Abstract
SummaryDespite 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.
Highlights
Human bodies are home to diverse and ever-changing collections of bacteria
Culturing Bacteria and G-protein-coupled receptors (GPCRs) Screening Bacteria from the simplified human microbiomes (SIHUMIs) consortium were individually fermented under anaerobic conditions in separate large-scale (20 L) culture vessels (Figure 1)
The resulting library of bacterial metabolites was screened with a cell-based assay for fractions that could agonize members of a panel of 241 GPCRs (Table S1)
Summary
Human bodies are home to diverse and ever-changing collections of bacteria. The ability of the microbiota to influence human health has been explored extensively (Knight et al, 2017). In addition to hypothesis-driven studies in model organisms, one of the most common methods for studying host-microbe interactions has featured ‘‘omics’’-based analyses that have examined genomic, transcriptomic, proteomic, or metabolic differences between patient cohorts (Fritz et al, 2013; Gagliani et al, 2014; Hugenholtz and de Vos, 2018; Qin et al, 2012, 2014; Turnbaugh et al, 2009) These informatics-based methods have served as powerful tools for uncovering correlations between changes in the microbiota and health and disease, they are somewhat limited in their ability to reveal the mechanistic details of how the microbiota might alter mammalian physiology (Cani, 2018). The number of well-defined interactions between metabolites produced by human associated bacteria and discrete human receptors is dwarfed by the number of reports attributing biological phenotypes to the microbiome, highlighting the need for a more systematic characterization of microbiota-encoded bioactive metabolites
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