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Specialized pro\u2010resolving mediators (SPMs) provide a mechanistic framework for understanding how inflammation intersects with microbial dysbiosis. Derived from omega\u20103 and omega\u20106 fatty acids, SPMs actively promote the resolution of inflammation through binding of specific cell surface receptors rather than nonspecifically suppressing it, highlighting their therapeutic potential as side\u2010effect\u2010free host modulators, with implications beyond periodontitis to other chronic inflammatory diseases. The evidence reviewed shows how SPMs can: (1) control inflammation by resolution rather than inhibition, (2) reverse microbial dysbiosis as a consequence of inflammation control, and (3) promote tissue regeneration through diverse biological pathways. Whether the primary dysregulation in periodontitis lies solely in resolution failure or involves additional\u2014possibly still unidentified\u2014mechanisms, remains unclear. All individuals harbor periodontal pathobionts, yet only a subset develop severe disease. Why do some individuals with significant biofilm accumulation maintain attachment levels, while others with reasonable plaque control become edentulous? This remains one of the most significant unanswered questions in periodontology. What is evident, however, is the need for a paradigm shift. While bacteria initiate the inflammatory process in all individuals, it is the host response that ultimately determines the progression to periodontitis.<\/jats:p>","DOI":"10.1111\/jre.13424","type":"journal-article","created":{"date-parts":[[2025,7,14]],"date-time":"2025-07-14T13:40:17Z","timestamp":1752500417000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["Periodontitis: Microbial Dysbiosis, Non\u2010Resolving Inflammation, or Both?"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0568-124X","authenticated-orcid":false,"given":"Thomas E.","family":"Van Dyke","sequence":"first","affiliation":[{"name":"Center for Clinical and Translational Research, ADA Forsyth Institute  Somerville Massachusetts USA"},{"name":"Department of Oral Medicine Infection and Immunity Faculty of Medicine, Harvard University  USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9395-4967","authenticated-orcid":false,"given":"Giacomo","family":"Baima","sequence":"additional","affiliation":[{"name":"Department of Surgical Sciences C.I.R. 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