Background: Perinatal depression is a growing public health crisis that impacts up to 20% of pregnant persons with possible adverse effects on maternal-fetal health. First-line treatment selective serotonin inhibitors (SSRIs) remain an enigma with a myriad of outcomes and potential adverse effects on fetal development. With evidence highlighting the interactions between the gut microbiome and host-responses to SSRIs, resolving the underlying mechanisms is essential to improve treatment of maternal depression while limiting adverse fetal outcomes.

Objective: In this study, we characterize the underlying microbial modulators of the most commonly prescribed SSRIs: fluoxetine, sertraline, and escitalopram. 

Methods: 7-9 week old pregnant specific pathogen-free and germ-free Swiss Webster female mice were given Fluoxetine (10mg/kg), Sertraline (10mg/kg), Escitalopram (15mg/kg) or Vehicle starting at E7.5. Fecal samples were collected at E4.5, E7.5, E11.5, E14.5, and E18.5. On E18.5, dams were sacrificed, tissue collection included: maternal brain, colon, small intestine, placenta, fetal brain, whole embryos, maternal and fetal serum. We performed 16S sequencing, and will explore alterations in the fetal brain transcriptome using RNA sequencing and synaptic organization via immunohistochemical analysis.

Results: SSRIs did not impact gestational weight gain, litter size, mean embryo, placenta, or fetal brain weight in SPF or GF dams. Mean embryo weight was significantly reduced in GF escitalopram mice. No distinct effect noted on neuronal proliferation in SPF fetal brains. Alpha diversity was significantly impacted by sertraline and escitalopram across gestation. No distinct global effect was noted in beta-diversity. Treatment with SSRIs was found to significantly increase the relative abundance of bacteria from the lachnospiraceae, clostridia, and ruminococcaceae families.

Conclusions: Our ongoing work highlights the role of the gut microbiome as a direct modulator of embryo weight in the setting of escitalopram treatment. This is the first step to resolving the underlying mechanisms of gut microbiome-SSRI interactions and their potential influences on maternal-fetal outcomes.