A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves glucose homeostasis via the orphan receptor MRGPRE

Jun Lin; Qixing Nie; Jie Cheng; Ya-Ni Zhong; Tianyao Zhang; Xiuying Zhang; Xiaoyan Ge; Yong Ding; Canyang Niu; Yuhua Gao; Kai Wang; Mingxin Gao; Xuemei Wang; Weixuan Chen; Chuyu Yun; Chuan Ye; Jinkun Xu; Weike Shaoyong; Lijun Zhang; Pan Shang; Xi Luo; Zhiwei Zhang; Xin Zheng; Xueying Sha; Jinxin Zhang; Shaoping Nie; Xuguang Zhang; Fazheng Ren; Huiying Liu; Erdan Dong; Xiao Yu; Linong Ji; Yanli Pang; Jin-Peng Sun; Changtao Jiang

doi:10.1016/j.cell.2025.05.010

A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves glucose homeostasis via the orphan receptor MRGPRE

Cell. 2025 May 22:S0092-8674(25)00560-4. doi: 10.1016/j.cell.2025.05.010. Online ahead of print.

Authors

Jun Lin¹, Qixing Nie², Jie Cheng³, Ya-Ni Zhong⁴, Tianyao Zhang⁴, Xiuying Zhang⁵, Xiaoyan Ge⁶, Yong Ding¹, Canyang Niu⁷, Yuhua Gao¹, Kai Wang¹, Mingxin Gao⁸, Xuemei Wang¹, Weixuan Chen⁹, Chuyu Yun⁹, Chuan Ye¹, Jinkun Xu¹, Weike Shaoyong¹, Lijun Zhang⁸, Pan Shang³, Xi Luo¹, Zhiwei Zhang¹, Xin Zheng⁸, Xueying Sha⁸, Jinxin Zhang¹, Shaoping Nie¹⁰, Xuguang Zhang¹¹, Fazheng Ren¹², Huiying Liu¹, Erdan Dong¹³, Xiao Yu¹⁴, Linong Ji¹⁵, Yanli Pang¹⁶, Jin-Peng Sun¹⁷, Changtao Jiang¹⁸

Affiliations

¹ Department of Immunology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China; Department of Physiology and Pathophysiology, Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China.
² Department of Immunology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China; State Key Laboratory of Food Science and Resources, China-Canada Joint Lab of Food Science and Technology, Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang, China.
³ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China; Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁴ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China.
⁵ Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Centre, Beijing, China.
⁶ Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, China.
⁷ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China; Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China.
⁸ Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China.
⁹ Department of Obstetrics and Gynecology, Peking University Third Hospital, Beijing, China.
¹⁰ State Key Laboratory of Food Science and Resources, China-Canada Joint Lab of Food Science and Technology, Key Laboratory of Bioactive Polysaccharides of Jiangxi Province, Nanchang University, Nanchang, China.
¹¹ Shanghai Institute of Nutrition and Health, The Chinese Academy of Sciences, Shanghai, China.
¹² Department of Nutrition and Health, Beijing Advanced Innovation Center for Food Nutrition and Human Health, China Agricultural University, No. 10 Tianxiu Road, Haidian District, Beijing 100193, China.
¹³ Research Center for Cardiopulmonary Rehabilitation, University of Health and Rehabilitation Sciences Qingdao Hospital (Qingdao Municipal Hospital), School of Health and Life Sciences, University of Health and Rehabilitation Sciences, Qingdao, China; The Institute of Cardiovascular Sciences, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Beijing Key Laboratory of Cardiovascular Receptors Research, Health Science Center, Peking University, Beijing, China; Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing, China.
¹⁴ Key Laboratory Experimental Teratology of the Ministry of Education and Department of Physiology, School of Basic Medical Sciences, Shandong University, Jinan, China. Electronic address: yuxiao@sdu.edu.cn.
¹⁵ Department of Endocrinology and Metabolism, Peking University People's Hospital, Peking University Diabetes Centre, Beijing, China. Electronic address: jiln@bjmu.edu.cn.
¹⁶ Department of Immunology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China; National Clinical Research Center for Obstetrics and Gynecology (Peking University Third Hospital), Beijing, China; Beijing Advanced Center of Cellular Homeostasis and Aging-Related Diseases, Institute of Advanced Clinical Medicine, Peking University, Beijing, China. Electronic address: yanlipang@bjmu.edu.cn.
¹⁷ Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong University, Jinan, China; Advanced Medical Research Institute, Meili Lake Translational Research Park, Cheeloo College of Medicine, Shandong University, Jinan, China. Electronic address: sunjinpeng@sdu.edu.cn.
¹⁸ Department of Immunology, School of Basic Medical Sciences, State Key Laboratory of Female Fertility Promotion, Center for Reproductive Medicine, Third Hospital, Peking University, Beijing, China; NHC Key Laboratory of Medical Immunology, Peking University, Beijing, China; Department of Physiology and Pathophysiology, Center for Obesity and Metabolic Disease Research, School of Basic Medical Sciences, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China; Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, China. Electronic address: jiangchangtao@bjmu.edu.cn.

PMID: 40446798
DOI: 10.1016/j.cell.2025.05.010

Abstract

Recently, microbial amino-acid-conjugated bile acids (MABAs) have been found to be prevalent in human samples. However, their physiological significance is still unclear. Here, we identify tryptophan-conjugated cholic acid (Trp-CA) as the most significantly decreased MABA in patients with type 2 diabetes (T2D), and its abundance is negatively correlated with clinical glycemic markers. We further demonstrate that Trp-CA improves glucose tolerance in diabetic mice. Mechanistically, we find that Trp-CA is a ligand of the orphan G protein-coupled receptor (GPCR) Mas-related G protein-coupled receptor family member E (MRGPRE) and determine the binding mode between the two. Both MRGPRE-Gs-cyclic AMP (cAMP) and MRGPRE-β-arrestin-1-aldolase A (ALDOA) signaling pathways contribute to the metabolic benefits of Trp-CA. Additionally, we find that the bacterial bile salt hydrolase/transferase of Bifidobacterium is responsible for the production of Trp-CA. Together, our findings pave the way for further research on MABAs and offer additional therapeutic targets for the treatment of T2D.

Keywords: GPCR; bile acids; microbiota; type 2 diabetes.