GlaxoSmithKline Pharma R&D, 1250 S. Collegeville Rd, Collegeville, PA, 19426-0989, USA.
EMD Serono Research & Development Institute, Inc. 45A Middlesex Turnpike, Billerica, MA, 01821, USA.
Commun Biol. 2021 Mar 5;4(1):288. doi: 10.1038/s42003-021-01822-x.
Metabolites produced in the human gut are known modulators of host immunity. However, large-scale identification of metabolite-host receptor interactions remains a daunting challenge. Here, we employed computational approaches to identify 983 potential metabolite-target interactions using the Inflammatory Bowel Disease (IBD) cohort dataset of the Human Microbiome Project 2 (HMP2). Using a consensus of multiple machine learning methods, we ranked metabolites based on importance to IBD, followed by virtual ligand-based screening to identify possible human targets and adding evidence from compound assay, differential gene expression, pathway enrichment, and genome-wide association studies. We confirmed known metabolite-target pairs such as nicotinic acid-GPR109a or linoleoyl ethanolamide-GPR119 and inferred interactions of interest including oleanolic acid-GABRG2 and alpha-CEHC-THRB. Eleven metabolites were tested for bioactivity in vitro using human primary cell-types. By expanding the universe of possible microbial metabolite-host protein interactions, we provide multiple drug targets for potential immune-therapies.
人体内产生的代谢物已知是宿主免疫的调节剂。然而，大规模鉴定代谢物-宿主受体相互作用仍然是一项艰巨的挑战。在这里，我们使用计算方法，利用人类微生物组计划 2 (HMP2) 的炎症性肠病 (IBD) 队列数据集，识别了 983 种潜在的代谢物-靶标相互作用。我们使用多种机器学习方法的共识，根据对 IBD 的重要性对代谢物进行排名，然后进行虚拟配体筛选，以确定可能的人类靶点，并添加来自化合物测定、差异基因表达、途径富集和全基因组关联研究的证据。我们证实了已知的代谢物-靶标对，如烟酸-GPR109a 或亚油酸乙醇酰胺-GPR119，并推断出感兴趣的相互作用，包括齐墩果酸-GABRG2 和 alpha-CEHC-THRB。使用人原代细胞对 11 种代谢物进行了体外生物活性测试。通过扩展可能的微生物代谢物-宿主蛋白相互作用的范围，我们为潜在的免疫治疗提供了多个药物靶点。
