Pure total flavonoids from citrus attenuate non-alcoholic steatohepatitis via regulating the gut microbiota and bile acid metabolism in mice

Background: Our previous studies found that Pure total flavnoids from citrus (PTFC) can effectively improve nonalcoholic steatohepatitis (NASH) in mice. Here, we discuss on the mechanism of PTFC in treating NASH with focus on the regulation of the gut microbiota and bile acid metabolism. Methods: C57BL/6 J mice were randomly divided into three groups: normal diet group (Normal), high-fat diet group (HFD) and high-fat + PTFC treatment group (PTFC). Mice in the Normal group were fed chow diet, while the other groups were fed high fat diet (HFD) for 16 weeks. In the 5th week, the mice in the PTFC group were treated with 50 mg/kg/day PTFC for an additional twelve weeks. After sacrifice, histopathology of the liver was assessed, and the gut microbial composition was analyzed by 16S rDNA gene sequencing. Bile Acid profiles in serum were determined by ultraperformance liquid chromatography (UPLC-MS/MS). Results: PTFC intervention significantly attenuated HFD-induced NASH symptoms compared with the HFD group in mice. 16S rDNA sequencing showed that PTFC treatment increased the phylogenetic diversity of the HFDinduced microbiota dysbiosis. PTFC intervention significantly increased the relative abundances of Bacteroidaceae and Christensenellaceae. Furthermore, PTFC reduced the content of toxic bile acids, such as TDCA, DCA, TCA, CA and increased the ratio of secondary to primary bile acids. FXR and TGR5 deficiency were significantly alleviated. Conclusion: PTFC can improve NASH via the the gut microbiota and bile acid metabolism.