Gut bacteria alleviate smoking-related NASH by degrading gut nicotine

Tobacco smoking is positively correlated with nonalcoholic 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. Notably, we identify the gut bacterium Bacteroides xylanisolvens as an effective nicotine degrader. B. xylanisolvens colonization 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 thus increasing intestinal ceramide formation, which contributes to NAFLD progression. Our results establish a role for intestinal nicotine accumulation in NAFLD progression and reveal an endogenous bacterium in the human intestine capable of metabolizing nicotine. These findings suggest a possible avenue to reduce tobacco smoking-exacerbated NAFLD progression.