Mechanisms by which exercise regulates gut microbiota in the prevention and treatment of non-alcoholic fatty liver disease

Abstract

BACKGROUND: The pathogenesis of non-alcoholic fatty liver disease is closely associated with gut microbiota dysbiosis. In recent years, accumulating evidence has indicated that exercise may exert beneficial effects on host metabolic homeostasis by modulating the composition and function of the gut microbiota, thereby playing a positive role in the prevention and treatment of non-alcoholic fatty liver disease. OBJECTIVE: To systematically summarize current research progress on the interplay between gut microbiota and non-alcoholic fatty liver disease, to further elucidate the regulatory effects of exercise on gut microbiota, and to explore in depth the potential mechanisms by which exercise intervention may prevent or ameliorate non-alcoholic fatty liver disease via the "gut–liver axis." METHODS: Search terms included "non-alcoholic fatty liver disease," "gut microbiota," "exercise," "bile acid," "short-chain fatty acid," "lipopolysaccharide," "trimethylamine oxide," and "indole" in Chinese and English, respectively. China National Knowledge Infrastructure (CNKI), and WanFang Database were searched for relevant studies published up to March 2025. A total of 85 core studies were identified based on the inclusion and exclusion criteria. RESULTS AND CONCLUSION: (1) The composition of gut microbiota in patients with non-alcoholic fatty liver disease is significantly abnormal, with increased abundance of pro-inflammatory bacteria (such as Proteobacteria, Escherichia coli, and Streptococcus) and pathogenic bacteria (such as Enterobacteriaceae), while the abundance of anti-inflammatory and homeostatic bacteria (such as Ruminococcus and Faecalibacterium) is decreased. These adverse changes in microbial composition may promote the entry of metabolites into the liver by increasing intestinal permeability, activating inflammatory pathways, and increasing endogenous ethanol production, thereby driving the pathological progression of non-alcoholic fatty liver disease. (2) Modulating gut microbiota through probiotic supplementation or fecal microbiota transplantation can effectively reduce transaminase levels and chronic inflammation in patients with non-alcoholic fatty liver disease, suggesting that gut microbiota may be an important target for the prevention and treatment of non-alcoholic fatty liver disease. (3) Exercise can regulate gut microbiota composition, increase the abundance of beneficial bacteria, reduce the abundance of pro-inflammatory bacteria, and promote the activation of key metabolic pathways, thereby improving host metabolic health. However, current research on the effects of exercise on gut microbiota in patients with non-alcoholic fatty liver disease remains relatively limited, especially the effects and mechanisms of different exercise types, intensities, and durations on gut microbiota and host metabolism are still unclear. (4) Exercise may regulate gut microbiota and increase short-chain fatty acid production to activate G protein-coupled receptors 41/43 and AMP-activated protein kinase pathways, inhibit histone deacetylase activity, thereby reducing hepatic fat accumulation, alleviating liver inflammation, and decreasing insulin resistance; exercise may regulate the gut microbiota-bile acid axis to improve bile acid metabolism, thereby mediating the farnesoid X receptor/G protein-coupled bile acid receptor 5 signaling pathway to prevent and treat non-alcoholic fatty liver disease; exercise may reshape gut microbiota to reduce the abundance of lipopolysaccharide-containing Gram-negative bacteria and improve intestinal barrier function to reduce lipopolysaccharide production and translocation, preventing and treating non-alcoholic fatty liver disease; exercise may regulate gut microbiota composition to enhance the synthesis of indole and its derivatives, while inhibiting the production of ethanol and trimethylamine oxide, thereby enhancing liver metabolic capacity, improving intestinal barrier function, and reducing liver inflammation, playing a positive role in the prevention and treatment of non-alcoholic fatty liver disease.

1. Introduction

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive fat deposition in the liver in the absence of significant alcohol intake. With the global rise in obesity and type 2 diabetes, the incidence of NAFLD has increased rapidly, affecting an estimated 25% of the world's population. The disease can progress from simple steatosis to non-alcoholic steatohepatitis, potentially leading to fibrosis, cirrhosis, and hepatocellular carcinoma. Due to its insidious nature, chronic progression, and high mortality, NAFLD has become a leading cause of liver-related death and transplantation. Therefore, understanding its pathological mechanisms is crucial for developing targeted prevention and treatment strategies.

The gut microbiota, a vast microbial community residing in the intestinal tract, plays a complex symbiotic role with the host, participating in metabolism, immune regulation, and nutrient absorption. In the pathogenesis of NAFLD, gut dysbiosis is considered a key driver. The "gut-liver axis" theory provides a framework for understanding how intestinal microbial alterations contribute to liver disease. This review systematically summarizes the interplay between gut microbiota and NAFLD, and explores the potential mechanisms by which exercise, through modulation of the gut microbiota, may prevent or ameliorate NAFLD.