Mengque Xu1, Mengsha Cen1, Yuqin Shen1, Yubin Zhu1, Fangli Cheng1, Linlin Tang1, Weiling Hu1, Ning Dai2. 1. Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China. 2. Department of Gastroenterology, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, No. 3 Qingchun East Road, Jianggan District, Hangzhou, 310016, China. ndaicn@zju.edu.cn.
Abstract
BACKGROUND: A Western diet is a risk factor for the development of inflammatory bowel disease (IBD). High levels of fecal deoxycholic acid (DCA) in response to a Western diet contribute to bowel inflammatory injury. However, the mechanism of DCA in the natural course of IBD development remains unanswered. AIMS: The aim of this study is to investigate the effect of DCA on the induction of gut dysbiosis and its roles in the development of intestinal inflammation. METHODS: Wild-type C57BL/6J mice were fed an AIN-93G diet, either supplemented with or without 0.2% DCA, and killed at 24 weeks. Distal ileum and colon tissues were assessed by histopathological analysis. Hepatic and ileal gene expression was examined by qPCR, and the gut microbiota was analyzed by high-throughput 16S rRNA gene sequencing. HPLC-MS was used for fecal bile acid quantification. RESULTS: Mice fed the DCA-supplemented diet developed focal areas of ileal and colonic inflammation, accompanied by alteration of the composition of the intestinal microbiota and accumulation of fecal bile acids. DCA-induced dysbiosis decreased the deconjugation of bile acids, and this regulation was associated with the repressed expression of target genes in the enterohepatic farnesoid X receptor-fibroblast growth factor (FXR-FGF15) axis, leading to upregulation of hepatic de novo bile acid synthesis. CONCLUSIONS: These results suggest that DCA-induced gut dysbiosis may act as a key etiologic factor in intestinal inflammation, associated with bile acid metabolic disturbance and downregulation of the FXR-FGF15 axis.
BACKGROUND: A Western diet is a risk factor for the development of inflammatory bowel disease (IBD). High levels of fecal deoxycholic acid (DCA) in response to a Western diet contribute to bowel inflammatory injury. However, the mechanism of DCA in the natural course of IBD development remains unanswered. AIMS: The aim of this study is to investigate the effect of DCA on the induction of gut dysbiosis and its roles in the development of intestinal inflammation. METHODS: Wild-type C57BL/6J mice were fed an AIN-93G diet, either supplemented with or without 0.2% DCA, and killed at 24 weeks. Distal ileum and colon tissues were assessed by histopathological analysis. Hepatic and ileal gene expression was examined by qPCR, and the gut microbiota was analyzed by high-throughput 16S rRNA gene sequencing. HPLC-MS was used for fecal bile acid quantification. RESULTS:Mice fed the DCA-supplemented diet developed focal areas of ileal and colonic inflammation, accompanied by alteration of the composition of the intestinal microbiota and accumulation of fecal bile acids. DCA-induced dysbiosis decreased the deconjugation of bile acids, and this regulation was associated with the repressed expression of target genes in the enterohepatic farnesoid X receptor-fibroblast growth factor (FXR-FGF15) axis, leading to upregulation of hepatic de novo bile acid synthesis. CONCLUSIONS: These results suggest that DCA-induced gut dysbiosis may act as a key etiologic factor in intestinal inflammation, associated with bile acid metabolic disturbance and downregulation of the FXR-FGF15 axis.
Entities:
Keywords:
Bile acids; Farnesoid X receptor; Fibroblast growth factor 15; Gut dysbiosis; Intestinal inflammation
Authors: Zhen-Hua Wu; Jing Yang; Lei Chen; Chuang Du; Qi Zhang; Shan-Shan Zhao; Xiao-Yu Wang; Jing Yang; Yang Liu; Demin Cai; Jian Du; Hui-Xin Liu Journal: Front Nutr Date: 2022-06-07
Authors: Ke Sui; Kevin M Tveter; Fiona G Bawagan; Patricia Buckendahl; Savannah A Martinez; Zehra H Jaffri; Avery T MacDonell; Yue Wu; Rocio M Duran; Sue A Shapses; Diana E Roopchand Journal: Front Pharmacol Date: 2022-06-21 Impact factor: 5.988