Cell
Volume 177, Issue 5, 16 May 2019, Pages 1217-1231.e18
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Article
A Forward Chemical Genetic Screen Reveals Gut Microbiota Metabolites That Modulate Host Physiology

https://doi.org/10.1016/j.cell.2019.03.036Get rights and content
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Highlights

  • Screening of gut microbiota metabolomes against hundreds of G protein-coupled receptors

  • Phylogenetically diverse gut microbes produce agonists for many GPCRs including orphans

  • Bioactivity-based screening reveals diet-microbe-host and microbe-microbe-host axes

  • Microbiota-derived GPCR ligands impact local and systemic host physiology

Summary

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.

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Lead Contact: Noah W. Palm