2. Academic Validation
  3. Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway

Gut symbionts alleviate MASH through a secondary bile acid biosynthetic pathway

  • Cell. 2024 May 23;187(11):2717-2734.e33. doi: 10.1016/j.cell.2024.03.034.
Qixing Nie 1,  Xi Luo 2,  Kai Wang 3,  Yong Ding 2,  Shumi Jia 4,  Qixiang Zhao 2,  Meng Li 2,  Jinxin Zhang 2,  Yingying Zhuo 2,  Jun Lin 2,  Chenghao Guo 2,  Zhiwei Zhang 2,  Huiying Liu 2,  Guangyi Zeng 2,  Jie You 5,  Lulu Sun 6,  Hua Lu 7,  Ming Ma 4,  Yanxing Jia 8,  Ming-Hua Zheng 9,  Yanli Pang 10,  Jie Qiao 11,  Changtao Jiang 12
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China; State Key Laboratory of Food Science and Resources, Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang, China.
  • 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.
  • 3 Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China; Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China.
  • 4 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences and Chemical Biology Center, Peking University, Beijing 100191, China.
  • 5 Department of Thyroid Surgery, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 6 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China; Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China.
  • 7 Beijing National Laboratory for Molecular Sciences, Center for Soft Matter Science and Engineering, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, People's Republic of China.
  • 8 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences and Chemical Biology Center, Peking University, Beijing 100191, China. Electronic address: [email protected].
  • 9 MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China; Translational Medicine Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China. Electronic address: [email protected].
  • 10 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China; Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China; National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. Electronic address: [email protected].
  • 11 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China; Institute of Advanced Clinical Medicine, Peking University, Beijing 100191, China; National Clinical Research Center for Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China; Beijing Key Laboratory of Reproductive Endocrinology and Assisted Reproductive Technology, Beijing, China. Electronic address: [email protected].
  • 12 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China; Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China; Department of Immunology, School of Basic Medical Sciences, NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China. Electronic address: [email protected].
PMID: 38653239 DOI: 10.1016/j.cell.2024.03.034
Abstract

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.

Keywords

3-sucCA; BAS-suc; MAFLD; acylated bile acids; bile acid; biosynthesis; gut microbiota.

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