作者
Dongping Li,Chunmei Yu,Meng Wan,Fengyi Mei,Fangzhao Wang,Peng Gu,Xianglong Zhang,Rongjuan Wei,Yunong Zeng,Heping Zheng,Chen Bang-guo,Qiyan Xiong,Ting Xue,Tianshan Guan,Jiayin Guo,Yuanxin Tian,Lingbing Zeng,Zhan‐Guo Liu,Huipin Yuan,Ling Yang,Hongbin Liu,Lei Dai,Yao Yu,Yi‐Feng Qiu,Peng Wu,Sanda Win,Tin Aung Than,Riqing Wei,Bernd Schnabl,Neil Kaplowitz,Yong Jiang,Qiang Ma,Peng Chen
摘要
Acetaminophen overuse is a common cause of acute liver failure (ALF). During ALF, toxins are metabolized by enzymes such as CYP2E1 and transformed into reactive species, leading to oxidative damage and liver failure. Here, we found that oral magnesium (Mg) alleviated acetaminophen-induced ALF through metabolic changes in gut microbiota that inhibit CYP2E1. The gut microbiota from Mg-supplemented humans prevented acetaminophen-induced ALF in mice. Mg exposure modulated Bifidobacterium metabolism and enriched indole-3-carboxylic acid (I3C) levels. Formate C-acetyltransferase (pflB) was identified as a key Bifidobacterium enzyme involved in I3C generation. Accordingly, a Bifidobacterium pflB knockout showed diminished I3C generation and reduced the beneficial effects of Mg. Conversely, treatment with I3C or an engineered bacteria overexpressing Bifidobacterium pflB protected against ALF. Mechanistically, I3C bound and inactivated CYP2E1, thus suppressing formation of harmful reactive intermediates and diminishing hepatocyte oxidative damage. These findings highlight how interactions between Mg and gut microbiota may help combat ALF.