Investigating intestinal farnesoid X receptor functions at the intestinal mucosal barrier and in the intestinal microbiota in a biliary obstruction mouse model.

Intestinal barrier dysfunction and dysbiosis are critical intestinal alterations in biliary obstructive diseases, for which farnesoid X receptor (FXR) is a potential intestinal therapeutic target, but its role and mechanism in the intestinal tract remain poorly defined. Using gut-specific knockout mice, we demonstrate that intestinal Fxr deficiency caused intestinal barrier function impairment and dysbiosis, and in a biliary obstruction model, obeticholic acid (OCA)-dependent intestinal Fxr activation protected against intestinal barrier injury and dysbiosis after bile duct ligation (BDL) surgery. Furthermore, from single-cell sequencing data, Fxr may directly regulate regenerating islet-derived protein 3γ (Reg3g) to influence intestinal functions. In conclusion, we elucidated FXR actions in the intestine under physiological and biliary obstruction conditions and suggest possible molecular targets that provide new insights for the intestinal treatment of biliary obstructive diseases.NEW & NOTEWORTHY Intestinal barrier dysfunction and dysbiosis are critical in biliary obstructive diseases, making farnesoid X receptor (FXR) a potential therapeutic target. Our study shows that Fxr deficiency impairs barrier function and causes dysbiosis. In a biliary obstruction model, obeticholic acid (OCA) activation of Fxr protects against these effects. In addition, single-cell sequencing suggests that Fxr may regulate Reg3g, influencing intestinal functions. This research reveals the role of FXR and offers new molecular targets for the treatment of biliary obstructive diseases.