P0094Gut microbiota-related bile acid metabolism-FXR/TGR5 axis impacts the response to anti-α4β7-integrin therapy in humanized mice with colitis

Background The gut microbiota and bile acid metabolites are key determinants in the response to biologic therapy for inflammatory bowel disease. However, the molecular mechanisms underlying the interaction between the treatment response to α4β7 integrin antagonists and the gut microbiota and bile acid metabolites remain unclear. This study explores the response and mechanism of action of inflammatory bowel disease to α4β7 integrin antagonists based on the gut microbiota-bile acid metabolite-FXR/TGR5 axis. Methods Using a humanized immune system mouse model, colitis was induced with 2,4,6-trinitrobenzenesulfonic acid, followed by treatment with α4β7 integrin antagonists. Mechanisms related to the treatment response level were explored through metagenomic sequencing and metabolomics analysis. Subsequently, baseline gut microbiota were depleted using combination antibiotic therapy, and fecal microbiota transplantation was performed using fecal suspensions from clinical patients, with targeted bile acid metabolomics analysis on fecal samples to deeply validate the regulatory role of gut microbiota and bile acid metabolites in treatment response. Finally, the activation effects of bile acid metabolites on FXR and TGR5 were evaluated in colitic mice and Caco-2 cells, further verifying the impact of FXR/TGR5 on the level of treatment response. Results This study demonstrates that α4β7 integrin antagonist treatment significantly ameliorates intestinal inflammation, pathological symptoms, and intestinal mucosal barrier damage in mice with colitis. Results from metagenomic sequencing and metabolomics analysis suggest that the baseline microbiome spectrum and bile acid metabolites can be used to predict the level of response to α4β7 integrin antagonist treatment. Moreover, the construction of germ-free mice and fecal microbiota transplantation revealed that specific anti-inflammatory microbes (Lactobacillus and Clostridium) in the baseline gut microbiota could enhance the treatment response level. Additionally, targeted bile acid metabolomics analysis indicated that bile acid metabolites associated with the aforementioned gut microbes also participate in regulating the response level. Finally, studies in colitic mice and Caco-2 cells suggest that bile acid metabolites CDCA and LCA can significantly improve intestinal barrier function and inhibit the inflammatory process by directly activating FXR and TGR5. Conclusion The gut microbiota-bile acid metabolite-FXR/TGR5 axis may be a potential mechanism affecting the response of inflammatory bowel disease to α4β7 integrin antagonists. Conflict of interest: Lv, Xiaoping: Han, Bing: No conflict of interest Lv, Xiaodan: No conflict of interest Lin, Jianing: No conflict of interest Chen, Lan: No conflict of interest Zhan, Lingling: No conflict of interest