Abstract：
Shifts in the magnitude and nature of gut microbial metabolites have been implicated in Alzheimer\'s disease (AD), but the host receptors that sense and respond to these metabolites are largely unknown. Here, we develop a systems biology framework that integrates machine learning and multi-omics to identify molecular relationships of gut microbial metabolites with non-olfactory G-protein-coupled receptors (termed the \"GPCRome\"). We evaluate 1.09 million metabolite-protein pairs connecting 408 human GPCRs and 335 gut microbial metabolites. Using genetics-derived Mendelian randomization and integrative analyses of human brain transcriptomic and proteomic profiles, we identify orphan GPCRs (i.e., GPR84) as potential drug targets in AD and that triacanthine experimentally activates GPR84. We demonstrate that phenethylamine and agmatine significantly reduce tau hyperphosphorylation (p-tau181 and p-tau205) in AD patient induced pluripotent stem cell-derived neurons. This study demonstrates a systems biology framework to uncover the GPCR targets of human gut microbiota in AD and other complex diseases if broadly applied.
摘要：
肠道微生物代谢物的大小和性质的变化与阿尔茨海默病(AD)有关。但是感知和响应这些代谢物的宿主受体在很大程度上是未知的。这里,我们开发了一个系统生物学框架，该框架集成了机器学习和多组学，以识别肠道微生物代谢物与非嗅觉G蛋白偶联受体的分子关系（称为“GPCRome”）。我们评估了109万个代谢物-蛋白质对，它们连接了408个人类GPCRs和335个肠道微生物代谢物。使用遗传学衍生的孟德尔随机化和人脑转录组和蛋白质组的综合分析，我们识别孤儿GPCR(即，GPR84）作为AD中的潜在药物靶标，并且三药嘌呤通过实验激活GPR84。我们证明苯乙胺和胍丁胺可显着降低AD患者诱导的多能干细胞衍生的神经元中的tau过度磷酸化（p-tau181和p-tau205）。这项研究证明了一个系统生物学框架，可以发现AD和其他复杂疾病中人类肠道微生物群的GPCR靶标。
