Plasma metabolic signatures of healthy dietary patterns and risk of metabolic dysfunction-associated steatotic liver disease and cirrhosis

BACKGROUND: The underlying mechanisms of the associations between dietary patterns and liver disease remain unclear. We aimed to identify metabolic signatures (MSs) reflecting adherence to ten healthy dietary patterns and to investigate their associations with metabolic dysfunction-associated steatotic liver disease (MASLD) and cirrhosis. METHODS: This cohort study included 82,259 participants with detailed dietary and metabolomic data. MSs for each dietary pattern were derived using elastic-net regression. Cox proportional hazards regression, Mendelian randomization, and mediation analyses were employed to explore potential associations and mechanisms. RESULTS: MSs for ten healthy dietary patterns were derived from 31 to 116 metabolites, primarily comprising fatty acids, lipids, and lipoprotein subclasses. Across all patterns, MSs were consistently associated with a lower risk of MASLD, with hazard ratios (HRs) ranging from 0.59 to 0.76. Notably, MSs for MIND, HPDI, rE-DII, and HLCD were associated with reduced cirrhosis risk (HRs: 0.56 to 0.63). Mendelian randomization analysis supported a potential causal relationship between MSs of MED, MIND, HPDI, and EAT-Lancet diets and liver diseases. Mediation analysis revealed that specific MSs accounted for 20.1% to 29.4% of the association between dietary patterns and MASLD, and 25.7% to 27.4% of that with cirrhosis. Metabolites from fatty acid metabolism and lipoprotein subclasses were significantly linked to liver diseases, and substantial mediated effects were observed across these metabolic pathways. CONCLUSIONS: Specific MSs linked to healthy dietary patterns are associated with reduced risk of liver disease, potentially underlying the diet's protective mechanism against MASLD and guiding future dietary guidelines in preventing progressive liver disease.