Fucoidan attenuates metabolic dysfunction-associated fatty liver disease in mice and is associated with gut microbiota remodeling and AMPK/PPARγ signaling

Background Metabolic dysfunction-associated fatty liver disease (MAFLD) is a growing metabolic disorder closely linked to gut micro biota dysbiosis and impaired gut–liver communication. Dietary interventions targeting the gut micro biota represent a promising strategy for MAFLD management. Fucoidan (FUC), a marine-derived bioactive polysaccharide with limited host digestibility, is primarily metabolized by intestinal microorganisms. However, whether FUC protects against MAFLD in association with micro biota-mediated mechanisms remains incompletely understood. Methods C57BL/6J mice were fed a high-fat diet (HFD) for 14 weeks, while the FUC intervention group received FUC by oral gavage at a dose of 200 mg/kg/day over the same period. Body weight, adiposity, serum lipid and glucose metabolism, liver function, and histopathology were evaluated. Gut micro biota composition was analyzed by 16S rRNA sequencing, and serum metabolomic profiling was performed using untargeted metabolomics combined with KEGG enrichment and Spearman correlation analyses. Results FUC supplementation markedly attenuated HFD-induced obesity, impaired glucose tolerance, dyslipidemia, hepatic steatosis, and HFD-associated alterations in intestinal barrier-related structural and molecular features. Microbiome analysis revealed that FUC administration was associated with changes in gut microbial diversity and community composition, including altered relative abundances of Akkermansia, Adlercreutzia , and Dubosiella . Metabolomic analysis further demonstrated changes in systemic metabolic profiles, particularly tricarboxylic acid (TCA) cycle-related metabolites. Correlation analyses identified associations among microbial features, circulating metabolites, and MAFLD-related phenotypes. FUC administration was associated with gut micro biota remodeling and altered hepatic AMPK/PPARγ signaling, accompanied by improved metabolic homeostasis and reduced hepatic inflammation. Conclusion Our findings demonstrate that FUC alleviates HFD-induced MAFLD and is associated with remodeling of the gut micro biota, alterations in circulating TCA cycle-related metabolites, and changes in hepatic AMPK/PPARγ signaling. Integrated analyses suggest a potential gut micro biota–metabolism–liver regulatory network associated with the hepato protective effects of FUC. These findings provide potential mechanistic insights into the beneficial effects of FUC and support further investigation of marine-derived polysaccharides as dietary strategies for metabolic disease management.