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

IF 45.5 1区生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY

Cell Pub Date : 2025-05-29 DOI:10.1016/j.cell.2025.05.010

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, Changtao Jiang

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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.

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微生物氨基酸缀合胆汁酸，色氨酸-胆酸，通过孤儿受体MRGPRE改善葡萄糖稳态

近年来，微生物氨基酸缀合胆汁酸（MABAs）已被发现在人体样本中普遍存在。然而，它们的生理意义尚不清楚。在这里，我们发现色氨酸共轭胆酸（Trp-CA）是2型糖尿病（T2D）患者中最显著降低的MABA，其丰度与临床血糖指标呈负相关。我们进一步证明了Trp-CA可以改善糖尿病小鼠的葡萄糖耐量。在机制上，我们发现Trp-CA是孤儿G蛋白偶联受体（GPCR） mass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方式。MRGPRE- gs -cyclic AMP （cAMP）和MRGPRE-β-arrestin-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maba铺平了道路，并为治疗T2D提供了额外的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell 生物-生化与分子生物学

CiteScore

110.00

自引率

0.80%

发文量

396

审稿时长

2 months

期刊介绍： Cells is an international, peer-reviewed, open access journal that focuses on cell biology, molecular biology, and biophysics. It is affiliated with several societies, including the Spanish Society for Biochemistry and Molecular Biology (SEBBM), Nordic Autophagy Society (NAS), Spanish Society of Hematology and Hemotherapy (SEHH), and Society for Regenerative Medicine (Russian Federation) (RPO). The journal publishes research findings of significant importance in various areas of experimental biology, such as cell biology, molecular biology, neuroscience, immunology, virology, microbiology, cancer, human genetics, systems biology, signaling, and disease mechanisms and therapeutics. The primary criterion for considering papers is whether the results contribute to significant conceptual advances or raise thought-provoking questions and hypotheses related to interesting and important biological inquiries. In addition to primary research articles presented in four formats, Cells also features review and opinion articles in its "leading edge" section, discussing recent research advancements and topics of interest to its wide readership.