Uncovering Microbial Modifiers of Antidepressant Responses during Pregnancy

项目摘要/摘要 抑郁症是一种流行的疾病，对女性的影响不成比例，其中高达20%的女性在 怀孕了。选择性5-羟色胺再摄取抑制剂(SSRIs)治疗妊娠期抑郁症 妇女在不同个体之间的疗效差异很大，有人担心孕产妇的SSRI治疗 有害地影响胎儿发育，增加产科不良结局和神经发育的风险 后代中的异常。需要进行研究，以确定调节SSRIs疗效的因素和 这改变了怀孕期间对SSRI治疗的母婴反应。了解以下变量： 调节SSRIs的影响对于寻找更安全和更有效的抑郁症治疗方法至关重要 旨在限制孕妇SSRI治疗对发育后代的有害影响。胆量 微生物组正在成为与SSRIs直接或间接相互作用的因素之一。我们最近 发现怀孕期间的SSRI治疗改变了母亲肠道微生物组的组成，并且 母体肠道微生物群的枯竭改变了胎儿大脑对母体SSRI治疗的反应。我们 进一步确定与SSRI相关的肠道细菌血透杆菌通过一种 以前未知的哺乳动物5-羟色胺转运蛋白的同源蛋白。这一证据提高了 肠道微生物群如何影响孕妇和胎儿对SSRI治疗的反应 产前忧郁症。为了解决这个问题，我们将定义SSRI治疗对母体功能的影响 怀孕小鼠、孕妇和SSRI结合细菌T.sanguinis中的肠道微生物组(目标1)。 我们将进一步检验这一假设，即母体肠道微生物群的变化会改变药代动力学。 SSRI在母胎界面的吸收和分布情况(目标2)。最后，我们将确定影响 孕妇肠道微生物群对SSRI治疗产前抑郁症状疗效的影响 (目标3)。我们还将评估母体肠道微生物群如何影响母体的有害影响 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，有可能转变干预性 治疗产前抑郁症状的策略，同时限制SSRIs的不良后果 发育中的后代。

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.