# Perinatal citalopram exposure alters the gut composition and microbial metabolic profiles of Sprague-Dawley rat dams and female offspring but not male offspring

## TL;DR

Citalopram use during pregnancy changes gut bacteria in mothers and female rat offspring, but not in males, highlighting the need to consider sex in antidepressant safety assessments.

## Contribution

This study reveals sex-specific effects of perinatal citalopram exposure on gut microbiome and metabolism in rats.

## Key findings

- Citalopram exposure altered gut microbiome and metabolism in dams and female offspring, but not in males.
- Female offspring showed microbial profiles similar to their mothers, suggesting sex-dependent vertical transmission.
- Male offspring showed minimal changes in gut microbiome and metabolism compared to females.

## Abstract

Selective serotonin reuptake inhibitors (SSRIs) like citalopram are commonly prescribed to pregnant women, yet their effects on the developing gut microbiome of offspring are not well understood. This study aimed to examine how citalopram exposure during pregnancy and nursing impacts gut bacteria and their metabolic influence both maternally and in offspring, with a focus on sex differences. Using cutting-edge metagenomic sequencing, we analyzed fecal samples from rat dams treated with citalopram, as well as from their male and female pups.

We found that citalopram exposure caused clear shifts in the gut microbiome and microbial metabolism in the dams and female offspring, but not in male offspring. Dams and female offspring showed changes in the diversity and composition of gut bacteria, as well as in the metabolic functions those microbes perform. Male offspring showed minimal changes, suggesting that they are less susceptible to SSRI-related microbial alterations.

Importantly, the gut microbial and metabolic profiles of female offspring resembled those of the mothers more closely than those of male offspring. These results highlight that exposure to SSRIs during development can lead to long-lasting and sex-specific changes in the gut microbiome.

Understanding how SSRIs impact the gut ecosystem is important for assessing the full spectrum of their effects during pregnancy and how that effects the subsequent generation. This research emphasizes the need to consider sex differences when evaluating the safety and long-term outcomes of antidepressant use during pregnancy.

The online version contains supplementary material available at 10.1186/s13293-025-00794-5.

Selective serotonin reuptake inhibitors are widely prescribed during pregnancy. Their main route of administration is through the gut. However, their impact on the maternal and offspring gut microbiome and microbial metabolic pathways remains poorly understood. This study used metagenomic shotgun sequencing to examine the effects of perinatal citalopram exposure in rat dams and their offspring on gut composition and downstream metabolic pathways.

We treated pregnant and nursing rat dams with either citalopram or vehicle (water). Their feces were collected, DNA from these samples was extracted and then sequenced using shotgun metagenomic sequencing. The BioBakery suite of microbiome analysis tools was utilized in tandem with RStudio to analyze the gut composition and microbial metabolic pathways of the rat dams and their offspring.

Pregnant and nursing dams treated with citalopram exhibited marked shifts in microbial community structure, including phylum-level alterations in Proteobacteria and Defferibacteria. Citalopram treated dams displayed significantly altered beta diversity. Species level alterations due to treatment were composed of five significantly altered microbes, two of which belong to the Proteobacteria phylum. These changes were highly diverse and were not congruent with microbe-level alterations observed in offspring. Alpha diversity of microbial metabolic pathways was compared using the Gini-Simpson index, which was significantly increased in dams suggesting greater metabolic functional diversity with age. Female offspring perinatally exposed to citalopram showed significant changes in gut beta diversity, with seven significant alterations at the microbe level. These microbial shifts were accompanied by twenty-one significantly altered microbial metabolic pathways. In contrast, male offspring showed no significant differences in microbial composition or beta diversity and only minor metabolic changes.

These findings demonstrate that maternal citalopram exposure during pregnancy and lactation has lasting, sex-specific impacts on the offspring’s gut microbiome and microbial metabolic pathways. The pronounced alterations in female, but not male offspring, suggest that host sex may be a critical determinant in the developmental response to citalopram exposure. This work underscores the value of metagenomic approaches in uncovering complex host-microbiome interactions and highlights the need to consider offspring sex in evaluating the safety and long-term effects of antidepressant use during pregnancy.

The online version contains supplementary material available at 10.1186/s13293-025-00794-5.

Citalopram exposure during pregnancy and nursing alters gut microbiome composition in rat dams and female offspring but not male offspring.Significant changes were observed in microbial beta diversity and metabolic pathways in dams and female offspring only.Female offspring had reduced levels of Actinobacteria and showed altered metabolic functions, while male offspring remained largely unaffected.Gut microbial profiles in female offspring more closely resembled those of their mothers, indicating possible sex-dependent vertical transmission.Findings underscore the importance of sex as a biological variable when assessing the safety of SSRIs during pregnancy.

Citalopram exposure during pregnancy and nursing alters gut microbiome composition in rat dams and female offspring but not male offspring.

Significant changes were observed in microbial beta diversity and metabolic pathways in dams and female offspring only.

Female offspring had reduced levels of Actinobacteria and showed altered metabolic functions, while male offspring remained largely unaffected.

Gut microbial profiles in female offspring more closely resembled those of their mothers, indicating possible sex-dependent vertical transmission.

Findings underscore the importance of sex as a biological variable when assessing the safety of SSRIs during pregnancy.

The online version contains supplementary material available at 10.1186/s13293-025-00794-5.