Circulating metabolite signatures mediating the association between minerals in domestic water and incident MASLD: a prospective cohort study.

BACKGROUND

Epidemiological evidence on minerals in domestic water and incident metabolic dysfunction-associated steatotic liver disease (MASLD) remains limited, particularly regarding potential mediating roles of circulating metabolites. We evaluated the association between minerals and incident MASLD and characterized metabolomic biomarkers that may mediate this association.

METHODS

We included 218,339 UK Biobank participants without MASLD or other liver disease at baseline. Domestic water hardness (DWH), including calcium (Ca), magnesium (Mg), and calcium carbonate (CaCO3), was obtained from water-utility outputs. MASLD was ascertained using linked health records. One hundred sixty-eight plasma biomarkers were measured using nuclear magnetic resonance profiling. We used Cox models to quantify associations between minerals and MASLD risk, while causal mediation analyses were used to evaluate mediation by these biomarkers.

RESULTS

During a median follow-up of 13.7 years, 3,004 participants developed MASLD. Higher Ca in domestic water was positively associated with incident MASLD (Hazard ratio 1.087, 95% confidence interval 1.013-1.166), whereas Mg (1.042, 0.993-1.094) and CaCO3 (1.006, 0.939-1.078) showed no significant associations with MASLD. In mediation analyses, Glutamine, Lactate, and Alanine may mediated the association, with proportions mediated of 21.42, 7.53, and 5.38%, respectively.

CONCLUSION

Ca in domestic water was positively associated with incident MASLD, with partial mediation by metabolites including glutamine, lactate, and alanine. These findings provide insight into the metabolic pathways of minerals-MASLD association and support prevention strategies.