Our previous study showed that nuciferine (NF) attenuated non-alcoholic fatty liver disease (NAFLD), which is attributed to a high-fat diet (HFD) through reinforcing intestinal barrier functions, regulating lipid metabolism, and improving inflammation. To clarify whether other mechanisms contribute to the anti-NAFLD efficacy of NF, the present study investigated the influence of NF on bile acid (BA) metabolism and gut microbiota in HFD-fed rats. The data demonstrated that NF changed the composition of colonic BA, particularly elevating conjugated BA and non-12OH BA levels. As shown by downregulated protein levels of FXR, FGF15, FGFR4, and ASBT and upregulated protein levels of CYP7A1 and CYP27A1, NF inhibited ileal FXR signaling, promoted BA synthesis, suppressed BA reabsorption, and facilitated fecal BA excretion. NF might affect hepatic FXR signaling, BA conjugation, and enterohepatic circulation by the changed mRNA levels of Fxr, Shp, Baat, Bacs, Bsep, Ntcp, Ibabp, and Ostα/β. Meanwhile, NF regulated the gut microbiota, characterized by decreased BSH-producing genus, 7α-dehydroxylation genus, and increased taurine metabolism-related genus. Spearman rank correlation analysis implied that Colidextribacter, Adlercreutzia, Family_XIII_AD3011_group, Lachnospiraceae_UCG-010, Eisenbergiella, and UCG-005 were robustly associated with particular BA monomers. In conclusion, our experiment results suggested that NF could exert a mitigating effect on NAFLD via regulating BA metabolism and modulating the gut microbiota.

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