Integrated transcriptomics, metabolomics, and gut microbiome analysis reveals the association between Rnf43 knockdown and intestinal epithelial hyperproliferation in HFD/AOM/DSS treated mice

Previous studies have demonstrated that individuals with MASLD have a higher incidence of colorectal polyps. However, it remains unclear whether bile acids and RNF43 are involved in the processes underlying intestinal epithelial cell changes and abnormal proliferation in MASLD. The GEO database was utilized to conduct bioinformatic analysis. Rnf43 knockdown in mice was achieved using AAV-shRNA. Bile acid levels in serum and feces were quantified using LC-MS/MS. Fecal microbiota composition was analyzed via 16 S rRNA sequencing. Additionally, immunohistochemistry was performed to evaluate the expression of proteins involved in bile acid metabolism. Mice in the shRnf43 group exhibited lower levels of the toxic bile acids DCA and LCA. Furthermore, hepatic expression of CYP7A1 and TGR5 were higher in the shRnf43 group compared to the scrambled control group, whereas BSEP expression was decreased. Knockdown of Rnf43 in a combined HFD/AOM/DSS-induced mouse model was associated with altered hepatic bile acid metabolism. These metabolic shifts occurred in parallel with intestinal epithelial improvement, and TGR5 upregulation. However, further mechanistic studies are warranted to establish the causal relationship between these changes and the observed therapeutic effects, which will help clarify the role of bile acid alterations in this process.