Deep lipidomics profiling captures the impact of improved dietary fat quality on cardiometabolic risk and provides potential tools for precision nutrition approaches

<title>Abstract</title> Current guidelines for cardiometabolic disease prevention recommend increasing dietary unsaturated fat intake while reducing saturated fats. However, standard cardiometabolic risk markers may not fully capture the metabolic benefits. Here, we demonstrate that a deep lipidomics-based multi-lipid score (MLS) accurately reflects the metabolic impact of controlled dietary substitution of saturated fats with unsaturated fats. We then show that the difference in this MLS, induced by a healthy fat-rich diet, is associated with a significant reduction in relative disease risk, such as 32% fewer incident cardiovascular disease and 26% fewer type 2 diabetes cases. These relative risk reductions surpass those extrapolated based on changes in standard surrogate biomarkers such as non-HDL cholesterol. Additionally, we utilize longitudinal lipidomics data to link long-term MLS changes with altered diabetes risk. Finally, we show a significant effect modification in a dietary intervention trial. An olive oil-rich Mediterranean diet intervention primarily reduced diabetes incidence among participants with unfavorable pre-intervention MLS levels. Together, our findings highlight the potential of lipidomics-based scores for targeting and monitoring dietary interventions in biomarker-guided precision nutrition approaches.