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

摘要 功能性胃肠道疾病（FGID）是常见的，昂贵的，并导致严重的损害， 开始于婴儿期。对FGID的了解仍然很少，治疗往往无效，这促使最近的 NIDDK研讨会得出结论，迫切需要改进理解和管理模式。在这 建议，我们测试的假设，5-羟色胺再摄取抑制剂（SSRI）抗抑郁药暴露在怀孕期间， 是导致儿童FGIDs的主要因素。这是基于一个前提，即SSRIs，当妇女使用时， 怀孕，改变胎儿血清素（5-HT）的可用性，这对健康的神经系统至关重要 大脑和肠道的发育。有重大的公共卫生影响，因为SSRI的使用， 怀孕人数不断增加，据估计，每年有350 000多名新生儿 在怀孕期间接触过SSRI迄今为止，大多数关于SSRI暴露的长期影响的研究 专注于后代的大脑发育。相反，关于母体SSRI暴露对 缺乏肠道发育。然而，我们的团队有令人信服的证据，通过两项已发表的研究， 新的初步数据表明，SSRI暴露与FGID风险之间存在关联， 独立于母亲抑郁症的影响。我们还发现了一种特殊的微生物组 （肠型）与FGID高度相关，我们的初步结果表明， 母亲传给婴儿，在那里它继续驱动升高的5-HT信号。因此，SSRI暴露可能会增加 子代FGID风险，这种风险可能是由母亲和孩子的微生物组变化介导的。我们将 通过对375对母婴进行的出生队列研究（“The MYRNA研究”;对照组，母亲抑郁+/- SSRI暴露）， 生命的头两年。我们的新研究，我们称之为，“在发育过程中的GESRI暴露， 功能性胃肠疾病（GETGAS）"，将利用MYRNA基础设施和人口， 增加FGID诊断和症状的广泛表征，并分析粪便样本（母亲在 怀孕，和婴儿出生时，1岁和2岁），以测试微生物群驱动的5-HT信号通路的作用。我们 目的1：确认妊娠期SSRI暴露对婴儿FGID的影响 前两年的发展轨迹。目的2：测试母亲在怀孕期间是否使用SSRI 促进产生5-HT的微生物组，该微生物组垂直转移到后代，在后代中增加FGID 风险目标3：使用数据驱动的方法来确定最具预测性的母婴因素群。 早期的FGID。从这项创新和具有成本效益的建议中得出的结果将有助于消除对影响的歧义 PMD、SSRI暴露和母体微生物群的传播对生命早期FGID的发展， 为FGID临床管理提供信息，并为生物标志物和治疗靶点发现提供基础。

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.