Potential mechanisms by which microbiota-accessible carbohydrates regulate hepatic lipid metabolism in MAFLD via the...

Metabolic dysfunction-associated fatty liver disease (MAFLD) is a prevalent chronic metabolic liver disorder, whose onset and progression are closely associated with dysregulated lipid metabolism, chronic inflammation, and intestinal microbial dysbiosis. The gut and liver are anatomically and functionally connected via the portal vein system, through which gut-derived metabolites, inflammatory mediators, and neuroendocrine signals are preferentially delivered to the liver, thereby influencing hepatocellular lipid metabolism and hepatic sinusoidal immune responses. Dietary complex carbohydrates, particularly Microbiota-accessible carbohydrates (MACs), are fermented by gut microbiota in the colon. By reshaping luminal carbon source distribution, microbial composition, and metabolic output, MACs modulate gut-liver axis function. This review summarizes the potential mechanisms by which MACs influence MAFLD via the gut-liver axis. Structurally complex and slowly fermentable MACs may prolong carbohydrate availability in the distal colon and reduce microbial shifts toward proteolytic fermentation, thereby decreasing the production of potentially harmful metabolites such as ammonia, phenols, p-cresol, and hydrogen sulfide. Short-chain fatty acids (SCFAs) produced from MAC fermentation, particularly acetate and propionate, as well as microbiota-modified bile acids, can enter the portal circulation and regulate hepatic metabolic signaling, thereby participating in the control of de novo lipogenesis, fatty acid oxidation, and inflammatory responses. In addition, MACs may improve intestinal barrier integrity and modulate 5-hydroxytryptamine (5-HT, serotonin) metabolism through effects on key microbial taxa such as Akkermansia muciniphila and regulation of SERT-dependent pathways. Gut-derived 5-HT may further participate in hepatic lipid metabolic regulation via pathways such as HTR2A-PPARγ signaling, although this mechanism remains to be fully validated. Overall, MACs may influence MAFLD progression through coordinated regulation of gut microbiota composition, gut-derived metabolites, and intestinal barrier function. However, their clinical translation still requires further validation through human studies and comprehensive safety evaluation.