Intestinal Epithelial Serotonin as a Novel Target for Treating Disorders of Gut-Brain Interaction and Mood

Authors

Lin Y Hung
Nuno D Alves
Andrew Del Colle
Ardesheer Talati
Sarah A Najjar
Virginie Bouchard
Virginie Gillet
Yan Tong
Zixing Huang
Kirsteen N Browning
Jialiang Hua
Ying Liu
James O Woodruff
Daniel Juarez
Melissa Medina
Jonathan Posner
Raquel Tonello
Nazli Yalcinkaya
Narek Israelyan
Roey Ringel
Letao Yang
Kam W Leong
Mu Yang
Ji Ying Sze
Tor Savidge
Jay Gingrich
Robert J Shulman
Michael D Gershon
Annie Ouellet
Larissa Takser
Mark S Ansorge
Kara Gross Margolis

Language

English

Publication Date

4-1-2025

Journal

Gastroenterology

DOI

10.1053/j.gastro.2024.11.012

PMID

39672518

PMCID

PMC12439035

PubMedCentral® Posted Date

9-17-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Background & aims: Mood disorders and disorders of gut-brain interaction (DGBI) are highly prevalent, commonly comorbid, and lack fully effective therapies. Although selective serotonin reuptake inhibitors (SSRIs) are first-line pharmacological treatments for these disorders, they may impart adverse effects, including anxiety, anhedonia, dysmotility, and, in children exposed in utero, an increased risk of cognitive, mood, and gastrointestinal disorders. SSRIs act systemically to block the serotonin reuptake transporter and enhance serotonergic signaling in the brain, intestinal epithelium, and enteric neurons. Yet, the compartments that mediate the therapeutic and adverse effects of SSRIs are unknown, as is whether gestational SSRI exposure directly contributes to human DGBI development.

Methods: We used transgenic, surgical, and pharmacological approaches to study the effects of intestinal epithelial serotonin reuptake transporter or serotonin on mood and gastrointestinal function, as well as relevant communication pathways. We also conducted a prospective birth cohort study to assess effects of gestational SSRI exposure on DGBI development.

Results: Serotonin reuptake transporter ablation targeted to the intestinal epithelium promoted anxiolytic and antidepressive-like effects without causing adverse effects on the gastrointestinal tract or brain; conversely, epithelial serotonin synthesis inhibition increased anxiety and depression-like behaviors. Afferent vagal pathways were found to be conduits by which intestinal epithelial serotonin affects behavior. In utero SSRI exposure is a significant and specific risk factor for development of the DGBI, functional constipation, in the first year of life, irrespective of maternal depressive symptoms.

Conclusion: These findings provide fundamental insights into how the gastrointestinal tract modulates emotional behaviors, reveal a novel gut-targeted therapeutic approach for mood modulation, and suggest a new link in humans between in utero SSRI exposure and DGBI development.

Keywords

Serotonin, Animals, Female, Selective Serotonin Reuptake Inhibitors, Intestinal Mucosa, Pregnancy, Serotonin Plasma Membrane Transport Proteins, Humans, Mood Disorders, Male, Mice, Affect, Mice, Transgenic, Prenatal Exposure Delayed Effects, Brain-Gut Axis, Brain, Prospective Studies, Disease Models, Animal, Vagus Nerve, In Utero SSRI, Disorders of Gut-Brain Interaction, Mood, Vagal Afferent Signaling

Published Open-Access

yes

Recommended Citation

Hung, Lin Y; Alves, Nuno D; Del Colle, Andrew; et al., "Intestinal Epithelial Serotonin as a Novel Target for Treating Disorders of Gut-Brain Interaction and Mood" (2025). Faculty and Staff Publications. 5642.
https://digitalcommons.library.tmc.edu/baylor_docs/5642