Microbial products trigger chemosensory dialogues through intestinal G protein-coupled receptors

Organismal reactions to changing environmental conditions require information relays that sense cues and elicit appropriate responses. G protein-coupled receptors (GPCRs), including olfactory receptors, comprise the largest receptor family that recognizes environmental cues, consisting of over 800 genes in the human genome. Here, by screening libraries of gut metabolites and natural products using a multiplexed GPCR reporter system, GPCR-seq, we reveal multiple intestinal chemosensory pathways. Among these, we determine that a cyclic fatty acid promotes serotonin production from enterochromaffin cells via olfactory receptor OR51E1. Two additional gut microbe-derived molecules, a β-carboline and 6-hydroxynicotinic acid (6-HNA), function as agonists for GPR35, a receptor linked to inflammatory bowel disease (IBD). The IBD-associated GPR35 risk variant, T108M, shows aberrant responses to 6-HNA, while Enterocloster bolteae, a species increased in IBD, generates high levels of 6-HNA. This approach provides an accelerated path to mapping critical chemosensory pathways and host physiological responses.