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

TitleA microbial metabolite synergizes with endogenous serotonin to trigger reproductive behavior.
Publication TypeJournal Article
Year of Publication2020
AuthorsChen, Y-C, Seyedsayamdost, MR, Ringstad, N
JournalProc Natl Acad Sci U S A
Volume117
Issue48
Pagination30589-30598
Date Published2020 12 01
ISSN1091-6490
KeywordsAnimals, Behavior, Animal, Biomarkers, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Gliotoxin, Microbiota, Neurons, Serotonin, Sexual Behavior, Animal, Symbiosis
Abstract

<p>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.</p>

DOI10.1073/pnas.2017918117
Alternate JournalProc Natl Acad Sci U S A
PubMed ID33199611
PubMed Central IDPMC7720207
Grant ListR35 GM122573 / GM / NIGMS NIH HHS / United States
DP2 AI124786 / AI / NIAID NIH HHS / United States
P40 OD010440 / OD / NIH HHS / United States