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

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

doi:10.1053/j.gastro.2024.11.012

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

Gastroenterology. 2024 Dec 11:S0016-5085(24)05751-2. doi: 10.1053/j.gastro.2024.11.012. Online ahead of print.

Authors

Lin Y Hung¹, Nuno D Alves², Andrew Del Colle¹, Ardesheer Talati², Sarah A Najjar¹, Virginie Bouchard³, Virginie Gillet³, Yan Tong¹, Zixing Huang¹, Kirsteen N Browning⁴, Jialiang Hua², Ying Liu², James O Woodruff², Daniel Juarez¹, Melissa Medina¹, Jonathan Posner⁵, Raquel Tonello¹, Nazli Yalcinkaya⁶, Narek Israelyan¹, Roey Ringel¹, Letao Yang⁷, Kam W Leong⁸, Mu Yang⁹, Ji Ying Sze¹⁰, Tor Savidge⁶, Jay Gingrich², Robert J Shulman¹¹, Michael D Gershon¹², Annie Ouellet¹³, Larissa Takser³, Mark S Ansorge¹⁴, Kara Gross Margolis¹⁵

Affiliations

¹ NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York.
² Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York; New York State Psychiatric Institute, New York, New York.
³ Department of Pediatrics, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
⁴ Department of Neural and Behavioral Sciences, Pennsylvania State College of Medicine, Hershey, Pennsylvania.
⁵ Department of Psychiatry, Duke University School of Medicine; Durham, North Carolina.
⁶ Department of Pathology and Department of Immunology, Baylor College of Medicine and Texas Children's Microbiome Center, Texas Children's Hospital, Houston, Texas.
⁷ Department of Biomedical Engineering, Columbia University, New York, New York.
⁸ Department of Biomedical Engineering, Columbia University, New York, New York; Department of Systems Biology, Columbia University Medical Center, New York, New York.
⁹ Neurobehavior Core, Institute of Genomic Medicine, Columbia University Irving Medical Center, New York, New York.
¹⁰ Department of Molecular Pharmacology, Albert Einstein College of Medicine, New York, New York.
¹¹ Department of Pediatrics and USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas.
¹² Department of Pathology and Cell Biology, Columbia University; New York, New York.
¹³ Department of Obstetrics, Université de Sherbrooke, Sherbrooke, Quebec, Canada.
¹⁴ Department of Psychiatry, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York; New York State Psychiatric Institute, New York, New York. Electronic address: [email protected].
¹⁵ NYU Pain Research Center, Department of Molecular Pathobiology, College of Dentistry, New York University, New York, New York; Department of Cell Biology, NYU Grossman School of Medicine; New York, New York; Department of Pediatrics, NYU Grossman School of Medicine; New York, New York. Electronic address: [email protected].

PMID: 39672518
DOI: 10.1053/j.gastro.2024.11.012

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: Disorders of Gut-Brain Interaction; In Utero SSRI; Mood; Vagal Afferent Signaling.