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This Review explores the key mechanistic pathways\u2014or \u201cgum\u2010shots\u201d\u2014underpinning the systemic impact of periodontitis. Seven interwoven mechanisms are identified. The first, microbial translocation, involves oral pathobionts and virulence factors breaching anatomical barriers and gaining systemic access via hematological, respiratory, and enteral routes, contributing to tissue damage at extra\u2010oral sites. The second, systemic (meta)inflammation, implicates both the spillover of inflammatory mediators from periodontal tissues into circulation and the immune response to translocated pathogens, fueling pro\u2010inflammatory processes. The third, maladaptive myelopoiesis, involves the periodontitis\u2010associated maladaptive trained immunity and aging\u2010related clonal hematopoiesis of indeterminate potential in the bone marrow, leading to myeloid cells with heightened proinflammatory potential. The fourth, immune players trafficking, centers on the systemic repercussions of periodontally generated autoantibodies, translocated orally primed inflammatory cells, and other local immune events. The fifth, masticatory dysfunction\u2010mediated dietary alterations, involves compromised chewing efficiency that alters dietary intake, resulting in nutritional and metabolic imbalances. The sixth, functional dysregulation of the oral microbiome, describes how periodontitis alters the metabolic activity of this densely populated microbial \u201csuperorganism\u201d, with downstream effects on both oral and systemic physiology. The final mechanism, shared underlying vulnerabilities, refers to background entities\u2014such as biological aging, oxidative stress, psychosocial stress, (epi)genetic predispositions, certain viral infections, and potentially other as\u2010yet\u2010unknown contributors\u2014that drive multi\u2010morbidity, including periodontitis. By dissecting these interconnected pathways, this critical Review challenges the traditional dichotomy of direct versus indirect mechanisms, revealing a more intricate and dynamic interplay.<\/jats:p>","DOI":"10.1111\/jre.70099","type":"journal-article","created":{"date-parts":[[2026,4,19]],"date-time":"2026-04-19T13:55:04Z","timestamp":1776606904000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Periodontal Medicine Rewired: Mechanisms Linking Periodontitis to Systemic Diseases"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5646-083X","authenticated-orcid":false,"given":"Mario","family":"Romandini","sequence":"first","affiliation":[{"name":"Ninth People's Hospital Shanghai Jiao Tong University School of Medicine  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7392-8852","authenticated-orcid":false,"given":"George","family":"Hajishengallis","sequence":"additional","affiliation":[{"name":"Department of Basic and Translational Sciences, Penn Dental Medicine University of Pennsylvania  Philadelphia Pennsylvania USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1563-9953","authenticated-orcid":false,"given":"Mike","family":"Curtis","sequence":"additional","affiliation":[{"name":"Centre for Host\u2010Microbiome Interactions, Faculty of Dentistry, Oral &amp; Craniofacial Sciences King's College London  London UK"}],"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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