背景:临床证据证实了炎症性肠病(IBD)之间的联系,特别是克罗恩病(CD),和代谢功能障碍相关的脂肪变性肝病(MASLD)。本研究旨在探索导致这种关联的潜在分子机制。
方法:通过给予高脂肪和西方饮食诱导MASLD,而用葡聚糖硫酸钠(DSS)和Il10KO小鼠模型诱导IBD。对次级胆汁酸(SBA)在回肠炎中的作用的研究涉及使用宏基因组测序,进行代谢组学检测,进行粪便细菌移植,构建CD8+T细胞特异性基因敲除小鼠。
结果:在MASLD+DSS和Il10KOMASLD小鼠中,我们观察到回肠末端以T细胞浸润和活化为特征的回肠炎。这种情况导致门静脉和肝脏的胆汁酸水平降低,抑制肝法尼醇X受体(FXR)激活,并加剧了MASLD。回肠内容物的宏基因组和代谢组学分析显示,在MASLD相关回肠炎中,梭菌增殖增加和SBA水平升高。使用无菌小鼠和粪便微生物群移植的实验表明SBA与MASLD相关的回肠炎之间存在关联。体外,SBA通过TGR5,mTOR,和氧化磷酸化(OXPHOS)途径。在体内,CD8+T细胞中的TGR5敲除有效缓解回肠炎并恶化MASLD表型。临床数据进一步支持了这些发现,表现出正相关的回肠炎和MASLD。
结论:MASLD诱导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,这通过TGR5/mTOR/OXPHOS信号通路导致严重的CD8+T细胞介导的回肠炎。血管炎引起的组织损伤损害肝肠循环,抑制肝脏FXR激活,并加剧了MASLD表型。
■我们的研究提供了关于回肠炎和MASLD的相互作用和潜在机制的全面调查。由肠道细菌产生的SBA,作为MASLD和回肠炎之间的关键联系。该化合物通过促进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,必须彻底说明肠道的影响,尤其是回肠,通过肝肠循环对肝功能的影响。
OBJECTIVE: 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.
CONCLUSIONS: 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.
UNASSIGNED: 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.