The oral - X axis: from periodontal dysbiosis to systemic disease

Chronic oral inflammatory diseases, particularly periodontitis, are increasingly recognized as important contributors to the onset and progression of systemic disorders. Accumulating epidemiological, clinical, and mechanistic evidence indicates that the oral cavity is not an isolated organ, but rather a critical hub and early window for systemic disease development. Through microbial translocation, chronic low-grade inflammation, immune dysregulation, oxidative stress, and epigenetic reprogramming, oral diseases engage in bidirectional communication with distant organs.We conceptualize this integrated network as the "oral-X axis, " encompassing the oral-cardiovascular, oral-metabolic, oral-respiratory, oral-gastrointestinal, oral-oncologic, oral-immune, oral-brain, and other systemic axes. At the core of these interactions lies periodontitis-associated microbial dysbiosis dominated by key pathogens such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Aggregatibacter actinomycetemcomitans. The ensuing inflammatory response compromises periodontal barrier integrity, facilitating the dissemination of bacteria, virulence factors, and inflammatory mediators into the systemic circulation. These processes promote endothelial dysfunction, insulin resistance, breakdown of immune tolerance, neuroinflammation, and the formation of pro-tumorigenic microenvironments, thereby mechanistically linking oral inflammation to a broad spectrum of systemic diseases. This review systematically summarizes the current evidence supporting the oral-X axis, with a particular focus on epidemiological associations and underlying molecular and cellular mechanisms. In addition, we discuss periodontal interventions and oral microbiome modulation as potential strategies for the prevention and treatment of systemic diseases. A deeper understanding of the oral-X axis may provide novel insights into integrated oral-systemic healthcare and precision medicine.