Oral Actinomyces Species Exposure is Associated with Anxiety‐Like Behavior, Mitochondrial Remodeling, and Altered GABAergic Pathways

Introduction The human oral microbiome is increasingly recognized as a contributor to brain health, yet its mechanisms remain unclear. We previously found an enrichment of oral Actinomyces species in chronic cannabis smokers. Method Wild‐type C57BL/6 mice were orally inoculated with Actinomyces species following antibiotic preconditioning and assessed using behavioral assays, multi‐tissue cytokine profiling, single‐cell RNA sequencing, metabolomics, and biochemical analyses. Selected metabolites were tested in neuronal cells in vitro. Results Oral inoculation with cannabis use‐associated Actinomyces species, especially A. meyeri , in mice was accompanied by anxiety‐like behaviors, alterations in mitochondrial pathways, and reduced GABAergic markers, without evidence of bacterial brain translocation, changes in the canonical proinflammatory cytokines measured in this study, or memory decline. Notably, integrated oral and brain metabolomic analyses prioritized arginine and argininosuccinate as candidate mediators associated with Actinomyces exposure for further investigation. Selected metabolites associated with Actinomyces exposure altered mitochondrial function and oxidative stress in neuronal cells in vitro, supporting their potential role in mediating the observed molecular changes. Conclusion Together, these results suggest that oral microbiome‐associated metabolites may contribute to behavioral alterations through mechanisms involving mitochondrial remodeling and altered GABAergic pathways, supporting further investigation of the oral‐brain metabolic axis in neuropsychiatric disorders.