Microbial and Immune Signatures of Stress and Antidepressants Across Sex and Generations

Abstract

The gut, brain, and immune system form an integrated and dynamic network that shapes development and health outcomes across the lifespan. Increasing evidence indicates that this axis is highly sensitive to stress exposure, displays robust sex-dependent properties, and may transmit biological effects across generations. This dissertation investigated how variable stress or perinatal antidepressant exposure alters gut microbial composition, immune signaling, and behavioral phenotypes in a sex-specific and multigenerational manner. To address these questions, we utilized 16S rRNA or whole-genome shotgun metagenomic sequencing in tandem with behavioral assays and multiplex cytokine profiling in rat and mouse models of chronic stress or perinatal SSRI exposure. Across studies, we demonstrate that the gut microbiome exhibits innate sex differences that are present early in life and continue to diversify with age. Aging was associated with increased alpha diversity and marked shifts in microbial metabolic pathway representation as well as a reversal of the Firmicutes–Bacteroidota ratio. Chronic stress induced distinct microbial alterations in males and females, with males showing a greater magnitude and diversity of microbial alterations. We further observed that female offspring more closely mirrored the microbial community structure of their dams, and that perinatal citalopram treatment produced stronger and more persistent effects in female offspring than in males. These findings reveal that stress and antidepressant exposure interact with sex and developmental stage to shape gut microbial composition and immune function. Microbial alterations following stress appear context-dependent, serving either compensatory or maladaptive roles depending on biological state and environmental challenge. Collectively, this work advances our understanding of how the gut–brain–immune axis integrates life experience across sex and generations and highlights the microbiome as a dynamic mediator and potential therapeutic target in stress-related neuropsychiatric vulnerability.