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The transfer of one-carbon units between molecules in metabolic pathways is essential for maintaining cellular homeostasis, but little is known about whether the circulating concentrations of metabolites involved in the one-carbon metabolism are affected by the prandial status. Epidemiological studies do not always consistently use fasting or non-fasting blood samples or may lack information on the prandial status of the study participants. Therefore, the main aim of the present study was to investigate the effects of a light breakfast on serum concentrations of selected metabolites and B-vitamins related to the one-carbon metabolism; i.e. the methionine-homocysteine cycle, the folate cycle, the choline oxidation pathway and the transsulfuration pathway. Sixty-three healthy adults (thirty-six women) with BMI ≥ 27 kg/m2 were included in the study. Blood was collected in the fasting state and 60 and 120 min after intake of a standardised breakfast consisting of white bread, margarine, white cheese, strawberry jam and orange juice (2218 kJ). The meal contained low amounts of choline, betaine, serine and vitamins B2, B3, B6, B9 and B12. Serum concentrations of total homocysteine, total cysteine, flavin mononucleotide, nicotinamide and pyridoxal 5’-phosphate were significantly decreased, and concentrations of choline, betaine, dimethylglycine, sarcosine, cystathionine and folate were significantly increased following breakfast intake (P < 0·05). Our findings demonstrate that the intake of a light breakfast with low nutrient content affected serum concentrations of several metabolites and B-vitamins related to the one-carbon metabolism.
The demand for cobalamin (vitamin B12) and folate is increased during pregnancy, and deficiency during pregnancy may lead to complications and adverse outcomes. Yet, the status of these micronutrients is unknown in many populations. We assessed the concentration of cobalamin, folate and their functional biomarkers, total homocysteine (tHcy) and methylmalonic acid (MMA), in 561 pregnant women enrolled in a community-based randomised controlled trial in Bhaktapur, Nepal. Plasma concentrations of cobalamin, folate, tHcy and MMA were measured and a combined indicator of vitamin B12 status (3cB12) was calculated. We report mean or median concentrations and the prevalence of deficiency according to commonly used cut-offs, and assessed their association with indicators of socio-economic status, and maternal and dietary characteristics by linear regression. Among the women at gestational week less than 15, deficiencies of cobalamin and folate were seen in 24 and 1 %, respectively. Being a vegetarian was associated with lower plasma cobalamin, and a higher socio-economic status was associated with a better micronutrient status. We conclude that cobalamin deficiency defined by commonly used cut-offs was common in Nepalese women in early pregnancy. In contrast, folate deficiency was rare. As there is no consensus on cut-off points for vitamin B12 deficiency during pregnancy, future studies are needed to assess the potential functional consequences of these low values.
Evidence linking fasting plasma total homocysteine (tHcy) and methylenetetrahydrofolate reductase (MTHFR) 677C>T genotype with hypertension is inconsistent. Differences in B vitamin status, other lifestyle factors or their consideration in analyses might explain this. We investigated these associations in the absence of mandatory fortification with folic acid and B vitamin supplement use. A cross-sectional study was conducted in 788 adults, aged 18–75 years, randomly selected from three Catalonian town population registers. Fasting plasma folate, cobalamin, tHcy, erythrocyte folate, erythrocyte glutathione reductase activation coefficient (EGRAC, functional riboflavin status indicator; increasing EGRAC indicates worsening riboflavin status), MTHFR 677C>T and solute carrier family 1 (SLC19A1) 80 G>A genotypes were determined. Medical history and lifestyle habits were recorded. Principal tHcy determinants differed between women (age, plasma folate, plasma cobalamin, cigarettes/d) and men (MTHFR 677TT genotype, plasma folate, plasma cobalamin and CT genotype). The MTHFR 677C>T polymorphism–tHcy association (β standardised regression coefficients) was stronger in male smokers (0·52, P < 0·001) compared with non-smokers (0·21, P = 0·001) and weaker in participants aged >50 years (0·19, P = 0·007) compared with ≤50 years (0·31, P < 0·001). Hypertension was more probable in the third tHcy tertile compared with other tertiles (OR 1·9; 95 % CI 1·2, 3·0), and in participants aged ≤50 years, for the MTHFR 677TT genotype compared with the CC genotype (OR 4·1; 95 % CI 1·0, 16·9). EGRAC was associated with increased probability of hypertension in participants aged >50 years (OR 6·2; 95 % CI 1·0, 38·7). In conclusion, moderately elevated tHcy and the MTHFR 677CT genotype were associated with hypertension. The MTHFR 677C>T genotype–hypertension association was confined to adults aged ≤50 years.
B vitamins involved in one-carbon metabolism have been implicated in the development of inflammation- and angiogenesis-related chronic diseases, such as colorectal cancer (CRC). Yet, the role of one-carbon metabolism in inflammation and angiogenesis among CRC patients remains unclear. The objective of this study was to investigate associations of components of one-carbon metabolism with inflammation and angiogenesis biomarkers among newly diagnosed CRC patients (n 238) in the prospective ColoCare Study, Heidelberg. We cross-sectionally analysed associations between twelve B vitamins and one-carbon metabolites and ten inflammation and angiogenesis biomarkers from pre-surgery serum samples using multivariable linear regression models. We further explored associations among novel biomarkers in these pathways with Spearman partial correlation analyses. We hypothesised that pyridoxal-5’-phosphate (PLP) is inversely associated with inflammatory biomarkers. We observed that PLP was inversely associated with C-reactive protein (CRP) (r –0·33, Plinear < 0·0001), serum amyloid A (SAA) (r –0·23, Plinear = 0·003), IL-6 (r –0·39, Plinear < 0·0001), IL-8 (r –0·20, Plinear = 0·02) and TNFα (r –0·12, Plinear = 0·045). Similar findings were observed for 5-methyl-tetrahydrofolate and CRP (r –0·14), SAA (r –0·14) and TNFα (r –0·15) among CRC patients. Folate catabolite acetyl-para-aminobenzoylglutamic acid (pABG) was positively correlated with IL-6 (r 0·27, Plinear < 0·0001), and pABG was positively correlated with IL-8 (r 0·21, Plinear < 0·0001), indicating higher folate utilisation during inflammation. Our data support the hypothesis of inverse associations between PLP and inflammatory biomarkers among CRC patients. A better understanding of the role and inter-relation of PLP and other one-carbon metabolites with inflammatory processes among colorectal carcinogenesis and prognosis could identify targets for future dietary guidance for CRC patients.
The bran and particularly the aleurone fraction of wheat are high in betaine and other physiological methyl donors, which may exert beneficial physiological effects. We conducted two randomised, controlled, cross-over postprandial studies to assess and compare plasma betaine and other methyl donor-related responses following the consumption of minimally processed bran and aleurone fractions (study A) and aleurone bread (study B). For both studies, standard pharmacokinetic parameters were derived for betaine, choline, folate, dimethylglycine (DMG), total homocysteine and methionine from plasma samples taken at 0, 0·5, 1, 2 and 3 h. In study A (n 14), plasma betaine concentrations were significantly and substantially elevated from 0·5 to 3 h following the consumption of both bran and aleurone compared with the control; however, aleurone gave significantly higher responses than bran. Small, but significant, increases were also observed in DMG measures; however, no significant responses were observed in other analytes. In study B (n 13), plasma betaine concentrations were significantly and substantially higher following consumption of the aleurone bread compared with the control bread; small, but significant, increases were also observed in DMG and folate measures in response to consumption of the aleurone bread; however, no significant responses were observed in other analytes. Peak plasma betaine concentrations, which were 1·7–1·8 times the baseline levels, were attained earlier following the consumption of minimally processed aleurone compared with the aleurone bread (time taken to reach peak concentration 1·2 v. 2·1 h). These results showed that the consumption of minimally processed wheat bran, and particularly the aleurone fraction, yielded substantial postprandial increases in plasma betaine concentrations. Furthermore, these effects appear to be maintained when aleurone was incorporated into bread.
Vitamins B2 and B6 are cofactors in the kynurenine pathway. Many of the kynurenines are neuroactive compounds with immunomodulatory effects. In the present study, we aimed to investigate plasma concentrations of vitamins B2 and B6 as determinants of kynurenines and two markers of interferon-γ-mediated immune activation (kynurenine:tryptophan ratio (KTR) and neopterin). We measured the concentrations of vitamins B2 and B6 vitamers, neopterin, tryptophan and six kynurenines (i.e. kynurenine, anthranilic acid, kynurenic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and xanthurenic acid) in plasma from 7051 individuals. Dietary intake of vitamins B2 and B6 was assessed using a validated FFQ. Associations were investigated using partial Spearman's correlations, generalised additive models, and segmented or multiple linear regression. The B2 vitamer, riboflavin, was positively associated with 3-hydroxyanthranilic acid and xanthurenic acid, with correlation coefficients, as obtained by segmented regression, of 0·20 (95 % CI 0·16, 0·23) and 0·24 (95 % CI 0·19, 0·28), at riboflavin concentrations below the median value (13·0 nmol/l). The vitamin B6 vitamer, pyridoxal 5′-phosphate (PLP), was positively associated with most kynurenines at PLP concentrations < 39·3–47·0 nmol/l, and inversely associated with 3-hydroxykynurenine with the association being more prominent at PLP concentrations < 18·9 nmol/l. Riboflavin and PLP were associated with xanthurenic acid only at relatively low, but normal concentrations of both vitamers. Lastly, PLP was negatively correlated with neopterin and KTR. These results demonstrate the significant and complex determination of kynurenine metabolism by vitamin status. Future studies on B-vitamins and kynurenines in relation to chronic diseases should therefore integrate data on relevant biomarkers related to B-vitamins status and tryptophan metabolism.
A combination of high folate with low vitamin B12 plasma status has been associated with cognitive impairment in a population exposed to mandatory folic acid fortification. The objective of the present study was to examine the interactions between plasma concentrations of folate and vitamin B12 markers in relation to cognitive performance in Norwegian elderly who were unexposed to mandatory or voluntary folic acid fortification. Cognitive performance was assessed by six cognitive tests in 2203 individuals aged 72–74 years. A combined score was calculated using principal component analysis. The associations of folate concentrations, vitamin B12 markers (total vitamin B12, holotranscobalamin (holoTC) and methylmalonic acid (MMA)) and their interactions in relation to cognitive performance were evaluated by quantile regression and least-squares regression, adjusted for sex, education, apo-ɛ4 genotype, history of CVD/hypertension and creatinine. Cross-sectional analyses revealed an interaction (P= 0·009) between plasma concentrations of folate and vitamin B12 in relation to cognitive performance. Plasma vitamin B12 concentrations in the lowest quartile ( < 274 pmol/l) combined with plasma folate concentrations in the highest quartile (>18·5 nmol/l) were associated with a reduced risk of cognitive impairment compared with plasma concentrations in the middle quartiles of both vitamins (OR 0·22, 95 % CI 0·05, 0·92). The interaction between folate and holoTC or MMA in relation to cognitive performance was not significant. In conclusion, this large study population unexposed to mandatory folic acid fortification showed that plasma folate, but not plasma vitamin B12, was associated with cognitive performance. Among the elderly participants with vitamin B12 concentrations in the lower range, the association between plasma folate and cognitive performance was strongest.
Choline is an essential nutrient that is found in many food sources and plays a critical role in the development of the central nervous system. Animal studies have shown that choline status pre- and postnatally can have long-lasting effects on attention and memory; however, effects in human subjects have not been well studied. The aim of the present study was to examine the association between plasma concentrations of free choline and its related metabolites in children and their neurodevelopment in the Seychelles Child Development Nutrition Study, an ongoing longitudinal study assessing the development of children born to mothers with high fish consumption during pregnancy. Plasma concentrations of free choline, betaine, dimethylglycine (DMG), methionine and homocysteine and specific measures of neurodevelopment were measured in 210 children aged 5 years. The children's plasma free choline concentration (9·17 (sd 2·09) μmol/l) was moderately, but significantly, correlated with betaine (r 0·24; P= 0·0006), DMG (r 0·15; P= 0·03), methionine (r 0·24; P= 0·0005) and homocysteine (r 0·19; P= 0·006) concentrations. Adjusted multiple linear regression revealed that betaine concentrations were positively associated with Preschool Language Scale – total language scores (β = 0·066; P= 0·04), but no other associations were evident. We found no indication that free choline concentration or its metabolites, within the normal physiological range, are associated with neurodevelopmental outcomes in children at 5 years of age. As there is considerable animal evidence suggesting that choline status during development is associated with cognitive outcome, the issue deserves further study in other cohorts.
Different lifestyle patterns across Europe may influence plasma concentrations of B-vitamins and one-carbon metabolites and their relation to chronic disease. Comparison of published data on one-carbon metabolites in Western European regions is difficult due to differences in sampling procedures and analytical methods between studies. The present study aimed, to compare plasma concentrations of one-carbon metabolites in Western European regions with one laboratory performing all biochemical analyses. We performed the present study in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort among 5446 presumptively healthy individuals. Quantile regression was used to compare sex-specific median concentrations between Northern (Denmark and Sweden), Central (France, Germany, The Netherlands and United Kingdom) and Southern (Greece, Spain and Italy) European regions. The lowest folate concentrations were observed in Northern Europe (men, 10·4 nmol/l; women, 10·7 nmol/l) and highest concentrations in Central Europe. Cobalamin concentrations were slightly higher in Northern Europe (men, 330 pmol/l; women, 352 pmol/l) compared with Central and Southern Europe, but did not show a clear north–south gradient. Vitamin B2 concentrations were highest in Northern Europe (men, 22·2 nmol/l; women, 26·0 nmol/l) and decreased towards Southern Europe (Ptrend< 0·001). Vitamin B6 concentrations were highest in Central Europe in men (77·3 nmol/l) and highest in the North among women (70·4 nmol/l), with decreasing concentrations towards Southern Europe in women (Ptrend< 0·001). In men, concentrations of serine, glycine and sarcosine increased from the north to south. In women, sarcosine increased from Northern to Southern Europe. These findings may provide relevant information for the study of regional differences of chronic disease incidence in association with lifestyle.
Choline and betaine are nutrients involved in one-carbon metabolism. Choline is essential for neurodevelopment and brain function. We studied the associations between cognitive function and plasma concentrations of free choline and betaine. In a cross-sectional study, 2195 subjects (55 % women), aged 70–74 years, underwent extensive cognitive testing including the Kendrick Object Learning Test (KOLT), Trail Making Test (part A, TMT-A), modified versions of the Digit Symbol Test (m-DST), Block Design (m-BD), Mini-Mental State Examination (m-MMSE) and Controlled Oral Word Association Test (COWAT). Compared with low concentrations, high choline (>8·4 μmol/l) was associated with better test scores in the TMT-A (56·0 v. 61·5, P= 0·004), m-DST (10·5 v. 9·8, P= 0·005) and m-MMSE (11·5 v. 11·4, P= 0·01). A generalised additive regression model showed a positive dose–response relationship between the m-MMSE and choline (P= 0·012 from a corresponding linear regression model). Betaine was associated with the KOLT, TMT-A and COWAT, but after adjustments for potential confounders, the associations lost significance. Risk ratios (RR) for poor test performance roughly tripled when low choline was combined with either low plasma vitamin B12 ( ≤ 257 pmol/l) concentrations (RRKOLT= 2·6, 95 % CI 1·1, 6·1; RRm-MMSE= 2·7, 95 % CI 1·1, 6·6; RRCOWAT= 3·1, 95 % CI 1·4, 7·2) or high methylmalonic acid (MMA) ( ≥ 3·95 μmol/l) concentrations (RRm-BD= 2·8, 95 % CI 1·3, 6·1). Low betaine ( ≤ 31·1 μmol/l) combined with high MMA was associated with elevated RR on KOLT (RRKOLT= 2·5, 95 % CI 1·0, 6·2). Low plasma free choline concentrations are associated with poor cognitive performance. There were significant interactions between low choline or betaine and low vitamin B12 or high MMA on cognitive performance.
Choline is an essential nutrient and can also be obtained by de novo synthesis via an oestrogen responsive pathway. Choline can be oxidised to the methyl donor betaine, with short-term supplementation reported to lower plasma total homocysteine (tHcy); however, the effects of longer-term choline supplementation are less clear. We investigated the effect of choline supplementation on plasma concentrations of free choline, betaine and tHcy and B-vitamin status in postmenopausal women, a group more susceptible to low choline status. We also assessed whether supplementation altered plasma lipid profiles. In this randomised, double-blinded, placebo-controlled study, forty-two healthy postmenopausal women received 1 g choline per d (as choline bitartrate), or an identical placebo supplement with their habitual diet. Fasting blood samples were collected at baseline, week 6 and week 12. Administration of choline increased median choline and betaine concentrations in plasma, with significant effects evident after 6 weeks of supplementation (P < 0·001) and remaining significant at 12 weeks (P < 0·001); no effect was observed on folate status or on plasma lipids. Choline supplementation induced a median (25th, 75th percentile) change in plasma tHcy concentration at week 6 of − 0·9 ( − 1·6, 0·2) μmol, a change which, when compared to that observed in the placebo group 0·6 ( − 0·4, 1·9) μmol, approached statistical significance (P = 0·058). Choline supplementation at a dose of 1 g/d significantly increases the circulating concentration of free choline, and can also significantly increase the concentration of the methyl donor, betaine, thereby potentially enhancing the betaine–homocysteine methyltransferase-mediated remethylation of tHcy. This trial was registered at http://www.controlled-trials.com/ISRCTN82708510.
Concerns about risks for older people with vitamin B12 deficiency have delayed the introduction of mandatory folic acid fortification in the UK. We examined the risks of anaemia and cognitive impairment in older people with low B12 and high folate status in the setting of voluntary fortification in the UK. Data were obtained from two cross-sectional studies (n 2403) conducted in Oxford city and Banbury in 1995 and 2003, respectively. Associations (OR and 95 % CI) of cognitive impairment and of anaemia with low B12 status (holotranscobalamin < 45 pmol/l) with or without high folate status (defined either as serum folate >30 nmol/l or >60 nmol/l) were estimated after adjustment for age, sex, smoking and study. Mean serum folate levels increased from 15·8 (sd 14·7) nmol/l in 1995 to 31·1 (sd 26·2) nmol/l in 2003. Serum folate levels were greater than 30 nmol/l in 9 % and greater than 60 nmol/l in 5 %. The association of cognitive impairment with low B12 status was unaffected by high v. low folate status (>30 nmol/l) (OR 1·50 (95 % CI 0·91, 2·46) v. 1·45 (95 % CI 1·19, 1·76)), respectively. The associations of cognitive impairment with low B12 status were also similar using the higher cut-off point of 60 nmol/l for folate status ((OR 2·46; 95 % CI 0·90, 6·71) v. (1·56; 95 % CI 1·30, 1·88)). There was no evidence of modification by high folate status of the associations of low B12 with anaemia or cognitive impairment in the setting of voluntary fortification, but periodic surveys are needed to monitor fortification.
The importance of the one-carbon metabolites, choline and homocysteine, to brain function is well known. However, the associations between the one-carbon metabolites choline, betaine, methionine and dimethylglycine with cognition in elderly are unclear. We therefore examined the associations of these metabolites with cognition in a double-blind, placebo-controlled trial. Individuals (n 195) were randomized to receive daily oral capsules with either 1000 μg cobalamin (vitamin B12), or 1000 μg cobalamin plus 400 μg folic acid, or placebo for 24 weeks. Concentrations of homocysteine, methionine, choline, betaine and dimethylglycine were assessed before and after 12 and 24 weeks of treatment. Cognitive function, including domains of attention, construction, sensomotor speed, memory and executive function, was assessed before and after 24 weeks of treatment. At baseline, elevated plasma homocysteine was associated with lower performance of attention, construction, sensomotor speed and executive function. In addition, betaine was positively associated with better performance of construction, sensomotor speed and executive function, whereas elevated concentrations of methionine were positively associated with sensomotor speed. Daily combined supplementation with cobalamin plus folic acid decreased total homocysteine concentrations by 36 %, and increased betaine concentrations by 38 %. Participants with the largest increases in betaine concentrations showed a borderline significant (P = 0·07) higher memory performance compared to those without it. Although this trial observed associations of homocysteine and betaine with cognitive domains prior to supplementation, decreased concentrations of homocysteine were not related to improved cognitive performance. There was a tendency of participants with the largest increases in betaine concentrations to show the greatest improvement in memory function.
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