Ileal FXR Knockdown Ameliorates MASLD Progression in Rats via Modulating Bile Acid Metabolism Mediated by Gut Microbiota.

Objective: Metabolic dysfunction associated steatotic liver disease (MASLD) is the predominant cause of chronic liver disease, with dysregulation of bile acid (BA) metabolism and intestinal microbiota being intricately associated with MASLD progression. In this study, we investigated the role of ileal FXR in MASLD progression and BA metabolism in portal blood.

Methods: Sprague-Dawley rats were fed a typical western diet for 20 weeks, followed by local perfusion of AAV2-shNr1h4 to downregulate Nr1h4 expression in ileum tissue. To investigate the effect of ileal FXR on BA reabsorption and gut microbiota, portal blood and cecal fecal samples were collected from MASLD rats injected with AAV2-Ctrl or AAV2-shNr1h4 for metabolomics targeting BAs and 16S rRNA sequencing analysis.

Results: Our results showed that hepatic steatosis and inflammation were alleviated, whereas the reabsorption of secondary BAs and unconjugated BAs into the portal blood was enhanced when ileal FXR was knocked down. Furthermore, knockdown of ileal FXR resulted in a significant alteration in composition of the cecal microbiota, characterized by an increasing abundance of microbes involved in secondary BA production, including Escherichia, Adlercreutzia, Eubacterium, and Clostridium.

Conclusions: These findings suggest that downregulation of ileal FXR ameliorates the progression of MASLD in rats by modulating BA metabolism mediated by the gut microbiota, indicating that ileal FXR might be a potential therapeutic target for the treatment of MASLD.