Determinants of the plasma metabolome: cross-sectional and longitudinal associations over 6 years in the NESDA cohort

The plasma metabolome represents a valuable molecular readout of a persons physiological state, yet its relation to health, stress and lifestyle remains underexplored collectively. Here, we conducted an untargeted metabolomics analysis using 3804 paired samples from 1902 participants of the Netherlands Study of Depression and Anxiety at baseline and 6-year follow-up, quantifying 680 plasma metabolites. We characterised five metabolome profiles using principal component analysis, three with distinct biochemical enrichments related to transmembrane transport, sphingolipid and amino acid metabolism. Metabolite levels showed moderate intrapersonal correlation between baseline and 6-year follow-up (ICCmedian = 0.482), and only 22% of metabolites showed standardized mean differences greater than 0.2, indicating minimal 6-year population-level change. Multivariate linear modelling on 18 determinants across demographics, psychosocial environment, lifestyle, somatic and mental health explained a maximum of 35% of baseline metabolome profile variance and 12.2% in 6-year changes. Demographic (e.g., sex, age), somatic health (e.g., BMI, medication) and lifestyle factors (e.g., smoking, alcohol intake) demonstrated strong associations, while psychosocial factors and mental health contributed minor explained variance. Altogether, our study provides novel insights into the cross-sectional and longitudinal implications of health, stress and lifestyle exposures for the plasma metabolome, contributing to the understanding of metabolomic signatures in population studies.