Antidepressant treatment modulates the gut microbiome and metabolome during pregnancy and lactation in rats with a depressive-like phenotype

Background: Up to 10% of women use selective serotonin reuptake inhibitor (SSRI) antidepressants during and after pregnancy to manage mood disorders, with possible implications for the developing offspring. The microbiota within the gastrointestinal tract contributes to the regulation of serotonin synthesis. However, the interaction between maternal depression, SSRI use, bacterial community composition, and availability of microbiota-derived metabolites during pregnancy and lactation is not clear and may be consequential to the long-term health of mother and offspring. To determine the impact of SSRI treatment on maternal microbial community dynamics, we conducted these studies in a rat model of maternal vulnerability (MV). All MV females are on a background of genetic vulnerability, where rats exposed to early life stress (sMV) develop a depressive-like phenotype. In adulthood, sMV- and control (cMV) females were treated with either the SSRI fluoxetine (FLX) or the vehicle (Veh) throughout pregnancy and lactation. High-resolution 16S ribosomal RNA gene sequencing and targeted metabolomic analysis were used to assess the fecal microbiome and metabolite availability, respectively. Results: The diversity, structure, and composition of the fecal bacterial community differed between pregnancy and lactation. Shifts in microbiota composition were accompanied by changes in fecal metabolite availability. FLX altered some key features of the transition from pregnancy to lactation, but only in females exposed to early life stress (sMV-Veh vs sMV-FLX). For instance, sMV-FLX females had lower fecal availability of the amino acids serine, proline, and aspartic acid than sMV-Veh females. These metabolite concentrations correlated negatively with the relative abundance of bacterial taxa Prevotella, Ruminococcus, and Oscillospira. Conclusions: Our studies demonstrate an important relationship between antidepressant use during the perinatal period and maternal fecal metabolite availability in sMV rats, possibly through parallel changes in the maternal gut microbiome. Since maternal microbial metabolites contribute to health outcomes in offspring, insults to the maternal microbiome by SSRIs might have inter-generational consequences.