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.

对乙酰氨基酚过度使用是急性肝衰竭（ALF）的常见原因。在 ALF 期间，毒素被 CYP2E1 等酶代谢并转化为活性物质，导致氧化损伤和肝衰竭。在这里，我们发现口服镁 (Mg) 通过抑制 CYP2E1 的肠道微生物群代谢变化来减轻对乙酰氨基酚诱导的 ALF。补充镁的人类肠道微生物群可以预防对乙酰氨基酚诱导的小鼠 ALF。镁暴露可调节双歧杆菌代谢并提高吲哚-3-羧酸 (I3C) 水平。甲酸 C-乙酰转移酶 ( pflB ) 被确定为参与 I3C 生成的关键双歧杆菌酶。因此，双歧杆菌 pflB敲除显示 I3C 生成减少并降低了 Mg 的有益作用。相反，用 I3C 或过度表达双歧杆菌 pflB 的工程细菌治疗可预防 ALF。从机制上讲，I3C 结合并灭活 CYP2E1，从而抑制有害反应中间体的形成并减少肝细胞氧化损伤。这些发现强调了镁和肠道微生物群之间的相互作用如何有助于对抗 ALF。