Trained immunity as a systemic bridge: the liver-gut-immune-oral axis in the comorbidity of chronic liver disease and periodontitis

Trained immunity (TI) reveals that innate immune cells acquire long-term functional memory through metabolic and epigenetic reprogramming. This review examines TI in chronic liver diseases and periodontitis, proposing the "Liver-Gut-Immune-Oral Axis" as a framework where TI bridges these comorbidities. The forward pathway, currently inferred from mechanistic and associative studies, proposes that liver-gut dysfunction induces bone marrow training, generating hyper-reactive monocytes that amplify periodontal inflammation. The reverse pathway, similarly conceptual, proposes that periodontal pathogens reprogram hematopoietic progenitors, accelerating liver disease progression. Both converge on shared metabolic-epigenetic reprogramming circuits. We emphasize that this axis represents a conceptual framework synthesized from current mechanistic and associative evidence; its validity as an integrated, causally-linked biological system awaits direct experimental validation. Targeting TI with metabolic modulators, epigenetic drugs, or periodontal interventions offers strategies to disrupt this cycle and advance precision medicine for inflammatory comorbidities.