝法尼醇X受体信号传导以改善NASH。为了评估DSF对人体肠道菌群的影响，我们进行了一项自身对照临床试验（ChiCTR 2100048035），包括23名健康志愿者，他们接受250 mg-qd DSF 7天。主要目标结果是评估干预对肠道微生物群多样性，组成和功能概况的影响。初步研究表明，DSF还降低了梭菌介导的7α-脱羟基活性。所有志愿者对DSF耐受良好，7天随访期内无严重不良事件发生。将从DSF处理的人获得的粪便微生物群转移到无菌小鼠中改善NASH。总的来说，DSF对小鼠和人的类似改善作用的观察结果表明，DSF通过调节肠道微生物群和胆汁酸代谢来改善NASH。非酒精性脂肪性肝炎（NASH）与肠-肝轴有关。在此，作者表明双硫仑（DSF）可降低梭菌介导的7α-脱羟基活性，从而抑制小鼠中的次级胆汁酸生物合成并改善NASH，并在一项自身对照临床试验中验证了DSF对健康男性肠-肝轴的调节。
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. Nonalcoholic steatohepatitis (NASH) has been linked with the gut-liver axis. Here, the authors show that disulfiram (DSF) reduces Clostridium-mediated 7α-dehydroxylation activity to suppress secondary bile acid biosynthesis and ameliorate NASH in mice, and validate DSF regulation of the gut-liver axis in healthy men in a self-controlled clinical trial.
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影响因子：
48
作者：
Langmead, Ben;Salzberg, Steven L.
通讯作者：
Salzberg, Steven L.
DOI：
10.1016/j.ijantimicag.2019.04.002
发表时间：
2019-07-01
影响因子：
10.8
作者：
Hamblin, Karleigh A.;Flick-Smith, Helen;Harding, Sarah V.
通讯作者：
Harding, Sarah V.
影响因子：
7.7
作者：
Beghini F;McIver LJ;Blanco-Míguez A;Dubois L;Asnicar F;Maharjan S;Mailyan A;Manghi P;Scholz M;Thomas AM;Valles-Colomer M;Weingart G;Zhang Y;Zolfo M;Huttenhower C;Franzosa EA;Segata N
通讯作者：
Segata N
影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
影响因子：
48
作者：
Callahan BJ;McMurdie PJ;Rosen MJ;Han AW;Johnson AJ;Holmes SP
通讯作者：
Holmes SP