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)很常见，成本很高，并会导致严重的功能障碍， 从婴儿期开始。FGID仍然知之甚少，治疗往往无效，促使最近 NIDDK讲习班结束了对改进理解和管理模式的迫切需要。在这 ，我们检验了5-羟色胺再摄取抑制物(SSRI)在怀孕期间暴露于抗抑郁药的假设 是儿童FGID的主要贡献者。这是基于这样一个前提，即当妇女在 怀孕会改变胎儿5-羟色胺(5-羟色胺)的可获得性，5-羟色胺对健康的神经系统至关重要 大脑和肠道的发育。这对公共卫生有重大影响，因为SSRI在 怀孕率持续上升，据估计，每年有超过35万名新生儿被 在怀孕期间暴露于SSRI。到目前为止，大多数关于SSRI暴露的长期影响的研究 都专注于后代的大脑发育。相比之下，关于母亲接触SSRI的影响的研究 肠道发育不足。然而，通过两项已发表的研究，我们小组有令人信服的证据 和新的初步数据，表明SSRI暴露和FGID风险之间的关联，这是 不受母亲抑郁的影响。我们还确定了一种特定的微生物群组 (肠型)与FGID高度相关的，我们的初步结果表明，可能是从 从母亲到婴儿，它继续驱动升高的5-羟色胺信号。因此，SSRI的暴露可能会增加 子代FGID风险，这种风险可能通过母亲和孩子的微生物群变化来调节。我们会 通过正在进行的对375个母婴双胞胎的出生队列研究来研究这些问题 Myrna研究“；对照，母亲抑郁+/-SSRI暴露)在整个怀孕期间和 生命的头两年。我们的新研究，我们称之为“妊娠期SSRI暴露在 功能性胃肠疾病(GETGAS)“，将利用没用的基础设施和人口，而 增加了FGID诊断和症状的广泛特征，并分析了粪便样本(母亲在 怀孕和婴儿出生时，1岁和2岁)，以测试微生物区系驱动的5-羟色胺信号通路的作用。我们 我将通过三个具体目标来做到这一点：目标1：确认孕期SSRI暴露对婴儿FGID的影响 头两年的发展轨迹。目的2：测试孕妇是否在怀孕期间使用SSRI 促进产生5-羟色胺的微生物群垂直转移到后代，在那里它增加FGID 风险。目标3：使用数据驱动的方法确定最具预测性的母婴因素群 早期的FGID。这项具有创新和成本效益的提案的结果将有助于消除影响 PMD、SSRI暴露和母体微生物区系传播对早期FGID发展的影响， 为FGIDs的临床治疗提供信息，为生物标记物和治疗靶点的发现提供基础。

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.