Cleveland Clinic Genome Center, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA; Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA.
Cell Rep. 2024 May 28;43(5):114128. doi: 10.1016/j.celrep.2024.114128. Epub 2024 Apr 21.
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.
肠道微生物代谢产物的数量和性质的变化与阿尔茨海默病（AD）有关，但宿主受体对这些代谢产物的感知和反应在很大程度上是未知的。在这里，我们开发了一个系统生物学框架，该框架将机器学习和多组学整合在一起，以识别肠道微生物代谢产物与非嗅觉 G 蛋白偶联受体（称为“GPCRome”）之间的分子关系。我们评估了连接 408 个人类 GPCR 和 335 种肠道微生物代谢产物的 109 万个代谢物-蛋白对。利用遗传衍生的孟德尔随机化和人类大脑转录组和蛋白质组谱的综合分析，我们确定了孤儿 GPCR（即 GPR84）是 AD 中的潜在药物靶点，并且三尖杉宁实验激活了 GPR84。我们证明了苯乙胺和胍丁胺可显着减少 AD 患者诱导多能干细胞衍生神经元中的 tau 过度磷酸化（p-tau181 和 p-tau205）。如果广泛应用，这项研究展示了一种系统生物学框架，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。
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