Despite evidence linking the human microbiome to health and disease, the mechanistic details of how the microbiota affects human physiology remain largely unknown. Metabolites encoded by bacteria are expected to play an integral role in the microbiota’s effect on its human host. Assigning function to these metabolites is therefore critical to determining the molecular underpinnings of the host-microbe relationship and ultimately developing microbiota inspired therapies. Here we use large-scale functional screening of small molecules produced by individual members of a simplified human microbiota to identify bacterial metabolites that agonize G-protein coupled receptors (GPCR). This analysis revealed a complex network of metabolite host receptor interactions and guided our identification of multiple microbiota derived agonists of GPCRs associated with diverse biological functions within the nervous and immune systems, among others. Collectively, the metabolite-receptor pairs we uncovered indicate that diverse aspects of human health are potentially modulated by structurally simple metabolites arising from primary bacterial metabolism.Statement of SignificanceBacteria residing within the human body have been shown to influence human health. It is likely that physiological responses to the human microbiota are mediated by the collection of small molecules encoded within these bacteria. In this study we use direct functional screening of small molecules produced by individual members of a simplified human microbiota to identify new G protein coupled receptor-metabolite interactions that seek to explain the molecular underpinnings of the microbiota’s influence on its human host.