Instability of personal human metabotype is linked to all-cause mortality

Disruption of metabolic homeostasis is an important factor in many diseases. Various metabolites have been linked to higher risk of morbidity and all-cause mortality using metabolomics in large population-based cohorts. In these studies, baseline metabolite levels were compared across subjects to identify associations with health outcomes, implying the existence of 'healthy' concentration ranges that are equally applicable to all individuals. Here, we focused on intra-individual changes in metabolite levels over time and their link to mortality, potentially allowing more personalized risk assessment. We analysed targeted metabolomics data for 134 blood metabolites from 1409 participants in the population-based CARLA cohort at baseline and after four years. Metabotypes of the majority of participants (59%) were extremely stable over time indicated by high correlation between the subjects' metabolite profiles at the two time points. Metabotype instability and, in particular, decrease of valine were associated with higher risk of all-cause mortality in 7.9 years of follow-up (hazard ratio (HR) = 1.5(95%CI = 1.0-2.3) and 0.2(95%CI = 0.1-0.3)) after multifactorial adjustment. Excluding deaths that occurred in the first year after metabolite profiling showed similar results (HR = 1.8(95%CI = 1.1-2.8)). Lower metabotype stability was also associated with incident cardiovascular disease (OR = 1.2(95%CI = 1.0-1.3)). Therefore, changes in the personal metabotype might be a valuable indicator of pre-clinical disease.