Dioscorea bulbifera L.induces liver injury in mice partly through bile acids metabolic disorders and gut microbiota dysbiosis mediated by the YY1-FXR/Nrf2 signaling pathwayOA

Background:This study aimed to comprehensively elucidate the hepatotoxic effects of Dioscorea bulbifera L.(DBL)in mice and to explore the underlying molecular mechanisms.Methods:Mice were administered different doses of DBL via intragastric gavage for 21 days.Organ indices of multiple organs were then measured,and histopathological changes were systematically evaluated.Particular attention was paid to biochemical markers and hepatic histopathological alterations associated with liver injury.Subsequently,the composition of the gut microbiota in colonic contents was analyzed using 16S rDNA sequencing,and the levels of short-chain fatty acids(SCFAs)were determined by gas chromatography(GC).Furthermore,protein expression levels of YinYang 1(YY1),Farnesoid X Receptor(FXR),Nuclear factor erythroid 2-related factor 2(Nrf2),and bile acids(BAs)-related proteins in the liver were assessed by Western blot analysis.Results:Our findings revealed that DBL induced varying degrees of multi-organ toxicity in mice,with the most pronounced hepatotoxicity observed.Liver injury was induced in a dose-dependent manner,accompanied by increased hepatic inflammation and oxidative stress,as well as enhanced hepatocyte apoptosis.Furthermore,DBL may modulate the YY1-FXR/Nrf2 signaling pathway,leading to upregulation of BAs-related proteins such as cholesterol 7α-hydroxylase(CYP7A1),while downregulating other BAs-related proteins,including sodium taurocholate cotransporting polypeptide(NTCP),bile salt export pump(BSEP),multidrug resistance protein 2(MRP2),and P-glycoprotein(P-gp).These changes promoted excessive BAs synthesis and impaired the excretion and reabsorption of BAs,ultimately disturbing BAs homeostasis.Additionally,DBL induces gut microbiota dysbiosis and reduces SCFAs production,leading to intestinal damage and disruption of intestinal barrier integrity.Conclusion:DBL-induced hepatotoxicity may be associated with altered expression of the YY1-FXR/Nrf2 signaling pathway and BAs–related proteins,accompanied by increased hepatic BAs accumulation and gut microbiota dysbiosis.