Abstract
Nicotine accumulation in the intestine is associated with an exacerbation of metabolic dysfunction-associated steatohepatitis (MASH), but the underlying mechanisms remain enigmatic. We investigated how nicotine impacted intestinal microbiota composition and barrier function in MASH. Our study revealed significant intestinal microbiota dysbiosis and upregulated hypoxia-inducible factor 1-alpha (HIF-1α) levels in nicotine-exposed MASH mice. HIF-1α knockdown worsened intestinal barrier dysfunction in nicotine-exposed MASH mice. This exacerbation resulted from the suppression of MEK/ERK signaling pathway phosphorylation in HIF-1α-deficient mice. Lactobacillus rhamnosus GG supernatant can alleviate hepatic injury in nicotine-exposed MASH mice; however, this protective effect was abolished in the absence of HIF-1α. Taken together, this study reveals a critical pathologic role of nicotine in exacerbating MASH through intestinal microbiota disruption and barrier dysfunction, which is associated with the downregulation of HIF-1α in the intestine. It also suggests exogenous probiotic supplementation as a potential therapeutic strategy for mitigating nicotine-induced MASH progression.