Modulation of the Gut Microbiota-Farnesoid X Receptor Axis Improves Deoxycholic Acid-induced Intestinal Inflammation in Mice

Inflammatory bowel disease (IBD) is associated with gut dysbiosis and dysregulation of bile acid metabolism. A high luminal content of deoxycholic acid (DCA) with consumption of a Westernized diet is implicated in the pathogenesis of IBD. The aim of the study is to explore the role of intestinal mic...

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Published in:Journal of Crohn's and colitis 2021-07, Vol.15 (7), p.1197-1210
Main Authors: Xu, Mengque, Shen, Yuqin, Cen, Mengsha, Zhu, Yubin, Cheng, Fangli, Tang, Linlin, Zheng, Xia, Kim, John J, Dai, Ning, Hu, Weiling
Format: Article
Language:English
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Summary:Inflammatory bowel disease (IBD) is associated with gut dysbiosis and dysregulation of bile acid metabolism. A high luminal content of deoxycholic acid (DCA) with consumption of a Westernized diet is implicated in the pathogenesis of IBD. The aim of the study is to explore the role of intestinal microbiota and bile acid metabolism in mice with DCA-induced intestinal inflammation. 4-week-old wild-type C57BL mice were fed with AIN-93G (control diet), AIN-93G+0.2% DCA, AIN-93G+0.2% DCA+6 weeks of fexaramine (FXR agonist), or AIN-93G+0.2% DCA+antibiotic cocktail for 24 weeks. Histopathology, Western blotting, and qPCR were performed on the intestinal tissue. Fecal microbiota was analyzed by 16S rDNA sequencing. Fecal bile acid and short-chain fatty acid (SCFA) levels were analyzed by chromatography. Gut dysbiosis and enlarged bile acid pool were observed in DCA-treated mice, accompanied by a lower farnesoid X receptor (FXR) activity in the intestine. Administration of fexaramine mitigated DCA-induced intestinal injury, restored intestinal FXR activity, activated fibroblast growth factor 15, and normalized bile acid metabolism. Furthermore, fexaramine administration increased the abundance of SCFA-producing bacteria. Depletion of the commensal microbiota with antibiotics decreased the diversity of the intestinal microbiota, attenuated bile acid synthesis, and reduced intestinal inflammation induced by DCA. DCA induced-intestinal inflammation is associated with alterations of gut microbiota and bile acid profiles. Interventions targeting the gut microbiota-FXR signaling pathway may reduce DCA-induced intestinal disease.
ISSN:1873-9946
1876-4479
DOI:10.1093/ecco-jcc/jjab003