Dysregulation of Oral Microbial Eicosapentaenoic Acid Induced by Chronic Restraint Stress Exacerbates Periodontitis via M1 Macrophage Polarization

The intricate interplay between chronic psychological stress and periodontitis, mediated by oral microbiota and macrophage polarization, remains largely enigmatic. Here, we demonstrate that chronic restraint stress (CRS) exacerbates periodontitis by inducing oral microbial dysbiosis and a consequential shift in host metabolism. Clinical observations reveal a significant correlation between depressive symptoms and the severity of periodontitis, which is underpinned by a distinct oral microbiome. Crucially, fecal microbiota transplantation from CRS-exposed mice into germ-free mice was sufficient to transmit the heightened periodontitis phenotype, establishing a causal role for the stress-altered microbiota. Metabolomic profiling identified a depletion of eicosapentaenoic acid (EPA) in stressed, ligature-induced periodontitis mice. Mechanistically, supplementation with EPA ameliorates periodontitis by suppressing the NF-κB signaling pathway, thereby inhibiting the pro-inflammatory M1 polarization of macrophages. Our findings unveil a novel gut-oral axis mediated by microbiota and metabolites under stress, and position the omega-3 fatty acid EPA as a promising therapeutic agent for mitigating stress-aggravated inflammatory disorders.