Faculty Bibliography

BACKGROUND & AIMS/OBJECTIVE:Mood disorders and DGBI are highly prevalent, commonly co-morbid and lack fully effective therapies. Although 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 SERT 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 utilized transgenic, surgical, and pharmacological approaches to study the effects of intestinal epithelial SERT 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:SERT ablation targeted to the intestinal epithelium promoted anxiolytic and anti-depressive-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/CONCLUSIONS: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.

Preclinical data suggest that gestational exposure to selective serotonin reuptake inhibitors (SSRI) alter gut innervation, and delays colonic motility. In this study we investigated associations between gestational SSRI exposure and offspring disorders of gut-brain interaction (DGBI). Using population-based registries, we included all single-birth Danish children born 1997-2015 with follow-up until outcome occurrence, age 15 years, death, emigration, or December 2018. Children to mothers who continued SSRIs during pregnancy and children to mothers who discontinued SSRI use before pregnancy were compared using Cox regression. Main outcomes were the first diagnosis of a childhood DGBI (functional nausea and vomiting, functional abdominal pain disorders, functional diarrhea, and functional constipation), or a physician-prescribed laxative. Among 1,158,560 children, 21,969 children (1.9%) were exposed to SSRIs prenatally and 30,174 children (2.6%) were born to mothers who discontinued SSRIs before pregnancy. Overall, the estimated 15-year cumulative incidence of any DGBI was 15.5% (95% CI, 14.9-16.2) in the SSRI-exposed group and 14.7% (14.0-15.3) in the unexposed group. SSRI-exposed children had an overall increased risk of DGBIs (HR 1.08, [1.02-1.14]), which was driven by functional constipation (HR 1.19, [1.10-1.28]) rather than functional nausea and vomiting (HR 0.97, [0.83-1.13]) or functional abdominal pain disorders (HR 0.90, [0.81-1.00]). These data suggest that prenatal SSRI exposure is associated with an increased risk of developing functional constipation. These findings are also consistent with extensive preclinical data supporting key roles for serotonin in gut development and function. Together findings support the need for further investigation of the long-term impact of maternal depression and SSRI exposure on development of common gastrointestinal disorders.