Insulin resistance modifies longitudinal multi-omics responses to habitual diet

Abstract How habitual diet influences the gut microbiome and plasma metabolome across insulin resistance states remains unclear. We conducted year-long multi-omics profiling of 71 deeply phenotyped adults, integrating repeated assessments of diet, metabolome, gut microbiome, clinical laboratory measures, and inflammatory markers. Using gold-standard insulin suppression tests and machine learning-derived dietary patterns, we examined how dietary patterns relate to metabolic and microbial landscapes by insulin resistance status. Insulin-sensitive individuals exhibited stronger and more numerous diet-omics associations than insulin-resistant individuals, identifying metabolic flexibility as a central determinant of dietary responsiveness. Parabacteroides emerged as a candidate microbial mediator between refined carbohydrate-rich dietary patterns and host metabolic signatures. Integrated into a cardiovascular risk prediction model, diet, metabolites, microbial taxa, and immune markers each contributed to 10-year atherosclerotic cardiovascular disease risk. These findings show that inter-individual variation in cardiometabolic risk partly reflects differences in molecular responsiveness to habitual diet, informing precision nutrition and cardiovascular prevention. Competing Interest Statement M.P.S. is a co founder of Personalis, SensOmics, Qbio, January AI, Filtricine, Protos and NiMo, and serves on the scientific advisory boards of Personalis, SensOmics, Qbio, January AI, Filtricine, Protos, NiMo and Genapsys. All other authors declare no competing interests.