摘要

近期研究發(fā)現(xiàn)，微生物氨基酸結(jié)合膽汁酸（MABAs）在人體樣本中普遍存在，但其生理學(xué)意義仍不明確。本研究發(fā)現(xiàn)，色氨酸結(jié)合膽酸（Trp-CA）是2型糖尿病患者體內(nèi)含量顯著降低的MABA，且其豐度與臨床血糖指標(biāo)呈負(fù)相關(guān)。進(jìn)一步研究表明，Trp-CA可改善糖尿病小鼠的葡萄糖耐量。從機(jī)制層面分析，我們發(fā)現(xiàn)Trp-CA是孤兒G蛋白偶聯(lián)受體（GPCR）Mas相關(guān)G蛋白偶聯(lián)受體家族成員E（MRGPRE）的配體，并闡明了二者結(jié)合模式。MRGPRE-Gs-cyclic AMP（cAMP）和MRGPRE-β-arrestin-1-aldolase A（ALDOA）信號通路共同介導(dǎo)了Trp-CA的代謝益處。此外，我們發(fā)現(xiàn)雙歧桿菌的細(xì)菌膽鹽水解酶/轉(zhuǎn)移酶是Trp-CA的合成途徑。本研究為微生物氨基酸結(jié)合膽汁酸的深入研究開辟了新方向，并為2型糖尿病治療提供了新的治療靶點。

研究亮點

?通過微生物氨基酸結(jié)合膽汁酸揭示微生物群與宿主的相互作用。

?Trp-CA作為孤兒GPCR MRGPRE的內(nèi)源性配體。

?發(fā)現(xiàn)瘙癢受體家族成員MRGPRE在葡萄糖調(diào)控中具有非瘙癢功能。

?激活MRGPRE可通過Gs-cAMP和β-arrestin-1-ALDOA通路促進(jìn)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

翻譯：伏曉曉

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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