Microbial metabolite deoxycholic acid-mediated ferroptosis exacerbates high-fat diet-induced colonic inflammation

Chen Wang; Qiao Chu; Wenxiao Dong; Xin Wang; Wenjing Zhao; Xin Dai; Wentian Liu; Bangmao Wang; Tianyu Liu; Weilong Zhong; Changtao Jiang; Hailong Cao

doi:10.1016/j.molmet.2024.101944

Microbial metabolite deoxycholic acid-mediated ferroptosis exacerbates high-fat diet-induced colonic inflammation

Mol Metab. 2024 Apr 18:84:101944. doi: 10.1016/j.molmet.2024.101944. Online ahead of print.

Authors

Chen Wang¹, Qiao Chu¹, Wenxiao Dong¹, Xin Wang¹, Wenjing Zhao¹, Xin Dai¹, Wentian Liu¹, Bangmao Wang¹, Tianyu Liu², Weilong Zhong³, Changtao Jiang⁴, Hailong Cao⁵

Affiliations

¹ Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China.
² Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China. Electronic address: liutianyu@tmu.edu.cn.
³ Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China. Electronic address: zhongweilong@tmu.edu.cn.
⁴ Center of Basic Medical Research, Institute of Medical Innovation and Research, Third Hospital, Peking University, Beijing, China. Electronic address: jiangchangtao@bjmu.edu.cn.
⁵ Department of Gastroenterology and Hepatology, General Hospital, Tianjin Medical University, National Key Clinical Specialty, Tianjin Institute of Digestive Diseases, Tianjin Key Laboratory of Digestive Diseases, Tianjin, China. Electronic address: caohailong@tmu.edu.cn.

Abstract

High-fat diet (HFD) has long been recognized as risk factors for the development and progression of ulcerative colitis (UC), but the exact mechanism remained elusive. Here, HFD increased intestinal deoxycholic acid (DCA) levels, and DCA further exacerbated colonic inflammation. Transcriptome analysis revealed that DCA triggered ferroptosis pathway in colitis mice. Mechanistically, DCA upregulated hypoxia-inducible factor-2α (HIF-2α) and divalent metal transporter-1 (DMT1) expression, causing the ferrous ions accumulation and ferroptosis in intestinal epithelial cells, which was reversed by ferroptosis inhibitor ferrostatin-1. DCA failed to promote colitis and ferroptosis in intestine-specific HIF-2α-null mice. Notably, byak-angelicin inhibited DCA-induced pro-inflammatory and pro-ferroptotic effects through blocking the up-regulation of HIF-2α by DCA. Moreover, fat intake was positively correlated with disease activity in UC patients consuming HFD, with ferroptosis being more pronounced. Collectively, our findings demonstrated that HFD exacerbated colonic inflammation by promoting DCA-mediated ferroptosis, providing new insights into diet-related bile acid dysregulation in UC.

Keywords: Byak-angelicin; Colitis; Deoxycholic acid; Ferroptosis; HIF-2α/DMT1; High-fat diet.