Genetic susceptibility and metabolic pathways linking oral health to metabolic dysfunction‐associated steatotic liver disease

BACKGROUND: Emerging evidence indicates that oral health and metabolic dysfunction-associated steatotic liver disease (MASLD) may be interconnected through shared genetic and metabolic pathways. However, the specific mechanisms underlying this association remains poorly understood. METHODS: This population-based study included 478,000 participants from the UK Biobank (mean age: 56.5 years; 54.4% females). The Oral Health Score (OHS) and Periodontal Disease Risk (PDR) Index were developed from six baseline oral health symptoms to evaluate the combined effects of oral health on MASLD risk. Mediation analysis was conducted to investigate potential nutrition-metabolism pathways involving 142 metabolic factors. A Polygenic Risk Score (PRS) was constructed to assess the joint impact and potential interactions between oral health and genetic susceptibility on MASLD risk. RESULTS: ). Several metabolomic pathways-particularly those involving very low-density lipoproteins, fatty acids, and triglycerides-significantly mediated the association, explaining up to 19.4% of the relationship. Across genetic risk strata, both OHS and PDR remained independently associated with MASLD incidence (HR range: 1.28-3.68). CONCLUSION: Poor oral health and periodontal disease may contribute to an increased risk of MASLD by regulating the metabolic milieu, independently of genetic predisposition. As a modifiable and nutritionally relevant factor, oral health represents a promising target for early MASLD prevention. Integrating dental and metabolic care through a multidisciplinary approach could improve liver outcomes by modulating the oral-gut-liver axis. KEY POINTS: Investigated the association between oral health and metabolic dysfunction-associated steatotic liver disease (MASLD) in a 13-year prospective cohort of ∼0.5 million individuals. Explored the potential mediating roles of 142 circulating metabolic biomarkers. Assessed the modifying role of genetic susceptibility in the oral health-MASLD link. Provided novel evidence supporting the oral-gut-liver axis in metabolic disease. PLAIN LANGUAGE SUMMARY: In this study, nearly half a million UK Biobank participants were followed over 13 years to investigate the association between oral health and liver disease. Poor oral health and periodontal disease were associated with an increased risk of developing metabolic dysfunction-associated steatotic liver disease (MASLD), a common chronic liver condition. Further analyses suggest that genetic susceptibility and metabolic alterations may underlie this association. These findings underscore the interconnections of the oral cavity, gut, and liver, and highlight the potential systemic benefits of maintaining good oral health.