A Prospective Study Examining the Role of Gestational SSRI Exposure in the Development of Functional Gastrointestinal Disorders

一项前瞻性研究探讨妊娠期 SSRI 暴露在功能性胃肠道疾病发展中的作用

基本信息

批准号：
10706585
负责人：
Kara Gross Margolis
金额：
$ 60.62万
依托单位：
NEW YORK UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-08-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10706585
关键词：
17 year old Address Adult Age Animals Antidepressive Agents Behavioral Biological Markers Biology Birth Blood Brain Child Clinical Management Cohort Studies Coupled DNA sequencing Data Denmark Development Diet Distress Educational workshop Exhibits Exposure to Feces Foundations Functional Gastrointestinal Disorders Funding Home environment Homeostasis Human Impairment Individual Infant Infrastructure Life Link Long-Term Effects Longitudinal Studies Mass Spectrum Analysis Measures Meconium Mediating Mental Health Methods Modeling Moods Morbidity - disease rate Mothers Mus National Institute of Diabetes and Digestive and Kidney Diseases Newborn Infant Onset of illness Outcome Pain Pathology Perinatal Phenotype Population Population Study Pregnancy Prospective Studies Public Health Publishing Risk Risk Factors Role Rome Selective Serotonin Reuptake Inhibitor Serotonin Signal Pathway Signal Transduction Stress Symptoms Testing Time Toddler Woman antagonist cost cost effective disorder risk fetal gastrointestinal disorder diagnosis gut microbiome gut microbiota improved infancy innovation maternal depression maternal microbiome maternal microbiota microbial microbiome microbiota motility disorder nervous system development neurodevelopment novel offspring postnatal prenatal prospective sample collection stool sample symptomatology therapeutic target transmission process

项目摘要

Abstract Functional gastrointestinal disorders (FGIDs) are common, costly, and cause significant impairment that can begin in infancy. FGIDs remain poorly understood, and treatment are often ineffective, prompting a recent NIDDK workshop to conclude an urgent need for improved understanding and management paradigms. In this proposal, we test the hypothesis that serotonin reuptake inhibitor (SSRI) antidepressant exposure in pregnancy is a major contributor to FGIDs in children. This is based on the premise that SSRIs, when used by women in pregnancy, alter the fetal availability of serotonin (5-HT), which is critical for healthy nervous system development in both the brain and the gut. There are significant public health implications, as SSRI use in pregnancy is continually increasing and it is estimated that upwards of 350,000 newborns per year were exposed to an SSRI during gestation. Most of the studies to date on the long-term effects of SSRI exposures have focused on offspring brain development. In contrast, studies on the effects of maternal SSRI exposure on gut development are lacking. However, our group has compelling evidence, through both published studies and new preliminary data, suggesting associations between SSRI exposure and FGID risk, which are independent of exposure to maternal depression. We have also identified a specific microbiome profile (enterotype) that is highly linked to FGIDs, and which our preliminary results suggest, may be transferred from mother to infant where it continues to drive elevated 5-HT signaling. Thus, SSRI exposure could increase offspring FGID risk, and this risk could be mediated by microbiome changes in the mother and child. We will investigate these questions by building on an ongoing birth cohort study of 375 mother-infant dyads (“The MYRNA Study”; controls, maternal depression +/- SSRI exposure) being followed through pregnancy and the first two years of life. Our new study, which we term, “Gestational SSRI Exposures in the DevelopmenT of Functional GAStrointestinal Disorders (GETGAS)”, will leverage MYRNA infrastructure and population, while adding extensive characterization of FGID diagnoses and symptoms, and analyzing stool samples (mother in pregnancy, and infant at birth, 1 yr and 2 yr) to test the role of microbiota-driven 5-HT signaling pathways. We will do this through three specific aims: Aim 1: Confirm effects of gestational SSRI exposure on infant FGID development trajectories in the first two years. Aim 2: Test whether maternal SSRI use during pregnancy promotes a 5-HT producing microbiome that is vertically transferred to the offspring where it increases FGID risk. Aim 3: Use data driven methods to identify clusters of maternal and infant factors most predictive of FGIDs in early life. Findings from this innovative and cost-effective proposal will help disambiguate the effects of PMD, SSRI exposure, and transmission of maternal microbiota on the development of FGIDs in early life, inform clinical management of FGIDs, and provide a foundation for biomarker and therapeutic target discovery.

抽象的功能性胃肠道疾病（FGID）是常见的，昂贵的，并且会造成重大损害，可以开始婴儿期。 FGID的理解仍然很少，治疗通常无效，促使最近 NIDDK研讨会包括迫切需要改善理解和管理范式。在这个提案，我们检验了5-羟色胺再摄取抑制剂（SSRI）抗抑郁药暴露于怀孕的假设是儿童FGID的主要贡献者。这是基于女性使用的前提。怀孕，改变5-羟色胺（5-HT）的胎儿利用率，这对于健康神经系统至关重要大脑和肠道的发展。 SSRI在怀孕不断增加，据估计，每年以上的新生儿超过350,000人妊娠期间暴露于SSRI。迄今为止，大多数研究对SSRI暴露的长期影响专注于后代大脑发育。相反，关于母体SSRI暴露对的研究缺乏肠道发展。但是，我们的小组通过两项已发表的研究都有令人信服的证据以及新的初步数据，表明SSRI暴露与FGID风险之间的关联是独立于暴露于孕产妇抑郁症。我们还确定了特定的微生物组轮廓（肠型）与FGID高度相关，我们的初步结果可能会从母亲到婴儿继续驱动升高的5-HT信号传导。那，SSRI暴露可能会增加后代fGID风险，这种风险可能是由母亲和儿童的微生物组变化介导的。我们将通过对375个母亲二元组进行的持续出生队列研究来研究这些问题（“ Myrna研究”；对照，母体抑郁+/- SSRI暴露）在怀孕和生命的头两年。我们称我们的新研究，“妊娠SSRI在开发中暴露功能性胃肠道疾病（Getgas）”，将利用Myrna基础设施和人口，而添加FGID诊断和符号的广泛表征，并分析粪便样本（母亲在怀孕，出生时的婴儿，1年和2年），以测试微生物群驱动的5-HT信号通路的作用。我们将通过三个特定目的来做到这一点：目标1：确认妊娠SSRI暴露对婴儿FGID的影响最初两年的发展轨迹。 AIM 2：测试孕妇在怀孕期间是否使用SSRI 促进一个5-HT产生的微生物组，该微生物组垂直转移到后代，并增加了FGID 风险。目标3：使用数据驱动方法来识别最预测的母体和婴儿因素群早期生命中的fgids。这项创新且具有成本效益的提案的发现将有助于消除效果 PMD，SSRI暴露和母体微生物群在早期生命中发育的发展，告知FGID的临床管理，并为生物标志物和治疗目标发现提供基础。