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Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway

Qixing Nie,Xi Luo,Kai Wang,Yong Ding,Shumi Jia,Qixiang Zhao,Meng Li,Jinxin Zhang,Yingying Zhuo,Jun Lin,Chenghao Guo,Zhiwei Zhang,Huiying Liu,Guangyi Zeng,Jie You,Lulu Sun,Hua Lu,Ming Ma,Yanxing Jia,Ming-Hua Zheng,Yanli Pang,Jie Qiao,Changtao Jiang

The gut microbiota has been found to play an important role in the progression of metabolic dysfunction-associated steatohepatitis (MASH), but the mechanisms have not been established. Here, by developing a click-chemistry-based enrichment strategy, we identified several microbial-derived bile acids, including the previously uncharacterized 3-succinylated cholic acid (3-sucCA), which is negatively correlated with liver damage in patients with liver-tissue-biopsy-proven metabolic dysfunction-associated fatty liver disease (MAFLD). By screening human bacterial isolates, we identified Bacteroides uniformis strains as effective producers of 3-sucCA both in vitro and in vivo . By activity-based protein purification and identification, we identified an enzyme annotated as β-lactamase in B. uniformis responsible for 3-sucCA biosynthesis. Furthermore, we found that 3-sucCA is a lumen-restricted metabolite and alleviates MASH by promoting the growth of Akkermansia muciniphila . Together, our data offer new insights into the gut microbiota-liver axis that may be leveraged to augment the management of MASH.