Abstract:
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.
摘要:
肠道不断遇到并适应由不同饮食营养素形成的外部环境。然而,在溃疡性结肠炎中,肠道对饮食挑战的适应性是否以及如何受到影响尚不清楚.这里,我们表明,短暂的高脂饮食会由于炎症受损的胆汁酸耐受性而加剧结肠炎.机械上,结肠炎发作时产生的过度肿瘤坏死因子(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,导致内质网胆汁酸超负荷和随之而来的细胞凋亡。符合胆汁酸和TNF在促进肠上皮损伤中的协同作用,高肠胆汁酸与英夫利昔单抗反应不良相关,胆汁酸清除可改善英夫利昔单抗在实验性结肠炎中的疗效。这项研究将胆汁酸确定为肠道中的“机会致病因子”,这将代表溃疡性结肠炎预防/治疗的有希望的目标和分层标准。