Mangiferin alleviates metabolic-associated fatty liver disease by modulating gut microbiota and FXR signaling pathway to regulate bile acid metabolism

Background Metabolic-associated fatty liver disease (MAFLD) is characterized by excessive hepatic lipid accumulation, with limited safe and effective therapeutic options currently available. Previous studies have demonstrated that mangiferin (MAN) alleviates nonalcoholic fatty liver disease via modulation of the AMPK and NLRP3 signaling pathways. However, there are no reports to date investigating whether MAN exerts anti-MAFLD effects by regulating bile acid (BAs) metabolism and its underlying molecular mechanisms. Methods In the present study, the anti-MAFLD effects of MAN were systematically investigated using a high-fat diet (HFD)-induced MAFLD mouse model. We evaluated the therapeutic mechanisms of MAN specifically from the perspectives of BAs metabolism regulated by the farnesoid X receptor (FXR) signaling pathway and the modulation of the gut microbiota, utilizing 16S rRNA sequencing and molecular docking analyses. Results MAN treatment (100 mg/kg) significantly ameliorated glucose and lipid metabolic disorders, as well as hepatic lipid accumulation in the HFD-induced MAFLD mice, which was accompanied by marked alterations in the BAs metabolic profile. Mechanistically, MAN activated the FXR signaling pathway, and molecular docking analysis predicted stable interactions with key FXR residues (Y365, M369, and Y373). Furthermore, 16S rRNA sequencing revealed that MAN significantly decreased the relative abundance of Lactobacillus and Limosilactobacillus , which were positively correlated with abnormal BAs (including 6,7-DKLCA, ILCA, GHDCA, and GUDCA), dyslipidemia, and liver injury markers. In contrast, MAN increased the relative abundance of Faecalibaculum , which was negatively correlated with these BAs and associated with an improved metabolic status. Conclusion MAN exerts anti-MAFLD effects through dual mechanisms: direct activation of the FXR signaling pathway to regulate BAs homeostasis and indirect modulation of the gut microbiota to influence BAs metabolism. These findings highlight the therapeutic potential of MAN and provide new insights into natural product-based strategies for MAFLD treatment.