2024年7月5日，来自山东大学李石洋等在于《细胞—代谢》杂志上发表了标题为“TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response.”的研究成果，研究提出TNF通过损害肠道胆汁酸耐受导致结肠炎恶化和英夫利西单抗反应受限。
据介绍，肠道不断地遇到并适应由多种膳食营养素形成的外部环境。然而，溃疡性结肠炎的肠道对饮食挑战的适应性是否以及如何受到影响尚不完全清楚。
研究人员发现，由于炎症损害了胆汁酸耐受性，短暂的高脂肪饮食会加剧结肠炎。从机制上讲，结肠炎发作时产生的过量肿瘤坏死因子（TNF）通过肠上皮细胞中受体相互作用的丝氨酸/苏氨酸蛋白激酶1/细胞外信号调节激酶途径干扰胆汁酸解毒，导致内质网中胆汁酸超负荷，并导致细胞凋亡。
与胆汁酸和TNF在促进肠道上皮损伤方面的协同作用一致，肠道胆汁酸含量高与英夫利昔单抗反应差相关，胆汁酸清除提高了英夫利单抗在实验性结肠炎中的疗效。
总之，这一研究将胆汁酸确定为肠道中的一种“机会性致病因素”，这将是溃疡性结肠炎预防以及治疗的一个有前景的靶点和分层标准。
Highlights
- Transient HFD promotes colitis progression and relapse via elevating intestinal BAs
- TNF-impaired BA tolerance endows BAs with cytotoxicity to intestinal epithelium
- TNF-caused BA accumulation in the ER induces gut epithelial apoptosis via IRE/XBP1
- High intestinal BAs hinder infliximab responsiveness in UC and experimental colitis
Summary
The intestine constantly encounters and adapts to the external environment shaped by diverse dietary nutrients. However, whether and how gut adaptability to dietary challenges is compromised in ulcerative colitis is incompletely understood. Here, we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromised bile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) produced at the onset of colitis interferes with bile-acid detoxification through the receptor-interacting serine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway in intestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulum and consequent apoptosis. In line with the synergy of bile acids and TNF in promoting gut epithelial damage, high intestinal bile acids correlate with poor infliximab response, and bile acid clearance improves infliximab efficacy in experimental colitis. This study identifies bile acids as an “opportunistic pathogenic factor” in the gut that would represent a promising target and stratification criterion for ulcerative colitis prevention/therapy.
文章来源：
Mengqi Zheng, Yunjiao Zhai et al, TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response.DOI: 10.1016/j.cmet.2024.06.008,Cell Metabolism：最新IF：31.373.
