The human serum metabolome of vitamin B-12 deficiency and repletion, and associations with neurological function in elderly adults

Abstract

Background:The specific metabolomic perturbations that occur in vitamin B-12 deficiency, and their associations withneurological function, are not well characterized.Objective:We sought to characterize the human serum metabolome in subclinical vitamin B-12 deficiency and repletion.Methods:A before-and-after treatment study provided 1 injection of 10 mg vitamin B-12 (with 100 mg pyridoxine and 100 mgthiamin) to 27 community-dwelling elderly Chileans (;74 y old) with vitamin B-12 deficiency, as evaluated with serum vitaminB-12, total plasma homocysteine (tHcy), methylmalonic acid (MMA), and holotranscobalamin. The combined indicator ofvitamin B-12 status (cB-12) was computed. Targeted metabolites [166 acylcarnitines, amino acids, sugars, glycerophospho-lipids, and sphingolipids (liquid chromatography–tandem mass spectrometry)], and untargeted metabolites [247 chemicalentities (gas chromatography time-of-flight mass spectrometry)] were measured at baseline and 4 mo after treatment. Aperipheral nerve score was developed. Differences before and after treatment were examined. For targeted metabolomics,the data from 18 individuals with adequate vitamin B-12 status (selected from the same population) were added to the before-and-after treatment data set. Network visualizations and metabolic pathways are illustrated.Results:The injection increased serum vitamin B-12, holotranscobalamin, and cB-12 (P< 0.001), and reduced tHcy and serumMMA (P< 0.001). Metabolomic changes from before to after treatment included increases (P< 0.001) in acylcarnitines,plasmalogens, and other phospholipids, whereas proline and other intermediaries of one-carbon metabolism—that is,methionine and cysteine—were reduced (P< 0.001). Direct significant correlations (P< 0.05 after the false discoveryrate procedure) were identified between acylcarnitines, plasmalogens, phospholipids, lyso-phospholipids, and sphingomyelinscompared with vitamin B-12 status and nerve function. Multiple connections were identified with primary metabolites (e.g., aninverse relation between vitamin B-12 markers and tryptophan, tyrosine, and pyruvic, succinic, and citric acids, and a directcorrelation between the nerve score and arginine).Conclusions:The human serum metabolome in vitamin B-12 deficiency and the changes that occur after supplemen-tation are characterized. Metabolomics revealed connections between vitamin B-12 status and serum metabolic markersof mitochondrial function, myelin integrity, oxidative stress, and peripheral nerve function, including some previously implicatedin Alzheimer and Parkinson diseases. This trial was registered at www.controlled-trials.com as ISRCTN02694183.