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A Forward Chemical Genetic Screen Reveals Gut Microbiota Metabolites That Modulate Host Physiology
- Chen, Haiwei, Nwe, Phu-Khat, Yang, Yi, Rosen, Connor E., Bielecka, Agata A., Kuchroo, Manik, Cline, Gary W., Kruse, Andrew C., Ring, Aaron M., Crawford, Jason M., Palm, Noah W.
- Cell 2019 v.177 no.5 pp. 1217-1231.e18
- G-protein coupled receptors, G-proteins, agonists, amine oxidase (flavin-containing), bacteria, blood-brain barrier, enzyme inhibitors, essential amino acids, histamine, histidine, humans, intestinal microorganisms, metabolites, metabolome, phenethylamine, poisoning
- The intestinal microbiota produces tens of thousands of metabolites. Here, we used host sensing of small molecules by G-protein coupled receptors (GPCRs) as a lens to illuminate bioactive microbial metabolites that impact host physiology. We screened 144 human gut bacteria against the non-olfactory GPCRome and identified dozens of bacteria that activated both well-characterized and orphan GPCRs, including strains that converted dietary histidine into histamine and shaped colonic motility; a prolific producer of the essential amino acid L-Phe, which we identified as an agonist for GPR56 and GPR97; and a species that converted L-Phe into the potent psychoactive trace amine phenethylamine, which crosses the blood-brain barrier and triggers lethal phenethylamine poisoning after monoamine oxidase inhibitor administration. These studies establish an orthogonal approach for parsing the microbiota metabolome and uncover multiple biologically relevant host-microbiota metabolome interactions.