Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation

Dan Li; Jiefei Zhou; Lingyu Wang; Zizhen Gong; Huijuan Le; Ye Huang; Congfeng Xu; Chunyan Tian; Wei Cai; Jin Wu

doi:10.1186/s13578-023-01109-0

Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation

Cell Biosci. 2023 Oct 3;13(1):186. doi: 10.1186/s13578-023-01109-0.

Authors

Dan Li^{1

2

3}, Jiefei Zhou^{1

2

3}, Lingyu Wang^{1

2

3}, Zizhen Gong^{1

2

3}, Huijuan Le^{1

2

3}, Ye Huang^{1

2

3}, Congfeng Xu⁴, Chunyan Tian^{5

6}, Wei Cai^{7

8

9}, Jin Wu^{10

11

12}

Affiliations

¹ Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
² Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
³ Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
⁴ Department of Cardiology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
⁵ State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China. tianchunyan@ncpsb.org.cn.
⁶ Research Unit of Proteomics-Driven Cancer Precision Medicine, Chinese Academy of Medical Sciences, Beijing, China. tianchunyan@ncpsb.org.cn.
⁷ Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. caiw204@sjtu.edu.cn.
⁸ Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. caiw204@sjtu.edu.cn.
⁹ Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. caiw204@sjtu.edu.cn.
¹⁰ Department of Pediatric Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China. wujin@xinhuamed.com.cn.
¹¹ Shanghai Institute for Pediatric Research, School of Medicine, Shanghai Jiaotong University, Shanghai, China. wujin@xinhuamed.com.cn.
¹² Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China. wujin@xinhuamed.com.cn.

Abstract

Background: High-fat diet (HFD) is closely associated with the increased prevalence of inflammatory bowel disease (IBD). Excessive gut microbial metabolite deoxycholic acid (DCA) caused by HFD plays significant roles in eliciting intestinal inflammation, however, the mechanism underlining the induction of inflammatory response by DCA has not been fully elucidated. The purpose of this study was to investigate the role of DCA in the triggering of inflammation via affecting CD4⁺ T cell differentiation.

Results: Murine CD4⁺T cells were cultured under Th1, Th2 or Th17-polarizing conditions treated with or without different dosage of DCA, and flowcytometry was conducted to detect the effect of DCA on CD4⁺ T cell differentiation. Alteration of gene expression in CD4⁺ T cells upon DCA treatment was determined by RNA-sequencing and qRT-PCR. Bioinformatic analysis, cholesterol metabolic profiling, ChIP assay and immuno-fluorescent staining were further applied to explore the DCA-regulated pathway that involved in CD4⁺T cell differentiation. The results showed that DCA could dose-dependently promote the differentiation of CD4⁺ T cell into Th17 linage with pathogenic signature. Mechanistically, DCA stimulated the expression of cholesterol biosynthetic enzymes CYP51 and led to the increased generation of endogenous RORγt agonists, including zymosterol and desmosterol, therefore facilitating Th17 differentiation. Up-regulation of CYP51 by DCA was largely mediated via targeting transcription factor SREBP2 and at least partially through bile acid receptor TGR5. In addition, DCA-supplemented diet significantly increased intestinal Th17 cell infiltration and exacerbated TNBS-induced colitis. Administration of cholestyramine to eliminate fecal bile acid obviously alleviated colonic inflammation accompanied by decreased Th17 cells in HFD-fed mice.

Conclusions: Our data establish a link between DCA-induced cholesterol biosynthesis in immune cells and gut inflammation. Modulation of bile acid level or targeting cholesterol metabolic pathway may be potential therapeutic measurements for HFD-related colitis.

Keywords: Bile acid; Colonic inflammation; High fat diet; Th17 differentiation.

Grants and funding

20ZR1446200/Natural Science Foundation of Shanghai