Relationship between serum 5methyltetrahydrofolate status and one-carbon metabolism-related metabolites in young women

Background and objectives: One Carbon Metabolism (OCM) consists of the folate cycle and choline metabolic pathway connected to the methionine cycle, and homocysteine (Hcy) in the methionine cycle is partially metabolized by the transsulfuration pathway. In this study, we comprehensively measured OCM-related metabolites in serum of women of childbearing age and investigated how serum 5methyltetrahydrofolate (5-MTHF) concentrations are related to the choline metabolic pathway, methionine cycle, and transsulfuration pathway. Methods: In this cross-sectional study, we recruited 227 young Japanese women. Serum concentrations of 18 OCM-related metabolites (5-MTHF, folic acid, choline, betaine, dimethylglycine, methionine, S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH), total Hcy (tHcy), homocysteic acid, cystathionine, total cysteine (tCys), taurine, serine, glycine, riboflavin, pyridoxine, pyridoxamine) were measured by LC-MS/MS. The association between the concentrations of OCM-related metabolites in serum were evaluated by Spearman's rank correlation coefficient. Serum 5-MTHF concentrations were stratified into two groups, low 5-MTHF group and high 5-MTHF group, based on median values. Results: Serum 5-MTHF concentration showed a significant positive correlation with betaine in the choline metabolic pathway, SAM in the methionine cycle, and tCys in the transsulfuration pathway, respectively (ρ=0.25, ρ=0.14, ρ=0.15). In addition, 5-MTHF and betaine showed significant negative correlations with tHcy, respectively (ρ=-0.46, ρ=-0.29). Furthermore, when stratified by serum 5-MTHF concentration, the correlation coefficient between 5-MTHF and tHcy was p=0.38 and betaine and tHcy was p=-0.10 in the high 5-MTHF group. In contrast, in the low 5-MTHF group, the correlation coefficient between 5-MTHF and tHcy was p=-0.36 and betaine and tHcy was p=-0.40. The negative correlation between betaine and tHcy was stronger in the low 5-MTHF group than in the high group. Conclusions: The results of this study suggest that 5-MTHF status and the metabolic dynamics of the choline metabolic pathway, methionine cycle and transsulfuration pathway may be linked. Although tHcy is remethylated and reduced by 5-MTHF or betaine, respectively, the strength of the correlation indicates which substance is responsible for the remethylation. Our study suggests that tHcy remethylation by betaine may be enhanced in the low 5-MTHF state.