Abstract Background This section explores the potential regulatory mechanisms of the response of Crohn’s disease (CD) to α4β7 integrin antagonists, providing new strategies for the application and clinical treatment of CD drugs. Methods On the 7th day of constructing the animal disease model, colon tissues were collected for transcriptomic sequencing. Through library construction sequencing and bioinformatics analysis, differential genes and signaling pathways related to the response level of CD treatment were screened out. Subsequently, specific bile acids related to the intestinal microbiota were intervened in Caco-2 cells. The expression of differential genes in each group was detected to verify the direct activation effect of bile acids on differential genes. Finally, the differential gene-related selective agonists INT747 and INT777 were applied to Caco-2 cells to detect the changes in the signaling pathways, in order to further verify the regulatory effect of the differential genes on the related signaling pathways. Results The transcriptomic sequencing results indicated that the differentially expressed genes related to the response level of CD treatment were FXR and TGR5, and the NF-κB signaling pathway had the largest proportion and the most significant difference in the enrichment analysis. After the construction of humanized gut microbiota, the expression levels of FXR, TGR5 and downstream target genes FGF19 and YAP in mice transplanted with the gut microbiota of clinically responsive patients were significantly increased compared with those transplanted with the gut microbiota of non-responsive patients (P 0.05), indicating that the gut microbiota has a regulatory effect on the differential genes. When specific bile acids related to the intestinal microbiota were intervened in Caco-2 cells, the expression levels of FXR and TGR5 in the bile acid group were significantly higher than those in the other groups (P 0.05), indicating the alteration of the bile acid pool mediated by the intestinal microbiota, especially the increase of chenodeoxycholic acid and choline. The differential gene-related selective agonists INT747 and INT777 were applied to Caco-2 cells. After the agonist intervention, the NF-κB signaling pathway was significantly inhibited (P 0.05). In summary, the alteration of the bile acid pool mediated by the gut microbiota can directly activate FXR and TGR5, and FXR and TGR5 will negatively feedback regulate the NF-κB signaling pathway, thereby affecting the therapeutic response level of CD. Conclusion FXR/TGR5 negative feedback regulates the NF-κB signaling pathway, thereby enhancing the therapeutic response level of CD to α4β7 integrin antagonists. Conflict of interest: Ms. Kang, Mei: No conflict of interest Wen, Hongtao: No conflict of interest Han, Bing: No conflict of interest Li, Ya: No conflict of interest
Kang et al. (Thu,) studied this question.