一种微生物氨基酸共轭胆汁酸，色氨酸-胆酸，通过孤儿受体MRGPRE改善葡萄糖稳态。
A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves glucose homeostasis via the orphan receptor MRGPRE.
作者信息
Lin Jun, Nie Qixing, Cheng Jie, Zhong Ya-Ni, Zhang Tianyao, Zhang Xiuying, Ge Xiaoyan, Ding Yong, Niu Canyang, Gao Yuhua, Wang Kai, Gao Mingxin, Wang Xuemei, Chen Weixuan, Yun Chuyu, Ye Chuan, Xu Jinkun, Shaoyong Weike, Zhang Lijun, Shang Pan, Luo Xi, Zhang Zhiwei, Zheng Xin, Sha Xueying, Zhang Jinxin, Nie Shaoping, Zhang Xuguang, Ren Fazheng, Liu Huiying, Dong Erdan, Yu Xiao, Ji Linong, Pang Yanli, Sun Jin-Peng, Jiang Changtao
机构信息
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.
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.
出版信息
Cell. 2025 Aug 21;188(17):4530-4548.e25. doi: 10.1016/j.cell.2025.05.010. Epub 2025 May 29.
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.
最近，人们发现微生物氨基酸共轭胆汁酸（MABAs）在人类样本中普遍存在。然而，它们的生理意义仍不清楚。在此，我们确定色氨酸共轭胆酸（Trp-CA）是2型糖尿病（T2D）患者中显著减少的MABA，其丰度与临床血糖指标呈负相关。我们进一步证明Trp-CA可改善糖尿病小鼠的葡萄糖耐量。从机制上讲，我们发现Trp-CA是孤儿G蛋白偶联受体（GPCR）Mas相关G蛋白偶联受体家族成员E（MRGPRE）的配体，并确定了两者之间的结合模式。MRGPRE-Gs-环磷酸腺苷（cAMP）和MRGPRE-β-抑制蛋白1-醛缩酶A（ALDOA）信号通路都有助于Trp-CA的代谢益处。此外，我们发现双歧杆菌的细菌胆汁盐水解酶/转移酶负责Trp-CA的产生。总之，我们的发现为进一步研究MABAs铺平了道路，并为T2D的治疗提供了额外的治疗靶点。
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