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

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 induct...

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Autores principales: Li, Dan, Zhou, Jiefei, Wang, Lingyu, Gong, Zizhen, Le, Huijuan, Huang, Ye, Xu, Congfeng, Tian, Chunyan, Cai, Wei, Wu, Jin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10548658/
https://www.ncbi.nlm.nih.gov/pubmed/37789469
http://dx.doi.org/10.1186/s13578-023-01109-0
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author Li, Dan
Zhou, Jiefei
Wang, Lingyu
Gong, Zizhen
Le, Huijuan
Huang, Ye
Xu, Congfeng
Tian, Chunyan
Cai, Wei
Wu, Jin
author_facet Li, Dan
Zhou, Jiefei
Wang, Lingyu
Gong, Zizhen
Le, Huijuan
Huang, Ye
Xu, Congfeng
Tian, Chunyan
Cai, Wei
Wu, Jin
author_sort Li, Dan
collection PubMed
description 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01109-0.
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spelling pubmed-105486582023-10-05 Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation Li, Dan Zhou, Jiefei Wang, Lingyu Gong, Zizhen Le, Huijuan Huang, Ye Xu, Congfeng Tian, Chunyan Cai, Wei Wu, Jin Cell Biosci Research 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13578-023-01109-0. BioMed Central 2023-10-03 /pmc/articles/PMC10548658/ /pubmed/37789469 http://dx.doi.org/10.1186/s13578-023-01109-0 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (https://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
spellingShingle Research
Li, Dan
Zhou, Jiefei
Wang, Lingyu
Gong, Zizhen
Le, Huijuan
Huang, Ye
Xu, Congfeng
Tian, Chunyan
Cai, Wei
Wu, Jin
Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation
title Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation
title_full Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation
title_fullStr Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation
title_full_unstemmed Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation
title_short Gut microbial metabolite deoxycholic acid facilitates Th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation
title_sort gut microbial metabolite deoxycholic acid facilitates th17 differentiation through modulating cholesterol biosynthesis and participates in high-fat diet-associated colonic inflammation
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10548658/
https://www.ncbi.nlm.nih.gov/pubmed/37789469
http://dx.doi.org/10.1186/s13578-023-01109-0
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