Department of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
Chemical Biology Institute and Department of Chemistry, Yale University, West Haven and New Haven, CT, USA.
Cell. 2019 May 16;177(5):1217-1231.e18. doi: 10.1016/j.cell.2019.03.036. Epub 2019 Apr 18.
The intestinal microbiota produces tens of thousands of metabolites. Here, we used host sensing of small molecules by G-protein coupled receptors (GPCRs) as a lens to illuminate bioactive microbial metabolites that impact host physiology. We screened 144 human gut bacteria against the non-olfactory GPCRome and identified dozens of bacteria that activated both well-characterized and orphan GPCRs, including strains that converted dietary histidine into histamine and shaped colonic motility; a prolific producer of the essential amino acid L-Phe, which we identified as an agonist for GPR56 and GPR97; and a species that converted L-Phe into the potent psychoactive trace amine phenethylamine, which crosses the blood-brain barrier and triggers lethal phenethylamine poisoning after monoamine oxidase inhibitor administration. These studies establish an orthogonal approach for parsing the microbiota metabolome and uncover multiple biologically relevant host-microbiota metabolome interactions.
肠道微生物群产生成千上万种代谢物。在这里，我们使用 G 蛋白偶联受体 (GPCR) 对小分子的宿主感应作为一个视角来阐明影响宿主生理的生物活性微生物代谢物。我们筛选了 144 种人类肠道细菌对非嗅觉 GPCR 组，并鉴定出数十种激活了既有特征明确的 GPCR 也激活了孤儿 GPCR 的细菌，包括将膳食组氨酸转化为组胺并塑造结肠蠕动的菌株；一种丰富的必需氨基酸 L-Phe 的产生者，我们将其鉴定为 GPR56 和 GPR97 的激动剂；以及一种将 L-Phe 转化为强效精神活性痕量胺苯乙胺的物种，该物质可穿过血脑屏障，并在单胺氧化酶抑制剂给药后引发致命的苯乙胺中毒。这些研究建立了一种解析微生物组代谢组的正交方法，并揭示了多种生物学相关的宿主-微生物组代谢组相互作用。
