<br>回肠炎通过胆汁酸调节和增强回肠 CD8+ T 细胞中的 TGR5 信号传导促进 MASLD 进展,Journal of Hepatology

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回肠炎通过胆汁酸调节和增强回肠 CD8+ T 细胞中的 TGR5 信号传导促进 MASLD 进展
Journal of Hepatology ( IF 26.8 ) Pub Date : 2024-01-04 , DOI: 10.1016/j.jhep.2023.12.024
Chang Zheng ₁ , Lei Wang ₁ , Tianhui Zou ₂ , Senlin Lian ₃ , Jiajing Luo ₃ , Yijun Lu ₃ , Hanbing Hao ₃ , Yuejie Xu ₄ , Ying Xiang ₁ , Xiaoqi Zhang ₁ , Guifang Xu ₁ , Xiaoping Zou ₅ , Runqiu Jiang ₆

Affiliation

临床证据证实炎症性肠病，特别是克罗恩病 (CD) 与代谢功能障碍相关的脂肪肝病 (MASLD) 之间存在联系。本研究旨在探索造成这种关联的潜在分子机制。 MASLD 是通过高脂肪和西方饮食诱导的，而炎症性肠病则是使用 DSS（葡聚糖硫酸钠）和基因敲除（KO）小鼠模型诱导的。对次级胆汁酸 (SBA) 在回肠炎中作用的研究涉及采用宏基因组测序、进行代谢组学检测、进行粪便微生物群移植以及构建 CD8 T 细胞特异性基因敲除小鼠。在 MASLD+DSS 和 KO MASLD 小鼠中，我们观察到以回肠末端 T 细胞浸润和激活为特征的回肠炎。这种情况导致门静脉和肝脏中胆汁酸水平降低，抑制肝脏法尼醇 X 受体 (FXR) 激活，并加剧 MASLD。回肠内容物的宏基因组学和代谢组学分析揭示了 MASLD 相关回肠炎中增殖增加和 SBA 水平升高。使用无菌小鼠和粪便微生物群移植进行的实验表明，SBA 与 MASLD 相关的回肠炎之间存在关联。，SBA 通过 TGR5、mTOR 和氧化磷酸化途径促进 CD8 T 细胞活化。，CD8 T细胞中的TGR5 KO有效缓解回肠炎并逆转MASLD表型。临床数据进一步支持了这些发现，证明回肠炎与 MASLD 之间呈正相关。 MASLD 引起的肠道菌群变化导致回肠中 SBA 水平升高。在肠道屏障受损的情况下，这会通过 TGR5/mTOR/氧化磷酸化信号通路导致严重的 CD8 T 细胞介导的回肠炎。回肠炎引起的组织损伤损害肠肝循环，抑制肝脏 FXR 激活，并加剧 MASLD 表型。我们的研究对回肠炎和代谢功能障碍相关脂肪肝病（MASLD）之间的相互作用和潜在机制进行了全面的研究。肠道细菌产生的次级胆汁酸是 MASLD 和回肠炎之间的关键联系。次级胆汁酸通过促进 CD8 T 细胞介导的回肠炎破坏肝脏脂质代谢来发挥其影响。在未来预防和治疗 MASLD 的努力中，必须彻底考虑肠道（尤其是回肠）通过肠肝循环对肝功能的影响。

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Ileitis promotes MASLD progression via bile acid modulation and enhanced TGR5 signaling in ileal CD8+ T cells

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. MASLD was induced by administering high-fat and western diets, while inflammatory bowel disease was induced using DSS (dextran sulfate sodium) and the 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. In MASLD+DSS and 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 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. , SBAs promoted CD8 T-cell activation via the TGR5, mTOR, and oxidative phosphorylation pathways. , 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. 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. 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.

更新日期：2024-01-04

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