BACKGROUND AND AIM: Limited studies have evaluated the joint influence of trace elements on metabolic pathways. We analyzed the association of 12 trace elements with 54 plasma metabolites in 1144 participants from the Hortega Study, a population-based sample from Spain. METHODS: Urine antimony (Sb), arsenic (As), As adjusted by arsenobetaine (Asb), barium (Ba), cadmium (Cd), chromium (Cr), cobalt (Co), molybdenum (Mo) and vanadium (V); and plasma copper (Cu), selenium (Se) and zinc (Zn) were measured with ICP-MS and AAS, respectively. Serum metabolomic profiles, including lipoprotein subclasses, were assessed by NMR-spectrometry. We jointly correlated metabolites by principal component (PC) analysis. Bayesian Kernel Machine Regression (BKMR) allowed to evaluate the influence of trace element mixtures on metabolomic profiles. RESULTS:The geometric means of trace element exposure biomarker levels were, 0.07, 68.69, 6.53, 62.03, 0.37, 3.55, 0.25, 26.09 and 2.08 μg/g for urine Sb, As, As adjusted by Asb, Ba, Cd, Cr, Co, Mo and V, and 93.88, 83.73 and 77.13 μg/L, for plasma Cu, Se and Zn. Cu was inversely associated with metabolic principal component (mPC) 1 (reflecting increasing non-essential and essential branch-chained aminoacids and bacterial co-metabolism versus decreasing VLDL lipoproteins subclasses); Se and Zn were inversely associated with mPC 2 (reflecting increasing essential aromatic aminoacids and bacterial co-metabolism); The corresponding associations for mPC 3 (reflecting increasing LDL lipoprotein subclasses) were positive for plasma Cu, Se and Zn and inverse for urine Co. Plasma Zn was inversely associated with mPC 4 (reflecting increasing HDL lipoprotein subclasses). These associations remained after multiple-trace element adjustment. BKMR to assess joint trace element exposure was confirmatory. CONCLUSIONS:Excessive exposure to Co, Cu, Se, and Zn was associated with metabolite profiles traditionally linked to cardiometabolic risk and bacterial co-metabolism. While our findings should be confirmed in other studies, interventions to prevent uncontrolled exposure to these trace elements may be needed. KEYWORDS: Microbiome, Mixtures, Metabolomics, Biomarkers of exposure