The gastrointestinal (GI) tract contains much of the body's serotonin (5-hydroxytryptamine,
5-HT), but mechanisms controlling the metabolism of gut-derived 5-HT remain unclear.
Here, we demonstrate that the microbiota plays a critical role in regulating host
5-HT. Indigenous spore-forming bacteria (Sp) from the mouse and human microbiota promote
5-HT biosynthesis from colonic enterochromaffin cells (ECs), which supply 5-HT to
the mucosa, lumen, and circulating platelets. Importantly, microbiota-dependent effects
on gut 5-HT significantly impact host physiology, modulating GI motility and platelet
function. We identify select fecal metabolites that are increased by Sp and that elevate
5-HT in chromaffin cell cultures, suggesting direct metabolic signaling of gut microbes
to ECs. Furthermore, elevating luminal concentrations of particular microbial metabolites
increases colonic and blood 5-HT in germ-free mice. Altogether, these findings demonstrate
that Sp are important modulators of host 5-HT and further highlight a key role for
host-microbiota interactions in regulating fundamental 5-HT-related biological processes.