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

Mengqi Zheng¹, Yunjiao Zhai², Yanbo Yu³, Jing Shen², Shuzheng Chu², Enrico Focaccia⁴, Wenyu Tian², Sui Wang⁵, Xuesong Liu², Xi Yuan², Yue Wang⁵, Lixiang Li³, Bingcheng Feng⁵, Zhen Li³, Xiaohuan Guo⁶, Ju Qiu⁷, Cuijuan Zhang⁸, Jiajie Hou⁹, Yiyuan Sun⁵, Xiaoyun Yang³, Xiuli Zuo³, Mathias Heikenwalder¹⁰, Yanqing Li¹¹, Detian Yuan¹², Shiyang Li¹³

Affiliations

¹ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China.
² Advanced Medical Research Institute, Shandong University, Jinan 250012, China.
³ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital of Shandong University, Jinan 250012, China.
⁴ Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China.
⁶ Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China.
⁷ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
⁸ Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, China; Department of Pathology, Qilu Hospital of Shandong University, Jinan 250012, China.
⁹ Cancer Centre, Faculty of Health Sciences University of Macau, Macau SAR, China; MOE Frontier Science Centre for Precision Oncology, University of Macau, Macau SAR, China.
¹⁰ Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; The M3 Research Center, Medical faculty, University Tübingen, Ottfried-Müller Strasse 37, Tübingen, Germany. Electronic address: m.heikenwaelder@dkfz.de.
¹¹ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: liyanqing@sdu.edu.cn.
¹² Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China. Electronic address: yuandt@sdu.edu.cn.
¹³ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Advanced Medical Research Institute, Shandong University, Jinan 250012, China; Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan 250012, China. Electronic address: lishiyang@sdu.edu.cn.

PMID: 38971153
DOI: 10.1016/j.cmet.2024.06.008

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

Mengqi Zheng et al. Cell Metab. 2024.

. 2024 Jun 28:S1550-4131(24)00233-X.

doi: 10.1016/j.cmet.2024.06.008. Online ahead of print.

Authors

Affiliations

¹ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China.
² Advanced Medical Research Institute, Shandong University, Jinan 250012, China.
³ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital of Shandong University, Jinan 250012, China.
⁴ Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁵ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China.
⁶ Institute for Immunology, School of Medicine, Tsinghua University, Beijing 100084, China; Beijing Key Laboratory for Immunological Research on Chronic Diseases, Tsinghua University, Beijing 100084, China.
⁷ CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
⁸ Institute of Pathology and Pathophysiology, Shandong University School of Medicine, Jinan 250012, China; Department of Pathology, Qilu Hospital of Shandong University, Jinan 250012, China.
⁹ Cancer Centre, Faculty of Health Sciences University of Macau, Macau SAR, China; MOE Frontier Science Centre for Precision Oncology, University of Macau, Macau SAR, China.
¹⁰ Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany; The M3 Research Center, Medical faculty, University Tübingen, Ottfried-Müller Strasse 37, Tübingen, Germany. Electronic address: m.heikenwaelder@dkfz.de.
¹¹ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Laboratory of Translational Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Robot Engineering Laboratory for Precise Diagnosis and Therapy of GI Tumor, Qilu Hospital of Shandong University, Jinan 250012, China. Electronic address: liyanqing@sdu.edu.cn.
¹² Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan 250012, China. Electronic address: yuandt@sdu.edu.cn.
¹³ Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan 250012, China; Shandong Provincial Clinical Research Center for Digestive Diseases, Jinan, China; Advanced Medical Research Institute, Shandong University, Jinan 250012, China; Key Laboratory for Experimental Teratology of Ministry of Education, Shandong University, Jinan 250012, China. Electronic address: lishiyang@sdu.edu.cn.

PMID: 38971153
DOI: 10.1016/j.cmet.2024.06.008

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.

Keywords: bile acid; detoxification; infliximab; tumor necrosis factor; ulcerative colitis.

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Declaration of interests The authors declare no competing interests.

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

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Abstract

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