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A Forward Chemical Genetic Screen Reveals Gut Microbiota Metabolites That Modulate Host Physiology.

Cell (2019-04-23)
Haiwei Chen, Phu-Khat Nwe, Yi Yang, Connor E Rosen, Agata A Bielecka, Manik Kuchroo, Gary W Cline, Andrew C Kruse, Aaron M Ring, Jason M Crawford, Noah W Palm
ABSTRACT

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.