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

• Published in: Cell host & microbe 2019-08, Vol.26 (2), p.273-282.e7
• Main Authors: Colosimo, Dominic A., Kohn, Jeffrey A., Luo, Peter M., Piscotta, Frank J., Han, Sun M., Pickard, Amanda J., Rao, Arka, Cross, Justin R., Cohen, Louis J., Brady, Sean F.
• Format: Article
• Language: English
• Subjects: Angiogenic Proteins - agonists; Animals; Bacteria - metabolism; Cadaverine - metabolism; Cadaverine - pharmacology; Fatty Acids - metabolism; Fatty Acids - pharmacology; Fermentation; G protein-coupled receptors; Germ-Free Life; Histamine Agonists; Host Microbial Interactions - immunology; Host Microbial Interactions - physiology; human microbiome; Humans; Immune System; Ligands; Mice; Mice, Inbred C57BL; Microbiota - immunology; Microbiota - physiology; Models, Animal; primary metabolites; Propionates - metabolism; Propionates - pharmacology; Receptors, G-Protein-Coupled - agonists; Receptors, G-Protein-Coupled - metabolism; Receptors, Histamine - drug effects; Receptors, Neurotransmitter - agonists
• ISSN: 1931-3128; 1934-6069
• DOI: 10.1016/j.chom.2019.07.002

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. [Display omitted] •Metabolite library from human microbiota screened for direct agonism of 241 GPCRs•Taxa-specific primary metabolites agonize individual GPCRs or broad GPCR families•Bacteria agonize receptors linked to metabolism, neurotransmission, and immunity•Simple bacterial metabolites may play a role in modulating host pathways 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.