A microbial metabolite synergizes with endogenous serotonin to trigger reproductive behavior. Author Yen-Chih Chen, Mohammad Seyedsayamdost, Niels Ringstad Publication Year 2020 Type Journal Article Abstract Natural products are a major source of small-molecule therapeutics, including those that target the nervous system. We have used a simple serotonin-dependent behavior of the roundworm , egg laying, to perform a behavior-based screen for natural products that affect serotonin signaling. Our screen yielded agonists of G protein-coupled serotonin receptors, protein kinase C agonists, and a microbial metabolite not previously known to interact with serotonin signaling pathways: the disulfide-bridged 2,5-diketopiperazine gliotoxin. Effects of gliotoxin on egg-laying behavior required the G protein-coupled serotonin receptors SER-1 and SER-7, and the G ortholog EGL-30. Furthermore, mutants lacking serotonergic neurons and mutants that cannot synthesize serotonin were profoundly resistant to gliotoxin. Exogenous serotonin restored their sensitivity to gliotoxin, indicating that this compound synergizes with endogenous serotonin to elicit behavior. These data show that a microbial metabolite with no structural similarity to known serotonergic agonists potentiates an endogenous serotonin signal to affect behavior. Based on this study, we suggest that microbial metabolites are a rich source of functionally novel neuroactive molecules. Keywords Animals, Caenorhabditis elegans, Sexual Behavior, Animal, Behavior, Animal, Neurons, Microbiota, Serotonin, Caenorhabditis elegans Proteins, Symbiosis, Biomarkers, Gliotoxin Journal Proc Natl Acad Sci U S A Volume 117 Issue 48 Pages 30589-30598 Date Published 2020 Dec 01 ISSN Number 1091-6490 DOI 10.1073/pnas.2017918117 Alternate Journal Proc Natl Acad Sci U S A PMCID PMC7720207 PMID 33199611 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML