A microbial metabolite synergizes with endogenous serotonin to trigger C. elegans reproductive behavior

Yen Chih Chen, Mohammad R. Seyedsayamdost, Niels Ringstad

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


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 Caenorhabditis elegans, 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 Gq 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.

Original languageEnglish (US)
Pages (from-to)30589-30598
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number48
StatePublished - Dec 1 2020

All Science Journal Classification (ASJC) codes

  • General


  • C. elegans | serotonin | animal–microbe interaction


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