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

Authors: BRITO, ALEX - University Of California; GRAPOV, DMITRY - University Of California; FAHRMANN, JOHANNES - University Of California; HARVEY, DANIELLE - University Of California; GREEN, RALPH - University Of California; MILLER, JOSHUA - Rutgers University; FEDOSOV, SERGEY - Aarhus University; Shahab-Ferdows, Setti; HAMPEL, DANIELA - University Of California; Pedersen, Theresa; FIEHN, OLIVER - University Of California; Newman, John; UAUY, RICARDO - University Of Chile; Allen, Lindsay - A

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 6/21/2017
Publication Date: 8/9/2017
Citation: Brito, A., Grapov, D., Fahrmann, J., Harvey, D., Green, R., Miller, J.W., Fedosov, S.N., Shahab-Ferdows, S., Hampel, D., Pedersen, T.L., Fiehn, O., Newman, J.W., Uauy, R., Allen, L.H. 2017. The human serum metabolome of vitamin B-12 deficiency and repletion, and associations with neurological function. Journal of Nutrition. 147(10):1839-1849. https://doi.org/10.3945/jn.117.248278.
DOI: https://doi.org/10.3945/jn.117.248278

Interpretive Summary: This is the first characterization of the human serum metabolome in vitamin B-12 deficiency and the changes that occur following supplementation. This study represents the introduction of metabolomics into classical vitamin deficiency research. The study has incorporated a systems biology approach providing new key information that links vitamin B-12 deficiency to a final expression of the phenotype. The description of the serum metabolome in vitamin B-12 deficiency was possible since we constructed a range of vitamin B-12 status using the most advanced biochemical indicators and applying untargeted and targeted metabolomics which have never been applied in a similar context. The characteristics of our population are unique; they were selected from a randomized controlled trial (RCT) because they had deficient B-12 status at the screening. They received treatment for ethical reasons. We were able to supplement this unique B-12 deficient group and to evaluate them after treatment. From the same RCT, we selected B-12 adequate participants from baseline to have a complete range of B-12 status (from deficiency to adequacy). Metabolomics revealed connections between vitamin B-12 status and serum metabolic markers of mitochondrial function, myelin integrity, oxidative stress, and peripheral nerve function, including metabolites implicated in Alzheimer’s and Parkinson’s diseases. The study has the potential to provide conceptual advances likely to generate strong multidisciplinary interest from researchers and practitioners focused on vitamin B-12 and micronutrient deficiencies, laboratory medicine as well as basic science and public health.

Technical Abstract: We characterize the human serum metabolome in sub-clinical vitamin B-12 (B-12) deficiency and repletion. A pre-post treatment study provided one injection of 10 mg B-12 to 27 community-dwelling elderly Chileans with B-12 deficiency evaluated with serum B-12, plasma homocysteine, methylmalonic acid and holotranscobalamin. The combined indicator of vitamin B-12 status was computed. Targeted metabolites [166 acylcarnitines, amino acids, sugars, glycerophospholipids and sphingolipids (LC/MS/MS)], and untargeted [247 chemical entities (GC-TOF-MS)] were measured at baseline and 4 months after treatment. Comparative data were also included from a group of participants with adequate vitamin B-12 status (n=18). The injection increased B-12 status (p<0.001), acylcarnitines, plasmalogens and other phospholipids while proline and other intermediaries of one-carbon metabolism were reduced (p<0.001). This is the first characterization of the human serum metabolome in B-12 deficiency. Metabolomics revealed connections between B-12 status and serum metabolic markers of mitochondrial function, myelin integrity, oxidative stress, and peripheral nerve function.