Research progress on exercise regulation of gut microbiota and metabolites in improving metabolic dysfunction-associated fatty liver disease

<?A3B2 tlsb=.02w?>Metabolic dysfunction-associated fatty liver disease (MAFLD) has emerged as a common chronic liver disease worldwide, and its pathogenesis is closely associated with gut microbiota (GM) dysbiosis and metabolic product disorders, including elevated lipopolysaccharide (LPS) levels, reduced short-chain fatty acids (SCFA) production, and abnormal bile acids (BAs) metabolism. These metabolic disturbances aggravate abnormalities in hepatic glucose and lipid metabolism as well as inflammatory responses via the “gut-liver axis”, thereby promoting the progression of MAFLD to steatohepatitis, liver fibrosis, and even hepatocellular carcinoma. Currently, no specific pharmacotherapy is available for the complete cure of MAFLD, and lifestyle interventions, including structured exercise and dietary interventions, remain the primary approaches for improving and treating MAFLD. This review systematically elaborates on how exercise ameliorates MAFLD via the “exercise-gut microbiota-microbial metabolites-liver tissue” axis. Studies have shown that MAFLD patients commonly exhibit gut microbiota dysbiosis, characterized by an increased Firmicutes/Bacteroidetes (F/B) ratio, reduced beneficial bacteria (e.g., Akkermansia muciniphila , Faecalibacterium prausnitzii), and increased pathogenic bacteria (e.g., Prevotella, Streptococcus). Gut microbiota dysbiosis leads to elevated lipopolysaccharide (LPS) production, disrupted intestinal barrier function, and induced metabolic endotoxemia. Concurrently, exercise suppresses the production of short-chain fatty acids (SCFAs), particularly butyrate, thereby impairing the protective effects of SCFAs on intestinal barrier integrity, antiinflammatory actions, and metabolic regulation. Aberrant bile acid (BA) metabolism manifests as excessive accumulation of primary BAs and reduced conversion to secondary BAs, further aggravating liver tissue injury. Exercise effectively remodels the composition, structure, and function of the gut microbiota, with the beneficial effects being influenced by exercise modality, intensity, volume, and individual differences. Studies indicate that both endurance exercise (EE) and high intensity interval training (HIIT), among other exercise modalities, modulate gut microbiota composition, notably increasing beneficial bacteria such as Bacteroidetes and Actinobacteria, and significantly lowering the F/B ratio in obese patients, thereby improving microbial diversity. Exercise induces beneficial alterations in the gut microbiota and subsequently modulates microbial metabolites: 1) It enhances SCFA (acetate, propionate, butyrate) production, which in turn suppresses inflammatory responses, improves insulin sensitivity, and strengthens intestinal barrier function via activation of G protein coupled receptors (e.g., FFAR3, formerly GPR41, and FFAR2, formerly GPR43), thereby regulating hepatic lipid metabolism. 2) It modulates BA metabolism, characterized by a significant increase in secondary BAs such as lithocholic acid (LCA), activation of the farnesoid X receptor (FXR)/takeda G protein coupled receptor 5 (TGR5) metabolic axis, promotion of cholesterol catabolism, amelioration of glucose and lipid metabolism, and inhibition of hepatic fat accumulation. 3) It reduces circulating LPS levels and alleviates endotoxemia. Furthermore, exercise directly improves intestinal barrier function by upregulating the expression of tight junction proteins (e.g., zonula occludens 1, ZO1; occludin), thereby inhibiting the translocation of harmful substances such as LPS to the liver. Additional studies suggest that exercise combined with dietary interventions such as probiotics (e.g., Lactobacillus rhamnosus) or dietary polysaccharides (e.g., Lycium barbarum polysaccharide) effectively improves gut microbiota composition and function, intestinal barrier integrity, and hepatic inflammatory responses, providing novel strategies for the prevention and treatment of MAFLD. In summary, exercise, as a safe, economical, and efficient nonpharmacological intervention, effectively ameliorates the pathophysiological progression of MAFLD through multitarget regulation of the composition and function of the gut microbiota and its metabolites. Future research should focus on establishing optimized exercise prescriptions for different populations (e.g., based on age, sex, disease stage, etc.) to improve MAFLD. Moreover, further exploration is warranted into the molecular mechanisms and clinical drug development of exercise combined with dietary interventions such as prebiotics, probiotics, and nutritional supplements, to develop personalized and precise strategies for the prevention and treatment of MAFLD. <alternatives id="alt2"> </alternatives>