Gut microbiota-derived UDCA enhanced by metformin inhibits FXR to activate autophagy against MCD diet-induced NAFLD in mice.

Nonalcoholic fatty liver disease (NAFLD), a prevalent chronic liver disease, poses a substantial global health burden. Metformin is known for its protective effects in NAFLD, but the role of gut microbiota in the underlying mechanisms remains unclear. In this study, metformin was found to mitigate methionine-choline deficient (MCD) -diet induced NAFLD through reshaping the gut microbiota to increase ursodeoxycholic acid (UDCA) level, thereby inhibiting farnesoid X receptor (FXR) accompanied with activated autophagy. Specifically, using dirty cage experiments and 16S rRNA sequencing, it identified that metformin could reshape microbiota to release liver injury as confirmed by the results of histopathology and biochemical index detection. Furthermore, the bile acids were found to be altered by metformin, in which, the UDCA, a FXR natural inhibitor, was observed a significantly increase. Meanwhile, the inhibited FXR and activated autophagy in metformin-treated mice were captured using western blot, qRT-PCR and immunofluorescence analysis. In addition, the benefit of UDCA against NAFLD was demonstrated in UDCA treated mice. Further investigation with FXR siRNA introduced to HepG2 cells revealed that inhibiting FXR can reduce oleic acids induced cell injury with the autophagy activation. In conclusion, this study highlights metformin's potential to ameliorate NAFLD by reshaping gut microbiota, thereby upregulating UDCA in the liver and restoring cholesterol synthesis capacity, possibly via inhibiting FXR to activate autophagy.