Metabolite Signatures and Their Mediation Effects on the Relationship Between Mediterranean Diet Adherence and MASLD Progression

Background Mediterranean Diet (MED) is recommended for managing patients with Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). However, the potential metabolic changes involved in this relationship remain unclear. This study aims to investigate how metabolic biomarkers mediate the association between MED adherence and liver-related events (LRE) and mortality in patients with MASLD. Methods We performed a prospective analysis using UK Biobank data, including 47,429 MASLD participants free of LRE at baseline. MED adherence was assessed as alternate Mediterranean Diet (aMED) score through a validated questionnaire covering 206 foods and 32 beverages. Metabolic biomarkers were measured using high-throughput nucleic magnetic resonance (NMR) spectroscopy. Cox regression and restricted cubic splines assessed the association of aMED, its components, with risk of LRE and mortality. Mediation analysis evaluated the role of metabolites in the relationship between aMED, its components, and MASLD progression. Results Over a median follow-up of 13.3 years, 296 LRE cases and 3,616 deaths occurred. Higher aMED scores (6–9) were associated with lower risks of LRE (HR: 0.553, 95% CI: 0.351–0.874) and mortality (HR: 0.854, 95% CI: 0.762–0.956) compared to the lowest scores (0–3). Linear dose-response relationships were observed for both LRE incidence ( P _nonlinear = 0.91) and mortality ( P _nonlinear = 0.07). Certain aMED components, including vegetables and legumes, were associated with a reduced risk of LRE, while vegetables, nuts, fish, the MUFA:SFA ratio, and moderate alcohol intake were linked to lower mortality risk. Of 143 metabolites, 46 were significantly associated with aMED. Positive associations included very large HDL particles (n = 3), unsaturated fatty acids (n = 8), albumin, and acetate, while negative associations were found with large VLDL (n = 11), small and middle HDL (n = 13), saturated fatty acids (n = 2), Apo-AI, and creatinine. Five aMED-related lipid metabolites were negatively associated with LRE, while five were positively linked to mortality. Mediation analysis revealed that omega-3 fatty acids, the omega-3 to total fatty acid ratio, and albumin accounted for 7.9%, 11.9%, and 2.6% of the reduction in LRE, and 19.4%, 23.1%, and 4.7% of the mitigation in mortality, respectively. Conclusions Adherence to MED is linked to reduced LRE risk and mortality in MASLD patients. Metabolic biomarkers such as small HDL particles and omega-3 fatty acids may mitigate MASLD progression.