Abstract Body: Introduction: The exposome encompasses cumulative environmental exposures, including particulate matter (PM ≤2.5μm) and psychosocial stress, that elevate stress hormone levels and influence cardiovascular health. Notably, the gut microbiome is highly responsive to environmental exposures, and its dysregulation can lead to deleterious outcomes, positioning it as a novel target for examining the effects of the exposome. We hypothesized that short-term exposure to PM ≤2.5μm or psychosocial stress promotes disruption in composition of the gut microbiome. Methods: Male C57BL/6 mice were exposed to filtered air (FA) or PM_2.5 (34.85 μg/m³) for 6 h/day, 5 days/week, for 3 weeks. Stress paradigms included social defeat (SD; 10 min/day for 10 days), social defeat with sensorial interaction (SDSI; 18-h post-defeat cohabitation), or daily restraint (DR; 2 h/day for 7 days). After exposures, five fecal samples were randomly collected per group. Microbial DNA was extracted from stool, and the V4-V5 region of the bacterial 16S rRNA gene was amplified for sequencing. Bioinformatics analyses were performed to assess Alpha Diversity, Beta Diversity, and relative taxonomic composition at the genus level across all groups. Data were analyzed using a one-way ANOVA with significance set at p<0.05 when compared to FA control. Results: Indices of alpha-diversity were increased following SD, including Shannon Diversity, Faith’s phylogenetic, and Pielou’s evenness (all p<0.05). Beta-diversity analysis demonstrated distinct clustering of microbial communities in the SD exposure. Unweighted UniFrac and Bray-Curtis dissimilarity metrics revealed a separation of SD mice not observed in other groups. SDSI exposure showed similarities in bacterial composition with the SD group but was not significantly altered when compared to FA. Conclusions: In this study, we have demonstrated that social defeat is associated with an increase in alpha diversity, and a distinct clustering of beta diversity. These findings suggest that social defeat differentially influences microbial community structure compared to other exposures, and that short-term PM, Daily Restraint, and Social Defeat combined with sensorial interaction exposures do not promote microbiome dysregulation.