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

ABSTRACT

The gut microbiota and bile acid metabolism are key determinants of the response of inflammatory bowel disease to biologic therapy. However, the molecular mechanisms underlying the interactions between the response to anti-α4β7-integrin therapy and the gut microbiota and bile acid metabolism remain unknown. In this research, we investigated the role of gut microbiota-related bile acid metabolism on the response to anti-α4β7-integrin therapy in a humanized immune system mouse model with colitis induced by 2,4,6-trinitrobenzene sulfonic acid. We found that anti-α4β7-integrin significantly mitigated intestinal inflammation, pathological symptoms, and gut barrier disruption in remission-achieving colitis mice. Whole-genome shotgun metagenomic sequencing demonstrated that employing baseline microbiome profiles to predict remission and the treatment response was a promising strategy. Antibiotic-mediated gut microbiota depletion and fecal microbiome transplantation revealed that the baseline gut microbiota contained common microbes with anti-inflammatory effects and reduced mucosal barrier damage, improving the treatment response. Targeted metabolomics analysis illustrated that bile acids associated with microbial diversity were involved in colitis remission. Furthermore, the activation effects of the microbiome and bile acids on FXR and TGR5 were evaluated in colitis mice and Caco-2 cells. The findings revealed that the production of gastrointestinal bile acids, particularly CDCA and LCA, further directly promoted the stimulation of FXR and TGR5, significantly improving gut barrier function and suppressing the inflammatory process. Taken together, gut microbiota-related bile acid metabolism-FXR/TGR5 axis may be a potential mechanism for impacting the response to anti-α4β7-integrin in experimental colitis. Thus, our research provides novel insights into the treatment response in inflammatory bowel disease.

KEYWORDS:

• Gut microbiota
• bile acids
• FXR/TGR5 signaling
• inflammatory bowel disease
• anti-α4β7-integrin
• response

Acknowledgments

Figure 10 in this study was created by Figdraw (www.figdraw.com).

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data generated during whole-genome shotgun metagenomic sequencing and 16S-rDNA gene high-throughput sequencing were deposited in the National Centre for Biotechnology Information (NCBI) Sequence Read Archive (SRA; https://www.ncbi.nlm.nih.gov/) under BioProject numbers PRJNA941025, PRJNA941019 and PRJNA941022.

Authors contribution

Bing Han and Xiaoping Lv designed and conceived the study. Bing Han, XiaoDan Lv, Gengfeng Liu, Shiquan Li, Junhua Fan, Lan Chen, Zhixi Huang, Guangfu Lin, Xiaofang Xu, and Ziqian Huang performed the experiments. Bing Han, XiaoDan Lv, and Gengfeng Liu analyzed and collated the data. Bing Han wrote the first draft. Xiaoping Lv and Lingling Zhan revised the paper. The final paper was reviewed and approved by all authors.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/19490976.2023.2232143

Additional information

Funding

This study was supported by grants from the National Natural Science Foundation of China (No. 81860104), the Innovation Project of Guangxi Graduate Education (No. YCBZ2022079), the Natural Science Foundation of Guangxi Zhuang Autonomous Region (No. 2017GXNSFAA198299), the Development and Application of Medical and Health Appropriate Technology Project in Guangxi Zhuang Autonomous Region (No. S2018049), the Youth Science Foundation of Guangxi Medical University (No. GXMUYSF202316), and the Self-financing Project of Health Commission of Guangxi Zhuang Autonomous Region (No. Z20200398).