Uncovering Microbial Modifiers of Antidepressant Responses during Pregnancy

项目总结/摘要 抑郁症是一种普遍的疾病，不成比例地折磨着女性，包括在怀孕期间高达20%的女性。 怀孕选择性5-羟色胺再摄取抑制剂（SSRIs）用于治疗孕妇产前抑郁症 女性在个体之间的疗效差异很大，有人担心母亲SSRI治疗 在精神上影响胎儿发育，增加不良产科结局和神经发育的风险 后代的畸形需要进行研究以确定调节SSRIs疗效的因素， 在怀孕期间改变母胎对SSRI治疗的反应。了解变量， 调节SSRIs的作用对于确定更安全，更有效的抑郁症治疗方法至关重要， 孕妇和限制母体SSRI治疗对发育中的后代的有害影响。肠道 微生物组正在成为直接和间接与SSRI相互作用的因素之一。我们最近 发现怀孕期间SSRI治疗改变了母体肠道微生物组的组成， 母体肠道微生物组的耗竭改变了胎儿大脑对母体SSRI治疗的反应。我们 进一步确定了SSRI相关的肠道细菌血尿酸杆菌通过 哺乳动物5-羟色胺转运蛋白的以前未表征的蛋白质直向同源物。这一证据提出了 肠道微生物组如何影响母体和胎儿对SSRI治疗的反应， 产前抑郁症为了解决这个问题，我们将确定SSRI治疗对产妇功能的影响。 怀孕小鼠、孕妇和SSRI结合细菌T. sanguinis（Aim 1）。 我们将进一步检验母体肠道微生物组的变化改变药代动力学的假设。 SSRI在母胎界面的吸收和分布（目的2）。最后，我们将确定影响 母体肠道微生物组对SSRI治疗产前抑郁症状的疗效 (Aim 3）。我们还将评估母体肠道微生物组如何影响母体肠道微生物的有害影响。 SSRI治疗对后代神经发育和行为的影响。我们的研究结果将揭示 微生物与SSRIs相互作用的基本机制，具有将干预性药物转化为 治疗产前抑郁症状的策略，同时限制SSRIs对 发育后代。

PROJECT SUMMARY/ABSTRACT Depression is a prevalent condition that disproportionately afflicts women, including up to 20% of women during pregnancy. Selective serotonin reuptake inhibitors (SSRIs) used to treat antenatal depression in pregnant women vary greatly in their efficacy across individuals, and there are concerns that maternal SSRI treatment detrimentally affects fetal development to elevate risk for adverse obstetric outcomes and neurodevelopmental abnormalities in the offspring. Research is needed to identify the factors that regulate the efficacy of SSRIs and that modify maternal-fetal responses to SSRI treatment during pregnancy. Understanding the variables that regulate the effects of SSRIs is paramount to identifying safer and more efficacious treatments for depression in pregnant women and to limiting harmful effects of maternal SSRI treatment on developing offspring. The gut microbiome is emerging as one such factor that interacts directly and indirectly with SSRIs. We recently discovered that SSRI treatment during pregnancy alters the composition of the maternal gut microbiome, and that depletion of the maternal gut microbiome modifies fetal brain responses to maternal SSRI treatment. We further determined that the SSRI-associated gut bacterium Turicibacter sanguinis binds SSRIs through a previously uncharacterized protein orthologue of the mammalian serotonin transporter. This evidence raises the important question of how the gut microbiome impacts maternal and fetal responses to SSRI treatment for antenatal depression. To address this, we will define the impact of SSRI treatment on the function of the maternal gut microbiome in pregnant mice, in pregnant women, and in the SSRI-binding bacterium T. sanguinis (Aim 1). We will further test the hypothesis that variations in the maternal gut microbiome modify the pharmacokinetics of SSRI absorption and distribution across the maternal-fetal interface (Aim 2). Finally, we will determine effects of the maternal gut microbiome on the efficacy of SSRI treatment against symptoms of antenatal depression (Aim 3). We will additionally assess how the maternal gut microbiome impacts the detrimental effects of maternal SSRI treatment on neurodevelopment and behavior of the offspring. Findings from our study will reveal fundamental mechanisms for microbial interactions with SSRIs, with the potential to transform interventional strategies for treating symptoms of antenatal depression, while limiting adverse consequences of SSRIs on developing offspring.