色氨酸-胆酸激活MRGPR受体改善血糖稳态

摘要

近期研究发现，微生物氨基酸结合胆汁酸（MABAs）在人体样本中普遍存在，但其生理学意义仍不明确。本研究发现，色氨酸结合胆酸（Trp-CA）是2型糖尿病患者体内含量显著降低的MABA，且其丰度与临床血糖指标呈负相关。进一步研究表明，Trp-CA可改善糖尿病小鼠的葡萄糖耐量。从机制层面分析，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，并阐明了二者结合模式。MRGPRE-Gs-cyclic AMP（cAMP）和MRGPRE-β-arrestin-1-aldolase A（ALDOA）信号通路共同介导了Trp-CA的代谢益处。此外，我们发现双歧杆菌的细菌胆盐水解酶/转移酶是Trp-CA的合成途径。本研究为微生物氨基酸结合胆汁酸的深入研究开辟了新方向，并为2型糖尿病治疗提供了新的治疗靶点。

研究亮点

•通过微生物氨基酸结合胆汁酸揭示微生物群与宿主的相互作用。

•Trp-CA作为孤儿GPCR MRGPRE的内源性配体。

•发现瘙痒受体家族成员MRGPRE在葡萄糖调控中具有非瘙痒功能。

•激活MRGPRE可通过Gs-cAMP和β-arrestin-1-ALDOA通路促进GLP-1分泌。

Summary

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.

Highlights

• Revealed microbiota-host interaction via microbial amino-acid-conjugated bile acids

• Trp-CA serves as the endogenous ligand of the orphan GPCR MRGPRE

• Identified a non-itch function of the itch family receptor MRGPRE in glucose control

• MRGPRE activation boosts GLP-1 secretion via the Gs-cAMP and β-arrestin-1-ALDOA pathways

翻译：伏晓晓

原文：Lin J, Nie Q, Cheng J, et al. A microbial amino-acid-conjugated bile acid, tryptophan-cholic acid, improves glucose homeostasis via the orphan receptor MRGPRE[J]. Cell, 2025.

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