This review explores the multifaceted relationship between periodontitis and its comorbidities, emphasizing the local and systemic mechanisms linking these conditions. Periodontitis, a chronic inflammatory disease affecting the oral mucosa, is epidemiologically associated with various chronic inflammatory disorders, including cardiovascular disease, type 2 diabetes, rheumatoid arthritis, inflammatory bowel disease (IBD), Alzheimer's disease, nonalcoholic fatty liver disease, and certain cancers. Recent studies have demonstrated that local treatment of periodontitis can improve surrogate markers of comorbid conditions, suggesting a causal link between the two. The review highlights how periodontal bacteria or locally activated lymphocytes can disseminate to extra-oral tissues, causing inflammatory and functional complications such as endothelial cell dysfunction, bone marrow alterations, gut dysbiosis, and immune suppression. These effects can aggravate or initiate comorbid pathologies. Additionally, the inflammatory adaptation of hematopoietic progenitors in the bone marrow may connect multiple chronic inflammatory diseases, as evidenced by advances in understanding the epigenetic basis of innate immune memory. The review also discusses the bidirectional relationship between periodontitis and systemic diseases like type 2 diabetes, where periodontitis can increase susceptibility to comorbidities by increasing the inflammatory burden on the periodontium or modulating the periodontal microbiome. Conversely, systemic diseases can promote susceptibility to periodontitis by increasing the inflammatory burden or modulating the periodontal microbiome. The review emphasizes that the mouth-body link is driven by multiple microorganism-induced immunological mechanisms, which increase the susceptibility of patients with periodontitis to non-communicable chronic inflammatory diseases. It also highlights the potential therapeutic options that may arise from a comprehensive understanding of these mechanisms.This review explores the multifaceted relationship between periodontitis and its comorbidities, emphasizing the local and systemic mechanisms linking these conditions. Periodontitis, a chronic inflammatory disease affecting the oral mucosa, is epidemiologically associated with various chronic inflammatory disorders, including cardiovascular disease, type 2 diabetes, rheumatoid arthritis, inflammatory bowel disease (IBD), Alzheimer's disease, nonalcoholic fatty liver disease, and certain cancers. Recent studies have demonstrated that local treatment of periodontitis can improve surrogate markers of comorbid conditions, suggesting a causal link between the two. The review highlights how periodontal bacteria or locally activated lymphocytes can disseminate to extra-oral tissues, causing inflammatory and functional complications such as endothelial cell dysfunction, bone marrow alterations, gut dysbiosis, and immune suppression. These effects can aggravate or initiate comorbid pathologies. Additionally, the inflammatory adaptation of hematopoietic progenitors in the bone marrow may connect multiple chronic inflammatory diseases, as evidenced by advances in understanding the epigenetic basis of innate immune memory. The review also discusses the bidirectional relationship between periodontitis and systemic diseases like type 2 diabetes, where periodontitis can increase susceptibility to comorbidities by increasing the inflammatory burden on the periodontium or modulating the periodontal microbiome. Conversely, systemic diseases can promote susceptibility to periodontitis by increasing the inflammatory burden or modulating the periodontal microbiome. The review emphasizes that the mouth-body link is driven by multiple microorganism-induced immunological mechanisms, which increase the susceptibility of patients with periodontitis to non-communicable chronic inflammatory diseases. It also highlights the potential therapeutic options that may arise from a comprehensive understanding of these mechanisms.