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Published on: August 21, 2017
Ileal FXR Knockdown Ameliorates MASLD Progression in Rats via Modulating Bile Acid Metabolism Mediated by Gut
Junjun Wang1,2, Jiaqi Gao1,2, Qingqing Zhang1,2
1Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University, Shanghai, China.
Background And Aim:
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.
Conclusion:
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.
Insights
Downregulating ileal Farnesoid X receptor (FXR) in rats ameliorates metabolic dysfunction associated steatotic liver disease (MASLD) by altering bile acid metabolism and gut microbiota composition. This suggests ileal FXR as a potential therapeutic target for MASLD.
Area of Science:
- Hepatology
- Gastroenterology
- Microbiome Research
Background:
- Metabolic dysfunction associated steatotic liver disease (MASLD) is a leading cause of chronic liver disease.
- Bile acid (BA) metabolism and gut microbiota dysregulation are key factors in MASLD progression.
Purpose of the Study:
- To investigate the role of ileal Farnesoid X receptor (FXR) in MASLD progression.
- To examine the impact of ileal FXR on bile acid metabolism and gut microbiota in MASLD.
Main Methods:
- Rats were fed a western diet to induce MASLD.
- Ileal FXR was downregulated using AAV2-shNr1h4.
- Portal blood and cecal samples were analyzed for bile acids and microbiota composition (16S rRNA sequencing).
Main Results:
- Downregulation of ileal FXR alleviated hepatic steatosis and inflammation.
- Secondary and unconjugated bile acid reabsorption into portal blood was enhanced.
- Cecal microbiota composition significantly altered, with increased abundance of microbes involved in secondary BA production.
Conclusions:
- Ileal FXR downregulation ameliorates MASLD progression in rats.
- This effect is mediated by modulation of bile acid metabolism influenced by gut microbiota.
- Ileal FXR represents a potential therapeutic target for MASLD treatment.
