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

Cell. 2019 May 16;177(5):1217-1231.e18. doi: 10.1016/j.cell.2019.03.036. Epub 2019 Apr 18.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Bacteria / growth & development*
  • Colon / microbiology*
  • Gastrointestinal Microbiome / physiology*
  • HEK293 Cells
  • Host Microbial Interactions / physiology*
  • Humans
  • Mice
  • Receptors, G-Protein-Coupled / metabolism*


  • ADGRG3 protein, human
  • GPR56 protein, mouse
  • Receptors, G-Protein-Coupled