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.