Oral magnesium prevents acetaminophen-induced acute liver injury by modulating microbial metabolism

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 throug...

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Bibliographic Details
Published in:Cell host & microbe 2024-01, Vol.32 (1), p.48-62.e9
Main Authors: Li, Dongping, Chen, Yu, Wan, Meijuan, Mei, Fengyi, Wang, Fangzhao, Gu, Peng, Zhang, Xianglong, Wei, Rongjuan, Zeng, Yunong, Zheng, Hanzhao, Chen, Bangguo, Xiong, Qingquan, Xue, Tao, Guan, Tianshan, Guo, Jiayin, Tian, Yuanxin, Zeng, Li-Yan, Liu, Zhanguo, Yuan, Hang, Yang, Ling, Liu, Hongbin, Dai, Lei, Yu, Yao, Qiu, Yifeng, Wu, Peng, Win, Sanda, Than, Tin Aung, Wei, Riqing, Schnabl, Bernd, Kaplowitz, Neil, Jiang, Yong, Ma, Qiang, Chen, Peng
Format: Article
Language:English
Subjects:
Acetaminophen - adverse effects
Acetaminophen - metabolism
Animals
Cytochrome P-450 CYP2E1 - metabolism
Cytochrome P-450 CYP2E1 - pharmacology
Humans
Liver - metabolism
Liver Failure, Acute - chemically induced
Liver Failure, Acute - metabolism
Magnesium - metabolism
Mice
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Summary: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.
ISSN:1931-3128
1934-6069
DOI:10.1016/j.chom.2023.11.006