Lipidomic analyses of large cohort studies define the role of lipid metabolism in bridging diet and cardio-metabolic health

Diet is a key factor for many diseases, yet the underlying metabolic pathways involved remain poorly understood. We analyze data from 13,335 participants across two large Australian cohorts examining comprehensive lipidomic profiles in relation to diet. We also assess the link between metabolic signatures of dietary quality with cardiometabolic health and all-cause mortality. Here, using linear models and lipid set enrichment analysis, we report characteristic lipidomic profiles associated with dairy [sphingomyelins and lipids esterified with 14:0, 15:0, 17:0 or 17:1 fatty acid], red meat and poultry [alkyl- and alkenyl-phosphatidylcholine and phosphatidylethanolamine notably, with arachidonic acid], and fish intake [higher 22:6, and lower 22:4 fatty acids]. In a Cox proportional hazard regression, metabolic signatures of diet quality showed inverse associations with all-cause mortality with hazard ratios (95% confidence intervals) of 0.89 (0.84-0.93), 0.87 (0.83-0.92), and 0.88 (0.84-0.93) for the Australian Dietary Guideline Index (DGI), the Global Diet Quality Score (DGQS), and the Mediterranean-DASH (Dietary Approaches to Stop Hypertension) Intervention for Neurodegenerative Delay (MIND) score, respectively. Additionally, the intake of nuts (β = -0.07, p = 7.92 × 10⁻¹⁸) and the MIND score (β = -0.07, p = 1.51 × 10⁻¹⁸) were inversely associated with CVD risk. Our data provide new insights into how dietary exposure relates to lipid metabolism and metabolic health, opening avenues for future mechanistic studies and dietary interventions that can inform targeted strategies for the prevention of cardiometabolic diseases.