Uncovering Microbial Modifiers of Antidepressant Responses during Pregnancy

揭示怀孕期间抗抑郁反应的微生物调节剂

• 批准号: 10600387
• 负责人: Elaine Hsiao
• 金额: $ 50.17万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10600387
• 关键词: Address; Affect; Antidepressive Agents; Bacteria; Behavior; Behavioral; Binding; Biochemical; Brain; Cell physiology; Disease; Drug Kinetics; Drug Screening; Epidemiology; Fetal Development; Fetal Tissues; Fetal health; Genetic Engineering; Gnotobiotic; Human; Individual; Intervention; Major Depressive Disorder; Maternal Health; Maternal-Fetal Exchange; Measures; Mental Depression; Metagenomics; Mus; Pharmaceutical Preparations; Physiological; Pregnancy; Pregnant Women; Proteins; Reporting; Research; Risk; Role; Selective Serotonin Reuptake Inhibitor; Shapes; Social isolation; Streptococcus sanguis; Symptoms; Testing; Time; Tissues; Transplantation; Variant; Woman; absorption; adverse outcome; antepartum depression; antidepressant effect; anxiety symptoms; depressive symptoms; efficacious treatment; fetal; gut bacteria; gut microbiome; gut microbiota; maternal depression; metabolomics; microbial; microbial signature; microbiome; microorganism interaction; mouse model; neurodevelopment; novel; obstetric outcomes; offspring; patient response; post pregnancy; postnatal; pregnant; response; serotonin transporter; symptom treatment; transcriptomics

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.

项目摘要/摘要 抑郁症是一种普遍的疾病，使妇女遭受不成比例的折磨，包括多达20％的妇女 怀孕。选择性5-羟色胺再摄取抑制剂（SSRI）用于治疗怀孕的产前抑郁症 妇女在各个个体的疗效方面差异很大，并且有人担心母亲SSRI治疗 不利影响胎儿发育，以提高不良产科结果和神经发育的风险 后代异常。需要研究以确定调节SSRI和 这修改了怀孕期间对SSRI治疗的母亲反应。了解变量 规范SSRI的影响对于确定对抑郁症的更安全，更有效的治疗方法至关重要 孕妇，并限制母体SSRI治疗对发展后代的有害影响。肠道 微生物组是与SSRI直接和间接相互作用的一种因素。我们最近 发现怀孕期间的SSRI治疗改变了母体肠道微生物组的组成，和 母体肠道微生物组的耗竭改变了胎儿脑对母体SSRI治疗的反应。我们 进一步确定了SSRI相关的肠道细菌曲霉杆菌sanguinis通过A结合SSRI 哺乳动物5-羟色胺转运蛋白的以前未表征的蛋白质直系同源物。这一证据提出了 肠道微生物组如何影响母体和胎儿对SSRI治疗的反应的重要问题 产前抑郁症。为了解决这个问题，我们将定义SSRI处理对母亲功能的影响 怀孕小鼠，孕妇和SSRI结合细菌T. sanguinis的肠道微生物组（AIM 1）。 我们将进一步检验以下假设：母体肠道微生物组的变化改变了药代动力学 跨母体界面界面的SSRI吸收和分布（AIM 2）。最后，我们将确定效果 孕产妇肠道微生物组对SSRI治疗的症状针对产前抑郁的症状 （目标3）。我们还将评估母体肠道微生物组如何影响母体的有害影响 SSRI对后代神经发育和行为的治疗。我们研究的发现将揭示 与SSRIS微生物相互作用的基本机制，有可能改变介入 治疗产前抑郁症状的策略，同时限制SSRI的不利后果 发展后代。