Background: Farnesoid X receptor (FXR) is a key metabolic target of
bile acids (BAs) and is also a target for drugs against several
liver diseases. However, the contribution of FXR in the pathogenesis of
cholestasis is still not fully understood. The purpose of this study is to provide a comprehensive insight into the metabolic properties of FXR-involved
cholestasis in mice. Materials and methods: In this study, an
alpha-naphthylisothiocyanate (ANIT)-induced
cholestasis mouse model and FXR-/- mice were established to investigate the effect of FXR on
cholestasis. The effect of FXR on liver and ileal pathology was evaluated. Simultaneously, Untargeted metabolomics combined with
16s rRNA gene sequencing analysis was applied to reveal the involvement of FXR in the pathogenesis of
cholestasis. Results: The results showed that ANIT (75 mg/kg) induced marked
cholestasis in WT and FXR -/- mice. It is noteworthy that FXR-/- mice developed spontaneous
cholestasis. Compared with WT mice, significant liver and ileal tissue damage were found. In addition,
16s rRNA gene sequencing analysis revealed gut microbiota
dysbiosis in FXR-/- mice and ANIT-induced
cholestasis mice. Differential
biomarkers associated with the pathogenesis of
cholestasis caused by FXR knockout were screened using untargeted metabolomics. Notably, Lactobacillus_ johnsonii_FI9785 has a high correlation with the differential
biomarkers associated with the pathogenesis and progression of
cholestasis caused by FXR knockout. Conclusion: Our results implied that the disorder of the intestinal flora caused by FXR knockout can also interfere with the metabolism. This study provides novel insights into the FXR-related mechanisms of
cholestasis.