Mapping Interactions of Microbial Metabolites with Human G-Protein-Coupled Receptors

Despite evidence linking the human microbiome to health and disease, how the microbiota affects human physiology remains largely unknown. Microbiota-encoded metabolites are expected to play an integral role in human health. Therefore, assigning function to these metabolites is critical to understanding these complex interactions and developing microbiota-inspired therapies. Here, we use large-scale functional screening of molecules produced by individual members of a simplified human microbiota to identify bacterial metabolites that agonize G-protein-coupled receptors (GPCRs). Multiple metabolites, including phenylpropanoic acid, cadaverine, 9-10-methylenehexadecanoic acid, and 12-methyltetradecanoic acid, were found to interact with GPCRs associated with diverse functions within the nervous and immune systems, among others. Collectively, these metabolite-receptor pairs indicate that diverse aspects of human health are potentially modulated by structurally simple metabolites arising from primary bacterial metabolism. Colosimo et al. use functional screening of small molecules produced by individual members of a simplified human microbiota to identify bacterial metabolites that agonize G protein-coupled receptors (GPCRs). These results indicate that diverse aspects of human health are potentially modulated by structurally simple metabolites arising from primary bacterial metabolism.