山东大学李石洋等取得重要工作进展。他们研究提出，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。相关研究成果2024年7月5日在线发表于《细胞—代谢》杂志上。

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。

附：英文原文

Title: TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response

Author: Mengqi Zheng, Yunjiao Zhai, Yanbo Yu, Jing Shen, Shuzheng Chu, Enrico Focaccia, Wenyu Tian, Sui Wang, Xuesong Liu, Xi Yuan, Yue Wang, Lixiang Li, Bingcheng Feng, Zhen Li, Xiaohuan Guo, Ju Qiu, Cuijuan Zhang, Jiajie Hou, Yiyuan Sun, Xiaoyun Yang, Xiuli Zuo, Mathias Heikenwalder, Yanqing Li, Detian Yuan, Shiyang Li

Issue&Volume: 2024-07-05

Abstract: The intestine constantly encounters and adapts to the external environment shapedby diverse dietary nutrients. However, whether and how gut adaptability to dietarychallenges is compromised in ulcerative colitis is incompletely understood. Here,we show that a transient high-fat diet exacerbates colitis owing to inflammation-compromisedbile acid tolerance. Mechanistically, excessive tumor necrosis factor (TNF) producedat the onset of colitis interferes with bile-acid detoxification through the receptor-interactingserine/threonine-protein kinase 1/extracellular signal-regulated kinase pathway inintestinal epithelial cells, leading to bile acid overload in the endoplasmic reticulumand consequent apoptosis. In line with the synergy of bile acids and TNF in promotinggut epithelial damage, high intestinal bile acids correlate with poor infliximab response,and bile acid clearance improves infliximab efficacy in experimental colitis. Thisstudy identifies bile acids as an “opportunistic pathogenic factor” in the gut thatwould represent a promising target and stratification criterion for ulcerative colitisprevention/therapy.

DOI: 10.1016/j.cmet.2024.06.008

Source: https://www.cell.com/cell-metabolism/abstract/S1550-4131(24)00233-X