Gut bacteria alleviate smoking-related NASH by degrading gut nicotine

• Published in: Nature (London) Vol. 610; no. 7932; pp. 562 - 568
• Main Authors: Chen, Bo, Sun, Lulu, Zeng, Guangyi, Shen, Zhe, Wang, Kai, Yin, Limin, Xu, Feng, Wang, Pengcheng, Ding, Yong, Nie, Qixing, Wu, Qing, Zhang, Zhiwei, Xia, Jialin, Lin, Jun, Luo, Yuhong, Cai, Jie, Krausz, Kristopher W., Zheng, Ruimao, Xue, Yanxue, Zheng, Ming-Hua, Li, Yang, Yu, Chaohui, Gonzalez, Frank J., Jiang, Changtao
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.10.2022; Nature Publishing Group
• Subjects: 38; 631/326/2522; 692/699/1503/1607/1604; AMP-Activated Protein Kinases - metabolism; Animals; Bacteria; Bacteria - drug effects; Bacteria - metabolism; Biopsy; Ceramide; Ceramides - biosynthesis; Digestive system; Disease Progression; Drinking water; E coli; Fatty liver; Gastrointestinal tract; Genes; Human performance; Humanities and Social Sciences; Humans; Intestine; Intestines - drug effects; Intestines - microbiology; Liver; Liver diseases; Metabolites; Mice; multidisciplinary; Nicotine; Nicotine - adverse effects; Nicotine - metabolism; NMR; Non-alcoholic Fatty Liver Disease - chemically induced; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - microbiology; Nuclear magnetic resonance; Phosphodiesterase; Phosphorylation; Science; Science (multidisciplinary); Small intestine; Smoking; Sphingomyelin phosphodiesterase; Sphingomyelin Phosphodiesterase - metabolism; Tobacco; Tobacco smoking; Tobacco Smoking - adverse effects; Tobacco Smoking - metabolism
• ISSN: 0028-0836; 1476-4687; 1476-4687
• DOI: 10.1038/s41586-022-05299-4

Tobacco smoking is positively correlated with non-alcoholic fatty liver disease (NAFLD) 1 – 5 , but the underlying mechanism for this association is unclear. Here we report that nicotine accumulates in the intestine during tobacco smoking and activates intestinal AMPKα. We identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. Colonization of B. xylanisolvens reduces intestinal nicotine concentrations in nicotine-exposed mice, and it improves nicotine-exacerbated NAFLD progression. Mechanistically, AMPKα promotes the phosphorylation of sphingomyelin phosphodiesterase 3 (SMPD3), stabilizing the latter and therefore increasing intestinal ceramide formation, which contributes to NAFLD progression to non-alcoholic steatohepatitis (NASH). Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine with the ability to metabolize nicotine. These findings suggest a possible route to reduce tobacco smoking-exacerbated NAFLD progression. Nicotine accumulates in the intestine during tobacco smoking and accelerates the progression of non-alcoholic fatty liver disease to non-alcoholic steatohepatitis (NASH), but it can be degraded effectively by the human symbiont Bacteroides xylanisolvens.