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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\u2010exposed mice into germ\u2010free mice was sufficient to transmit the heightened periodontitis phenotype, establishing a causal role for the stress\u2010altered microbiota. Metabolomic profiling identified a depletion of eicosapentaenoic acid (EPA) in stressed, ligature\u2010induced periodontitis mice. Mechanistically, supplementation with EPA ameliorates periodontitis by suppressing the NF\u2010\u03baB signaling pathway, thereby inhibiting the pro\u2010inflammatory M1 polarization of macrophages. Our findings unveil a novel gut\u2010oral axis mediated by microbiota and metabolites under stress, and position the omega\u20103 fatty acid EPA as a promising therapeutic agent for mitigating stress\u2010aggravated inflammatory disorders.<\/jats:p>","DOI":"10.1002\/advs.202521346","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T19:26:41Z","timestamp":1772998001000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dysregulation of Oral Microbial Eicosapentaenoic Acid Induced by Chronic Restraint Stress Exacerbates Periodontitis via M1 Macrophage Polarization"],"prefix":"10.1002","volume":"13","author":[{"given":"Shihong","family":"Luo","sequence":"first","affiliation":[{"name":"The Affiliated Stomatological Hospital Chongqing Medical University Chongqing China"},{"name":"The Affiliated Stomatological Hospital Southwest Medical University  Luzhou China"},{"name":"Chongqing Key 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