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.

PROJECT NARRATIVE The gut microbiome interacts with many common medications, with the ability to modify their efficacy for treating disease. We aim to uncover fundamental mechanisms underlying interactions between the gut microbiome and antidepressants, and how such interactions impact the effects of antidepressant treatments for maternal depression during pregnancy.