Microbiome‐Derived Metabolite Networks in Metabolic Dysfunction‐Associated Fatty Liver Disease: Mechanistic Integration of Gut‐Liver Axis Signaling and Therapeutic Targeting

Metabolic dysfunction‐associated fatty liver disease (MAFLD), recently reclassified within the broader framework of metabolic dysfunction‐associated steatotic liver disease (MASLD), has emerged as one of the leading causes of chronic liver disease. Although a substantial proportion of the mechanistic literature was originally generated under the non‐alcoholic fatty liver disease (NAFLD)/non‐alcoholic steatohepatitis (NASH) nomenclature, increasing evidence implicates the gut microbiome and its metabolic products as important contributors to disease pathogenesis. However, current understanding remains limited by fragmented analyses of individual pathways and an incomplete integration of microbial metabolism with host signaling networks. This review critically synthesizes the roles of microbiome‐associated metabolites and microbial products within the gut‐liver axis, with particular emphasis on bile acid signaling, short‐chain fatty acid (SCFA) metabolism, and tryptophan‐derived pathways, including kynurenine, indole, and serotonin metabolism. These pathways are discussed within an integrated mechanistic framework involving farnesoid X receptor (FXR)/TGR5, AMP‐activated protein kinase (AMPK), aryl hydrocarbon receptor (AhR), nuclear factor kappa B (NF‐κB), and inflammasome signaling. Particular attention is given to the context‐dependent effects of bile acids and SCFAs, the complex immunometabolic functions of the kynurenine pathway, and the interplay between microbial metabolites and innate immune activation. Future therapeutic strategies will likely combine microbiome‐directed approaches, including dietary interventions and microbiome modulation, with metabolite‐targeted and pathway‐specific interventions designed to improve mechanistic precision and therapeutic efficacy. This review aims to provide an integrated perspective on microbiome‐metabolite‐host interactions and highlights future opportunities for biomarker discovery, therapeutic development, and precision medicine in MAFLD.