TY - JOUR
T1 - The human serum metabolome of vitamin B-12 deficiency and repletion, and associations with neurological function in elderly adults
AU - Brito, Alex
AU - Grapov, Dmitry
AU - Fahrmann, Johannes
AU - Harvey, Danielle
AU - Green, Ralph
AU - Miller, Joshua W.
AU - Fedosov, Sergey N.
AU - Shahab-Ferdows, Setareh
AU - Hampel, Daniela
AU - Pedersen, Theresa L.
AU - Fiehn, Oliver
AU - Newman, John W.
AU - Uauy, Ricardo
AU - Allen, Lindsay H.
N1 - Funding Information:
Supported in part by the Chilean National Science and Technology Research Fund (FONDECYT grant award 1070592 to principal investigator RU) and by USDA Agricultural Research Service grant 2032-51000-004-00. DG and JF are supported through NIH DK097154, and TLP and JWN through USDA project no. 2032-51530-022-00D. Author disclosures: AB, DG, JF, D Harvey, RG, JWM, SNF, SS-F, D Hampel, TLP, OF, JWN, RU, and LHA, no conflicts of interest. Supplemental Tables 1–4 are available from the ‘‘Online Supporting Material’’ link in the online posting of the article and from the same link in the online table of contents at http://jn.nutrition.org. AB, DG, and JF contributed equally to this work. Address correspondence to LHA (e-mail: lindsay.allen@ars.usda.gov). Abbreviations used: cB-12, combined indicator of vitamin B-12 status; EAR, estimated average requirement; FDR, false discovery rate; MMA, methylmalonic acid; PACAM, Chile’s national nutritional supplementation program for the elderly; ROS, reactive oxygen species; SAM, S-adenosylmethionine; tHcy, total plasma homocysteine.
Publisher Copyright:
© 2017 American Society for Nutrition.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - Background: The specific metabolomic perturbations that occur in vitamin B-12 deficiency, and their associations with neurological 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 100mg pyridoxine and 100mg thiamin) to 27 community-dwelling elderly Chileans (74 y old) with vitamin B-12 deficiency, as evaluated with serum vitamin B-12, total plasma homocysteine (tHcy), methylmalonic acid (MMA), and holotranscobalamin. The combined indicator of vitamin B-12 status (cB-12) was computed. Targeted metabolites [166 acylcarnitines, amino acids, sugars, glycerophospholipids, and sphingolipids (liquid chromatography-tandem mass spectrometry)], and untargeted metabolites [247 chemical entities (gas chromatography time-of-flight mass spectrometry)] were measured at baseline and 4 mo after treatment. A peripheral 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 beforeand- 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 serum MMA (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 discovery rate procedure) were identified between acylcarnitines, plasmalogens, phospholipids, lyso-phospholipids, and sphingomyelins compared with vitamin B-12 status and nerve function.Multiple connectionswere identified with primarymetabolites (e.g., an inverse relation between vitamin B-12 markers and tryptophan, tyrosine, and pyruvic, succinic, and citric acids, and a direct correlation between the nerve score and arginine). Conclusions: The human serum metabolome in vitamin B-12 deficiency and the changes that occur after supplementation are characterized. Metabolomics revealed connections between vitamin B-12 status and serum metabolic markers of mitochondrial function, myelin integrity, oxidative stress, and peripheral nerve function, including some previously implicated in Alzheimer and Parkinson diseases. This trial was registered at www.controlled-trials.com as ISRCTN02694183.
AB - Background: The specific metabolomic perturbations that occur in vitamin B-12 deficiency, and their associations with neurological 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 100mg pyridoxine and 100mg thiamin) to 27 community-dwelling elderly Chileans (74 y old) with vitamin B-12 deficiency, as evaluated with serum vitamin B-12, total plasma homocysteine (tHcy), methylmalonic acid (MMA), and holotranscobalamin. The combined indicator of vitamin B-12 status (cB-12) was computed. Targeted metabolites [166 acylcarnitines, amino acids, sugars, glycerophospholipids, and sphingolipids (liquid chromatography-tandem mass spectrometry)], and untargeted metabolites [247 chemical entities (gas chromatography time-of-flight mass spectrometry)] were measured at baseline and 4 mo after treatment. A peripheral 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 beforeand- 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 serum MMA (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 discovery rate procedure) were identified between acylcarnitines, plasmalogens, phospholipids, lyso-phospholipids, and sphingomyelins compared with vitamin B-12 status and nerve function.Multiple connectionswere identified with primarymetabolites (e.g., an inverse relation between vitamin B-12 markers and tryptophan, tyrosine, and pyruvic, succinic, and citric acids, and a direct correlation between the nerve score and arginine). Conclusions: The human serum metabolome in vitamin B-12 deficiency and the changes that occur after supplementation are characterized. Metabolomics revealed connections between vitamin B-12 status and serum metabolic markers of mitochondrial function, myelin integrity, oxidative stress, and peripheral nerve function, including some previously implicated in Alzheimer and Parkinson diseases. This trial was registered at www.controlled-trials.com as ISRCTN02694183.
KW - Acylcarnitines
KW - Metabolomics
KW - Nerve function
KW - Omics
KW - Plasmalogens
KW - Vitamin B-12
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U2 - 10.3945/jn.117.248278
DO - 10.3945/jn.117.248278
M3 - Article
C2 - 28794205
AN - SCOPUS:85030539433
SN - 0022-3166
VL - 147
SP - 1839
EP - 1849
JO - Journal of Nutrition
JF - Journal of Nutrition
IS - 10
ER -