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

Published:3 September 2024 DOI: 10.1016/j.cmet.2024.06.008 PMID: 38971153
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

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.

Substances (92)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Andrographolide 5508-58-7 C20H30O5 771 suppliers $10.00-$807.00
Andrographolide 5508-58-7 C20H30O5 771 suppliers $10.00-$807.00
Andrographolide 5508-58-7 C20H30O5 771 suppliers $10.00-$807.00
Andrographolide 5508-58-7 C20H30O5 771 suppliers $10.00-$807.00
TUNICAMYCIN 11089-65-9 C37H60N4O16 289 suppliers $32.00-$1112.00
TUNICAMYCIN 11089-65-9 C37H60N4O16 289 suppliers $32.00-$1112.00
TUNICAMYCIN 11089-65-9 C37H60N4O16 289 suppliers $32.00-$1112.00
TUNICAMYCIN 11089-65-9 C37H60N4O16 289 suppliers $32.00-$1112.00
PD 0325901 391210-10-9 C16H14F3IN2O4 280 suppliers $8.00-$3990.00
PD 0325901 391210-10-9 C16H14F3IN2O4 280 suppliers $8.00-$3990.00
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