دورية أكاديمية
Ileitis promotes MASLD progression via bile acid modulation and enhanced TGR5 signaling in ileal CD8 + T cells.
| العنوان: | Ileitis promotes MASLD progression via bile acid modulation and enhanced TGR5 signaling in ileal CD8 + T cells. |
|---|---|
| المؤلفون: | Zheng C; Department of Gastroenterology, Affiliated Nanjing Drum Tower Hospital, and Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China., Wang L; Department of Gastroenterology, Affiliated Nanjing Drum Tower Hospital, and Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China., Zou T; Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology & Hepatology, Ministry of Health, State Key Laboratory of Oncogene and Related Genes, Shanghai Institute of Digestive Disease, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200233, China., Lian S; Medical School of Nanjing University, Nanjing 210993, Jiangsu Province, China., Luo J; Medical School of Nanjing University, Nanjing 210993, Jiangsu Province, China., Lu Y; Medical School of Nanjing University, Nanjing 210993, Jiangsu Province, China., Hao H; Medical School of Nanjing University, Nanjing 210993, Jiangsu Province, China., Xu Y; Department of Traditional Chinese Medicine, Nanjing Drum Tower Hospital Clinical College of Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing 210008, China., Xiang Y; Department of Gastroenterology, Affiliated Nanjing Drum Tower Hospital, and Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China., Zhang X; Department of Gastroenterology, Affiliated Nanjing Drum Tower Hospital, and Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China., Xu G; Department of Gastroenterology, Affiliated Nanjing Drum Tower Hospital, and Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China. Electronic address: 13852293376@163.com., Zou X; Department of Gastroenterology, Affiliated Nanjing Drum Tower Hospital, and Medical School of Nanjing University, Nanjing 210008, Jiangsu Province, China; Department of Gastroenterology, Taikang Xianlin Drum Tower Hospital, Nanjing 210000, China. Electronic address: zouxp@nju.edu.cn., Jiang R; Department of Clinical Laboratory, The First Affiliated Hospital of Anhui Medical University, Hefei, 230022, People's Republic of China. Electronic address: jiangrq@ahmu.edu.cn. |
| المصدر: | Journal of hepatology [J Hepatol] 2024 May; Vol. 80 (5), pp. 764-777. Date of Electronic Publication: 2024 Jan 04. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8503886 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1600-0641 (Electronic) Linking ISSN: 01688278 NLM ISO Abbreviation: J Hepatol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2001- : Amsterdam : Elsevier Original Publication: Copehnagen : Munksgaard International Publishers, [c1984- |
| مواضيع طبية MeSH: | Ileitis* , Fatty Liver* , Crohn Disease*, Mice ; Animals ; Bile Acids and Salts ; Interleukin-10 ; CD8-Positive T-Lymphocytes ; Signal Transduction/genetics ; Ileum ; Mice, Knockout ; TOR Serine-Threonine Kinases |
| مستخلص: | Background & Aims: Clinical evidence substantiates a link between inflammatory bowel disease, particularly Crohn's disease (CD), and metabolic dysfunction-associated steatotic liver disease (MASLD). This study aims to explore the underlying molecular mechanisms responsible for this association. Methods: MASLD was induced by administering high-fat and western diets, while inflammatory bowel disease was induced using DSS (dextran sulfate sodium) and the Il10 knockout (KO) mouse model. The investigation into the role of secondary bile acids (SBAs) in ileitis involved employing metagenomic sequencing, conducting metabolomics detection, performing fecal microbiota transplantation, and constructing CD8 + T cell-specific gene knockout mice. Results: In MASLD+DSS and Il10 KO MASLD mice, we observed ileitis characterized by T-cell infiltration and activation in the terminal ileum. This condition resulted in decreased bile acid levels in the portal vein and liver, inhibited hepatic farnesoid X receptor (FXR) activation, and exacerbated MASLD. Metagenomic and metabolomic analysis of ileal contents revealed increased Clostridium proliferation and elevated SBA levels in MASLD-associated ileitis. Experiments using germ-free mice and fecal microbiota transplantation suggested an association between SBA and MASLD-related ileitis. In vitro, SBAs promoted CD8 + T-cell activation via the TGR5, mTOR, and oxidative phosphorylation pathways. In vivo, TGR5 KO in CD8 + T cells effectively alleviated ileitis and reversed the MASLD phenotype. Clinical data further supported these findings, demonstrating a positive correlation between ileitis and MASLD. Conclusion: MASLD-induced changes in intestinal flora result in elevated levels of SBAs in the ileum. In the presence of a compromised intestinal barrier, this leads to severe CD8 + T cell-mediated ileitis through the TGR5/mTOR/oxidative phosphorylation signaling pathway. Ileitis-induced tissue damage impairs enterohepatic circulation, inhibits hepatic FXR activation, and exacerbates the MASLD phenotype. Impact and Implications: Our study provides a comprehensive investigation of the interplay and underlying mechanisms connecting ileitis and metabolic dysfunction-associated steatotic liver disease (MASLD). Secondary bile acids produced by intestinal bacteria act as the critical link between MASLD and ileitis. Secondary bile acids exert their influence by disrupting liver lipid metabolism through the promotion of CD8 + T cell-mediated ileitis. In future endeavors to prevent and treat MASLD, it is essential to thoroughly account for the impact of the intestinal tract, especially the ileum, on liver function via the enterohepatic circulation. (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.) |
| فهرسة مساهمة: | Keywords: CD8(+)T cells; Crohn’s disease; FXR; TGR5; bile acids; metabolic dysfunction associated steatotic liver disease |
| المشرفين على المادة: | 0 (Bile Acids and Salts) 130068-27-8 (Interleukin-10) EC 2.7.11.1 (TOR Serine-Threonine Kinases) |
| تواريخ الأحداث: | Date Created: 20240105 Date Completed: 20240422 Latest Revision: 20240422 |
| رمز التحديث: | 20240422 |
| DOI: | 10.1016/j.jhep.2023.12.024 |
| PMID: | 38181823 |
| قاعدة البيانات: | MEDLINE |
Full Text via ClinicalKey 
Full Text Finder كن أول من يترك تعليقا!