2024年7月5日，來自山東大學李石洋等在于《細胞—代謝》雜志上發表了標題為“TNF compromises intestinal bile-acid tolerance dictating colitis progression and limited infliximab response.”的研究成果，研究提出TNF通過損害腸道膽汁酸耐受導致結腸炎惡化和英夫利西單抗反應受限。
據介紹，腸道不斷地遇到并適應由多種膳食營養素形成的外部環境。然而，潰瘍性結腸炎的腸道對飲食挑戰的適應性是否以及如何受到影響尚不完全清楚。
研究人員發現，由于炎癥損害了膽汁酸耐受性，短暫的高脂肪飲食會加劇結腸炎。從機制上講，結腸炎發作時產生的過量腫瘤壞死因子（TNF）通過腸上皮細胞中受體相互作用的絲氨酸/蘇氨酸蛋白激酶1/細胞外信號調節激酶途徑干擾膽汁酸解毒，導致內質網中膽汁酸超負荷，并導致細胞凋亡。
與膽汁酸和TNF在促進腸道上皮損傷方面的協同作用一致，腸道膽汁酸含量高與英夫利昔單抗反應差相關，膽汁酸清除提高了英夫利單抗在實驗性結腸炎中的療效。
總之，這一研究將膽汁酸確定為腸道中的一種“機會性致病因素”，這將是潰瘍性結腸炎預防以及治療的一個有前景的靶點和分層標準。
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.
文章來源：
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.
