FASEB journal : official publication of the Federation of American Societies for Experimental BiologyJan 1, 2015

Gut microbes may boost colon serotonin by helping gut cells respond to short-chain fatty acids

GLP-1 Therapies Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 4, 2026

Abstract

5-HT concentrations were significantly higher in humanized (HM) and conventionally raised (CR) mice compared to germ-free (GF) mice, with levels of 25 ± 2 ng/mg and 35 ± 3 ng/mg respectively.

Gut microbiota from HM and conventionally raised mice increased colonic mRNAs related to serotonin synthesis, specifically Tph1 and chromogranin A.
5-HT reduced the duration of colonic contractions in both GF and HM mice.
There was no effect of microbiota on the expression of genes involved in serotonin breakdown or receptor activity.
Microbiota influenced the production of short-chain fatty acids, which promoted serotonin production in human enterochromaffin cell models.
Enterochromaffin cell numbers remained unchanged despite increased serotonin levels.

Simplified

Gut microbiota alterations have been described in several diseases with altered gastrointestinal (GI) motility, and awareness is increasing regarding the role of the gut microbiome in modulating GI function. Serotonin [5-hydroxytryptamine (5-HT)] is a key regulator of GI motility and secretion. To determine the relationship among gut microbes, colonic contractility, and host serotonergic gene expression, we evaluated mice that were germ-free (GF) or humanized (HM; ex-GF colonized with human gut microbiota). 5-HT reduced contractile duration in both GF and HM colons. Microbiota from HM and conventionally raised (CR) mice significantly increased colonic mRNAs Tph1 [(tryptophan hydroxylase) 1, rate limiting for mucosal 5-HT synthesis; P < 0.01] and chromogranin A (neuroendocrine secretion; P < 0.01), with no effect on monoamine oxidase A (serotonin catabolism), serotonin receptor 5-HT4, or mouse serotonin transporter. HM and CR mice also had increased colonic Tph1 protein (P < 0.05) and 5-HT concentrations (GF, 17 ± 3 ng/mg; HM, 25 ± 2 ng/mg; and CR, 35 ± 3 ng/mg; P < 0.05). Enterochromaffin (EC) cell numbers (cells producing 5-HT) were unchanged. Short-chain fatty acids (SCFAs) promoted TPH1 transcription in BON cells (human EC cell model). Thus, gut microbiota acting through SCFAs are important determinants of enteric 5-HT production and homeostasis.

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Gut microbes may boost colon serotonin by helping gut cells respond to short-chain fatty acids

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