Periodontitis and MASLD: a narrative review of the direct oral-hepatic pathway

Metabolic dysfunction-associated steatotic liver disease (MASLD) affects over 30% of adults globally, yet no pharmacotherapies are approved for its early stages. Emerging evidence from preclinical models and limited observational studies suggests that periodontitis may represent a biologically plausible, modifiable risk factor for MASLD through proposed direct oral--hepatic pathways; however, causal relationships remain to be established, and these pathways are currently insufficiently validated in humans. This narrative review synthesizes evidence ranging predominantly from in vitro and animal studies to limited human observational and interventional data consistent with three proposed mechanistic pathways by which periodontal pathogens and their derivatives may potentially contribute to MASLD pathogenesis: (i) disruption of hepatocyte lipid homeostasis through TLR4-mediated inflammatory signaling, (ii) amplification of hepatic inflammation via activation of Kupffer cells and liver sinusoidal endothelial cells, and (iii) promotion of fibrogenesis through hepatic stellate cell activation. We emphasize that these pathways remain largely hypothetical, derived principally from preclinical models, and await robust validation in human populations. Preclinical studies further suggest that reactive oxygen species (ROS) and associated inflammasome signaling-particularly NLRP3 pathway activation-may function as interconnected integrative nodes linking these processes, although the relative contribution of NLRP3-mediated mechanisms within this proposed framework remains to be systematically defined. Clinical evidence is currently limited to a single small prospective interventional study (n = 40) reporting that periodontal treatment may improve hepatic steatosis and inflammatory markers in patients with comorbid periodontitis and MASLD; these preliminary findings should be regarded as hypothesis-generating rather than confirmatory, and require independent replication in larger, adequately powered randomized controlled trials before any definitive clinical conclusions can be drawn. We critically appraise the current evidence base, highlighting the predominance of monomicrobial Porphyromonas gingivalis models, the lack of standardized methodologies, and the absence of human interventional studies capable of distinguishing direct from gut-mediated pathways. We explicitly note that the proposed oral-hepatic mechanisms are predominantly supported by preclinical data and remain insufficiently validated in humans, and we propose a standardized framework to advance causal inference and clinical translation.