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Nitrate and nitrite in the diet: How to assess their benefit and risk for human health
Habermeyer, M. ; Roth, A. ; Guth, S. ; Rietjens, I.M.C.M. - \ 2015
Molecular Nutrition & Food Research 59 (2015)1. - ISSN 1613-4125 - p. 106 - 128.
n-nitroso compounds - neural-tube defects - nih-aarp diet - ischemia-reperfusion injury - fluke opisthorchis-viverrini - nitrosatable drug exposure - reduces blood-pressure - colorectal-cancer risk - coronary-heart-disease - inorganic nitrate
Nitrate is a natural constituent of the human diet and an approved food additive. It can be partially converted to nitrogen monoxide, which induces vasodilation and thereby decreases blood pressure. This effect is associated with a reduced risk regarding cardiovascular disease, myocardial infarction, and stroke. Moreover, dietary nitrate has been associated with beneficial effects in patients with gastric ulcer, renal failure, or metabolic syndrome. Recent studies indicate that such beneficial health effects due to dietary nitrate may be achievable at intake levels resulting from the daily consumption of nitrate-rich vegetables. N-nitroso compounds are endogenously formed in humans. However, their relevance for human health has not been adequately explored up to now. Nitrate and nitrite are per se not carcinogenic, but under conditions that result in endogenous nitrosation, it cannot be excluded that ingested nitrate and nitrite may lead to an increased cancer risk and may probably be carcinogenic to humans. In this review, the known beneficial and detrimental health effects related to dietary nitrate/nitrite intake are described and the identified gaps in knowledge as well as the research needs required to perform a reliable benefit/risk assessment in terms of long-term human health consequences due to dietary nitrate/nitrite intake are presented.
Biomarker responses to folic acid intervention in healthy adults: a meta-analysis of randomized controlled trials
Duffy, M.E. ; Hoey, L. ; Hughes, C.F. ; Strain, J.J. ; Rankin, A. ; Souverein, O.W. ; Dullemeijer, C. ; Collings, R. ; Hooper, L. ; McNulty, H. - \ 2014
American Journal of Clinical Nutrition 99 (2014)1. - ISSN 0002-9165 - p. 96 - 106.
plasma homocysteine concentrations - neural-tube defects - folate status - older-adults - dose-response - blood folate - serum folate - young-women - stroke risk - supplementation
Background: The task of revising dietary folate recommendations for optimal health is complicated by a lack of data quantifying the biomarker response that reliably reflects a given folate intake. Objective: We conducted a dose-response meta-analysis in healthy adults to quantify the typical response of recognized folate biomarkers to a change in folic acid intake. Design: Electronic and bibliographic searches identified 19 randomized controlled trials that supplemented with folic acid and measured folate biomarkers before and after the intervention in apparently healthy adults aged >= 18 y. For each biomarker response, the regression coefficient (beta) for individual studies and the overall pooled beta were calculated by using random-effects meta-analysis. Results: Folate biomarkers (serum/plasma and red blood cell folate) increased in response to folic acid in a dose-response manner only up to an intake of 400 mu g/d. Calculation of the overall pooled beta for studies in the range of 50 to 400 mu g/d indicated that a doubling of folic acid intake resulted in an increase in serum/plasma folate by 63% (71% for microbiological assay; 61% for nonmicrobiological assay) and red blood cell folate by 31% (irrespective of whether microbiological or other assay was used). Studies that used the microbiological assay indicated lower heterogeneity compared with studies using nonmicrobiological assays for determining serum/plasma (I-2 = 13.5% compared with I-2 = 77.2%) and red blood cell (I-2 = 45.9% compared with I-2 = 70.2%) folate. Conclusions: Studies administering >400 mu g folic acid/d show no dose-response relation and thus will not yield meaningful results for consideration when generating dietary folate recommendations. The calculated folate biomarker response to a given folic acid intake may be more robust with the use of a microbiological assay rather than alternative methods for blood folate measurement.
Dietary intake and biological measurement of folate: A qualitative review of validation studies
Park, Y.H. ; Vollset, S.E. ; Boonstra, A. ; Chajes, V. ; Ueland, P.M. ; Slimani, N. - \ 2013
Molecular Nutrition & Food Research 57 (2013)4. - ISSN 1613-4125 - p. 562 - 581.
food-frequency questionnaire - neural-tube defects - plasma homocysteine concentrations - whole-blood folate - folic-acid - micronutrient intake - additional measurements - degradation-products - biochemical markers - statistical-methods
Folate is a nutrient of major health significance, but its dietary intake assessment is particularly complex to quantify through traditional approaches. Attempts have been made to validate dietary instruments for assessing folate intake against circulating concentration biomarkers. However, this requires careful attention on various methodological issues. We conducted a qualitative review of 17 recently published validation studies to identify these issues. The majority of the tested instruments were self-administered food frequency questionnaires while the biomarker most frequently used was serum/plasma folate. Seasonality was not considered in most studies. Little attention was given to using updated food composition databases based on reliable chemical methods and including fortified foods and dietary supplements. Time sequence of the test instrument and the reference biomarker used was often ambiguous, and reference periods did not always match. Correlation coefficient was the metric most commonly used, and correlations between dietary folate intake and blood folate concentration varied from weak to moderate (r = 0.05–0.54). The correlations were stronger when dietary supplement use was considered, and when serum/plasma rather than red blood cell folate was used. This review summarises issues that need to be considered in future studies intending to validate instruments for dietary folate assessment against concentration biomarkers.
Association between vitamin B12 intake and EURRECA’s prioritized biomarkers of vitamin B12 in young populations: a systematic review
Iglesia, I. ; Dhonukshe-Rutten, R.A.M. ; Bel-Serrat, S. ; Doets, E.L. ; Cavelaars, A.J.E.M. ; Veer, P. van 't; Nissenshohn, M. ; Benetou, V. ; Hermoso, M. ; Berti, C. ; Groot, C.P.G.M. de; Moreno, L.A. - \ 2013
Public Health Nutrition 16 (2013)10. - ISSN 1368-9800 - p. 1843 - 1860.
neural-tube defects - plasma homocysteine concentrations - nutrient intake values - maternal serum folate - birth-weight infants - early-pregnancy loss - folic-acid - micronutrient status - cobalamin status - school-children
Objective To review evidence on the associations between vitamin B12 intake and its biomarkers, vitamin B12 intake and its functional health outcomes, and vitamin B12 biomarkers and functional health outcomes. Design A systematic review was conducted by searching electronic databases, until January 2012, using a standardized strategy developed in the EURRECA network. Relevant articles were screened and sorted based on title and abstract, then based on full text, and finally included if they met inclusion criteria. A total of sixteen articles were included in the review. Setting Articles covered four continents: America (n 4), Europe (n 8), Africa (n 1) and Asia (n 3). Subjects Population groups included healthy infants, children and adolescents, and pregnant and lactating women. Results From the total number of 5815 papers retrieved from the initial search, only sixteen were eligible according to the inclusion criteria: five for infants, five for children and adolescents, and six for pregnant and lactating women. Conclusions Only one main conclusion could be extracted from this scarce number of references: a positive association between vitamin B12 intake and serum vitamin B12 in the infant group. Other associations were not reported in the eligible papers or the results were not provided in a consistent manner. The low number of papers that could be included in our systematic review is probably due to the attention that is currently given to research on vitamin B12 in elderly people. Our observations in the current systematic review justify the idea of performing well-designed studies on vitamin B12 in young populations.
Effect of folate intake on health outcomes in pregnancy: a systematic review and meta-analysis on birth weight, placental weight and length of gestation
Fekete, K. ; Berti, C. ; Trovato, M. ; Lohner, S. ; Dullemeijer, C. ; Souverein, O.W. ; Cetin, I. ; Decsi, T. - \ 2012
Nutrition Journal 11 (2012). - ISSN 1475-2891
folic-acid supplementation - neural-tube defects - serum folate - growth-retardation - orofacial clefts - fetal-growth - infants - risk - vitamin - mothers
The beneficial effect of folic acid supplementation before and shortly after conception is well recognized, whereas the effect of supplementation during the second and third trimesters is controversial and poorly documented. Our aims were to systematically review randomized controlled trials (RCTs) investigating the effect of folate supplementation on birth weight, placental weight and length of gestation and to assess the dose–response relationship between folate intake (folic acid plus dietary folate) and health outcomes. The MEDLINE, EMBASE and Cochrane Library CENTRAL databases were searched from inception to February 2010 for RCTs in which folate intake and health outcomes in pregnancy were investigated. We calculated the overall intake-health regression coefficient ( ß ˆ ) by using random-effects meta-analysis on a loge-loge scale. Data of 10 studies from 8 RCTs were analyzed. We found significant dose–response relationship between folate intake and birth weight (P=0.001), the overall ß ˆ was 0.03 (95% confidence interval (CI): 0.01, 0.05). This relationship indicated 2% increase in birth weight for every two-fold increase in folate intake. In contrast, we did not find any beneficial effect of folate supplementation on placental weight or on length of gestation. There is a paucity of well-conducted RCTs investigating the effect of folate supplementation on health outcomes in pregnancy. The dose–response methodology outlined in the present systematic review may be useful for designing clinical studies on folate supplementation and for developing recommendations for pregnant women.
A maternal dietary pattern characterised by fish and seafood in association with the risk of congenital heart defects in the offspring
Obermann-Borst, S.A. ; Vujkovic, M. ; Vries, J.H.M. de; Wildhagen, M.F. ; Looman, C.W. ; Jonge, R. de; Steegers, E.A.P. ; Steegers-Theunissen, R.P.M. - \ 2011
BJOG : an international journal of obstetrics and gynaecology 118 (2011)10. - ISSN 1470-0328 - p. 1205 - 1215.
folic-acid supplements - neural-tube defects - nutritional-status - gene-expression - energy-intake - homocysteine - methylation - pregnancy - methionine - period
Objective To identify maternal dietary patterns related to biomarkers of methylation and to investigate associations between these dietary patterns and the risk of congenital heart defects (CHDs) in the offspring. Design Case–control study. Setting Western part of the Netherlands, 2003–08. Population One hundred and seventy-nine mothers of children with CHD and 231 mothers of children without a congenital malformation. Methods Food intake was obtained by food frequency questionnaires. The reduced rank regression method was used to identify dietary patterns related to the biomarker concentrations of methylation in blood. Main outcome measures Dietary patterns, vitamin B and homocysteine concentrations, biomarkers of methylation (S-adenosylmethionine [SAM] and S-adenosylhomocysteine [SAH]) and the risk of CHD estimated by odds ratios and 95% confidence intervals. Results The one-carbon-poor dietary pattern, comprising a high intake of snacks, sugar-rich products and beverages, was associated with SAH (ß = 0.92, P <0.001). The one-carbon-rich dietary pattern with high fish and seafood intake was associated with SAM (ß = 0.44, P <0.001) and inversely with SAH (ß = -0.08, P <0.001). Strong adherence to this dietary pattern resulted in higher serum (P <0.05) and red blood cell (P <0.01) folate and a reduced risk of CHD in offspring: odds ratio, 0.3 (95% confidence interval, 0.2–0.6). Conclusions The one-carbon-rich dietary pattern, characterised by the high intake of fish and seafood, is associated with a reduced risk of CHD. This finding warrants further investigation in a randomised intervention trial.
Supplementation with engineered Lactococcus lactis improves the folate status in deficient rats
LeBlanc, J.G. ; Sybesma, W.F.H. ; Starrenburg, M. ; Sesma, F. ; Vos, W.M. de; Giori, G.S. de; Hugenholtz, J. - \ 2010
Nutrition 26 (2010)7. - ISSN 0899-9007 - p. 835 - 841.
neural-tube defects - folic-acid - riboflavin status - plasma homocysteine - dietary-folate - bacteria - bioavailability - prevention - vitamin - propionibacteria
Objective: The aim of this study was to establish the bioavailability of different folates produced by engineered Lactococcus lactis strains using a rodent depletion-repletion bioassay. Methods: Rats were fed a folate-deficient diet, which produces a reversible subclinical folate deficiency, supplemented with different L lactis cultures that were added as the only source of folate. Three bacterial strains that overexpressed the folC, folKE, or folC + KE genes were used. These strains produce folates with different poly glutamyl tail lengths. The growth response of the rats and the concentration of folates in different organs and blood samples were monitored. Results: The folate produced by the engineered strains was able to compensate the folate depletion in the diet and showed similar bioavailability compared with commercial folic acid that is normally used for food fortification. Folate concentrations in organ and blood samples increased significantly in animals that received the folate-producing strains compared with those that did not receive bacterial supplementation. Hematologic studies also showed that administration of the L towns strains was able to revert a partial megaloblastic anemia caused by folate deficiency. No significant differences were observed in the bioavailability of folates containing different glutamyl tail lengths. Conclusion: To our knowledge, this is the first study that demonstrated that folates produced by engineered lactic acid bacteria represent a bioavailable source of this essential vitamin. (C) 2010 Elsevier Inc. All rights reserved.
Which are the greatest recent discoveries and the greatest future challenges in nutrition?
Katan, M.B. ; Boekschoten, M.V. ; Connor, W.E. ; Mensink, R.P. ; Seidell, J. ; Vessby, B. ; Willett, W. - \ 2009
European Journal of Clinical Nutrition 63 (2009). - ISSN 0954-3007 - p. 2 - 10.
density-lipoprotein cholesterol - coronary-heart-disease - neural-tube defects - n-3 fatty-acids - dependent diabetes-mellitus - impaired glucose-tolerance - fetal origins hypothesis - serum-cholesterol - blood-pressure - beta-carotene
Background: Nutrition science aims to create new knowledge, but scientists rarely sit back to reflect on what nutrition research has achieved in recent decades. Methods: We report the outcome of a 1-day symposium at which the audience was asked to vote on the greatest discoveries in nutrition since 1976 and on the greatest challenges for the coming 30 years. Most of the 128 participants were Dutch scientists working in nutrition or related biomedical and public health fields. Candidate discoveries and challenges were nominated by five invited speakers and by members of the audience. Ballot forms were then prepared on which participants selected one discovery and one challenge. Results: A total of 15 discoveries and 14 challenges were nominated. The audience elected Folic acid prevents birth defects as the greatest discovery in nutrition science since 1976. Controlling obesity and insulin resistance through activity and diet was elected as the greatest challenge for the coming 30 years. This selection was probably biased by the interests and knowledge of the speakers and the audience. For the present review, we therefore added 12 discoveries from the period 1976 to 2006 that we judged worthy of consideration, but that had not been nominated at the meeting. Conclusions: The meeting did not represent an objective selection process, but it did demonstrate that the past 30 years have yielded major new discoveries in nutrition and health.
Bread cofortified with folic acid and vitamin B-12 improves the folate and vitamin B-12 status of healthy older people: a randomized controlled trial
Winkels, R.M. ; Brouwer, I.A. ; Clarke, R. ; Katan, M.B. ; Verhoef, P. - \ 2008
American Journal of Clinical Nutrition 88 (2008)2. - ISSN 0002-9165 - p. 348 - 355.
neural-tube defects - double-blind - homocysteine concentrations - food fortification - serum vitamin-b-12 - cognitive function - oral vitamin-b-12 - united-states - deficiency - supplementation
Background: Mandatory fortification of flour with folic acid has reduced the number of neural tube defects in North America. Concerns that high intakes of folic acid might mask vitamin B-12 deficiency in older persons have delayed the introduction of fortification in many European countries. Cofortification of flour with folic acid and vitamin B-12 could simultaneously improve folate and vitamin B-12 status. Objective: The objective was to estimate the effect of the consumption of bread fortified with modest amounts of folic acid and vitamin B-12 on folate and vitamin B-12 status in healthy older persons living in the Netherlands, where folic acid fortification is not taking place. Design: Men and women aged 50-75 y were randomly assigned in this 12-wk double-blind, placebo-controlled trial to consume bread fortified with 138 mu g folic acid and 9.6 mu g vitamin B-12 daily (n = 72) or unfortified bread (n = 70). Results: The consumption of fortified bread increased serum folate concentrations by 45% (mean: 6.3 nmol/L; 95% CI: 4.5, 8.1 nmol/L) and serum vitamin B-12 concentrations by 49% (mean: 102 pmol/L; 95% CI: 82, 122 pmol/L) relative to the placebo group. Fortified bread increased erythrocyte folate concentrations by 22% and holo-transcobalamin concentrations by 35%; it decreased homocysteine concentrations by 13% and methylmalonic acid concentrations by 10%. Consumption of fortified bread decreased the proportion of individuals with marginal serum vitamin B-12 concentrations (
Iron and zinc deficiencies in China: what is a feasible and cost-effective strategy?
Ma, G. ; Ying, J. ; Li Yanping, ; Zhai, F. ; Kok, F.J. ; Jacobsen, E. ; Yang, Xiaoguang - \ 2008
Public Health Nutrition 11 (2008)6. - ISSN 1368-9800 - p. 632 - 638.
neural-tube defects - developing-countries - food fortification - molar ratios - supplementation - nutrition - anemia - women - acid - interventions
In order to prioritise interventions for micronutrient deficiencies in China, the populations affected by iron and zinc deficiencies were assessed based on data from the 2002 China National Nutrition and Health Survey. The costs and cost-effectiveness of supplementation, food diversification and food fortification were estimated using the standard World Health Organization ingredients approach. Results indicated that 30% of children (60 years), pregnant and lactating women, and 20% of women of reproductive age were anaemic, some 245 million people. Approximately 100 million people were affected by zinc deficiency (zinc intake inadequacy and stunting), the majority living in rural areas. Among interventions on iron and zinc deficiency, biofortification showed the lowest costs per capita, I$0.01 (international dollars), while dietary diversification through health education represented the highest costs at I$1148. The cost-effectiveness of supplementation, food fortification and dietary diversification for iron deficiency alone was I$179, I$66 and I$103 per disability-adjusted life-year (DALY), respectively. Data for biofortification were not available. For zinc deficiency, the corresponding figures were I$399, I$153 and I$103 per DALY, respectively. In conclusion, iron and zinc deficiencies are of great public health concern in China. Of the two long-term intervention strategies, i.e. dietary diversification and biofortification with improved varieties, the latter is especially feasible and cost-effective for rural populations. Supplementation and fortification can be used as short-term strategies for specific groups.
The methionine synthase reductase 66A>G polymorphism is a maternal risk factor for spina bifida
Linden, I.J. van der; Heijer, M. den; Afman, L.A. ; Gellekink, H. ; Vermeulen, S.H. ; Kluijtmans, L.A.J. ; Blom, H.J. - \ 2006
Journal of Molecular Medicine 84 (2006)12. - ISSN 0946-2716 - p. 1047 - 1054.
periconceptional vitamin supplementation - neural-tube defects - plasma homocysteine - methylmalonic acid - flavoprotein - prevention - cobalamin
The methionine synthase reductase (MTRR) enzyme restores methionine synthase (MTR) enzyme activity and therefore plays an essential role in homocysteine remethylation. In some studies, the 66A>G polymorphism in the MTRR gene was associated with increased neural tube defect (NTD) risk. Using a case-control design, we studied the association between the MTRR 66A>G polymorphism and spina bifida risk in 121 mothers, 109 spina bifida patients, 292 control women, and 234 pediatric controls. Possible interactions between the MTRR 66A>G variant and the MTR 2756A>G polymorphism, the MTHFR 677C>T variant, plasma vitamin B12, and plasma methylmalonic acid (MMA) levels were examined in the 121 mothers and 292 control women. Meta-analyses were conducted to set the results of the case-control study in the context of eligible literature on the relation between the MTRR 66A>G variant and NTD risk. Finally, a transmission disequilibrium test was performed for 82 complete mother–father–child triads to test for preferential transmission of the MTRR risk allele. In our case-control study, the MTRR 66A>G polymorphism had no influence on spina bifida risk in children [odds ratio (OR) 0.6, 95% confidence interval (CI) 0.4–1.1]. The MTRR 66GG genotype increased maternal spina bifida risk by 2.1-fold (OR 2.1, 95% CI 1.3–3.3). This risk became more pronounced in combination with the MTHFR 677TT genotype (OR 4.0, 95% CI 1.3–12.5). Moreover, we demonstrate a possible interaction between the MTRR 66GG genotype and high plasma MMA levels (OR 5.5, 95% CI 2.2–13.5). The meta-analyses demonstrated that the maternal MTRR 66GG genotype was associated with an overall 55% (95% CI 1.04–2.30) increase in NTD risk and that the MTRR 66GG genotype did not increase NTD risk in children (OR 0.96, 95% CI 0.46–2.01). These data show that the MTRR 66GG genotype is a maternal risk factor for spina bifida especially when intracellular vitamin B12 status is low.
Research goals for folate and related B vitamin in Europe
Finglas, P.M. ; Meer, K. de; Molloy, A. ; Verhoef, P. ; Pietrzik, K. ; Powers, H.J. ; Straeten, D. van der; Jagerstad, M. ; Varela-Moreiras, G. ; Vliet, T. van; Havenaar, R. ; Buttriss, J. - \ 2006
European Journal of Clinical Nutrition 60 (2006)2. - ISSN 0954-3007 - p. 287 - 294.
neural-tube defects - folic-acid fortification - glutamate carboxypeptidase-ii - total homocysteine concentrations - food fortification - dietary-folate - plasma folate - older persons - united-states - prevention
In the past decade, the understanding of folate bioavailability, metabolism and related health issues has increased, but several problems remain, including the difficulty of delivering the available knowledge to the populations at risk. Owing to the low compliance of taking folic acid supplements, for example, among women of child-bearing age who could lower the risk of having a baby with a neural tube defect, food-based strategies aimed at increasing the intake of folate and other B-group vitamins should be a priority for future research. These should include the development of a combined strategy of supplemental folate ( possibly with vitamin B-12), biofortification using engineered plant-derived foods and micro-organisms and food fortification for increasing folate intakes in the general population. Currently, the most effective population-based strategy to reduce NTDs remains folic acid fortification. However, the possible adverse effect of high intakes of folic acid on neurologic functioning among elderly persons with vitamin B12 deficiency needs urgent investigation. The results of ongoing randomized controlled studies aimed at reducing the prevalence of hyperhomocysteinemia and related morbidity must be available before food-based total population approaches for treatment of hyperhomocysteinemia can be recommended. Further research is required on quantitative assessment of folate intake and bioavailability, along with a more thorough understanding of physiological, biochemical and genetic processes involved in folate absorption and metabolism.
Bioavailability of folic acid from fortified pasteurised and UHT-treated milk in humans
Jong, R.J. ; Verwei, M. ; West, C.E. ; Vliet, T. van; Siebelink, E. ; Berg, H. van den; Castenmiller, J.J.M. - \ 2005
European Journal of Clinical Nutrition 59 (2005)8. - ISSN 0954-3007 - p. 906 - 913.
folate-binding-protein - plasma homocysteine concentrations - neural-tube defects - methylenetetrahydrofolate reductase - food fortification - vascular-disease - common mutation - dietary-folate - risk factor - cows milk
Objective The aim of this study was to investigate whether milk fortified with folic acid enhances the folate status of humans and whether the presence of folate-binding proteins (FBP) in pasteurised milk affects the bioavailability of folic acid from fortified milk. In untreated and pasteurised milk, folate occurs bound to FBP, while FBP is (partly) denatured in ultra-high-temperature (UHT)-treated milk. The effect of FBP on folate bioavailability is still unclear. Design, subjects and setting Healthy, free-living subjects (n=69) aged 18-49 y participated in a 4-week double-blind, placebo-controlled dietary intervention study. Intervention In addition to a fully controlled diet, the subjects consumed each day 500 ml of pasteurised or UHT milk, either fortified or not with 200 g folic acid. Results Consumption of fortified milk increased folate concentrations in serum and in red blood cells (RBC) by 6.6-7.0 nmol/l (P
Bioavailability of polyglutamyl folic acid relative to that of monoglutamyl folic acid in subjects with different genotypes of the glutamate carboxypeptidase II gene
Boonstra, A. ; Lievers, K.J.A. ; Blom, H.J. ; Verhoef, P. - \ 2004
American Journal of Clinical Nutrition 80 (2004)3. - ISSN 0002-9165 - p. 700 - 704.
neural-tube defects - total homocysteine levels - plasma homocysteine - heart-disease - risk factor - folate - polymorphism - serum - vitamin - hyperhomocysteinemia
Background: Before dietary folate is absorbed, polyglutamate folates are deconjugated to monoglutamates by folylpoly-gamma-glutamyl carboxypeptidase in the small intestine. The 1561T allele of the glutamate carboxypeptidase II gene (GCPII), which codes for folylpoly-gamma-glutamyl carboxypeptidase, may impair intestinal absorption of dietary folates. Objective: Our aim was to study the bioavailability of polyglutamyl folic acid relative to that of monoglutamyl folic acid across GCPII 1561 genotypes. Design: In a randomized study, 180 healthy adults aged 50-75 y received 323 nmol monoglutamyl folic acid/d (n = 59), 262 nmol heptaglutamyl folic acid/d (n = 61), or placebo (n = 60) for 12 wk. Genotypes were assessed after the intervention. The bioavailability of heptaglutamyl folic acid relative to that of monoglutamyl folic acid was calculated by using the changes in serum folate concentration in the treatment groups, after correction for changes in the placebo group and for the administered dose. Results: No subjects with the TT genotype were encountered. At baseline, serum and erythrocyte folate concentrations were higher (P <0.05) in subjects with the CT genotype [16.3 nmol/L (geometric (x) over bar; 95% CI: 13.7,19.3 nmol/L) and 863 nmol/L (735,1012 nmol/L), respectively; n = 19] than in subjects with the CC genotype [ 13.7 (13.1, 14.3) and 685 (652, 721) nmol/L, respectively; n = 161]. Baseline homocysteine concentrations were not significantly different between genotypes. The bioavailability of heptaglutamyl folic acid relative to that of monoglutamyl folic acid was not significantly different between subjects with the CC (64%; 52%, 76%) and CT genotypes (70%; 49%, 91%). Conclusions: The 1561 T allele of the GCPII gene does not impair the bioavailability of polyglutamyl folic acid. However, the allele is associated with higher folate status. This association may be explained by yet unidentified factors controlling the expression of the GCPII gene.
Maternal Nutritional Status and the Risk for Orofacial Cleft Offspring in Humans
Krapels, I.P.C. ; Rooij, I.A.L.M. van; Ocké, M.C. ; West, C.E. ; Horst, C.M.A.M. van der; Steegers-Theunissen, R.P.M. - \ 2004
The Journal of Nutrition 134 (2004)11. - ISSN 0022-3166 - p. 3106 - 3113.
food frequency questionnaire - neural-tube defects - relative validity - folate intake - spina-bifida - folic-acid - life-style - pregnancy - vitamin - palate
Periconceptional folate and folic acid intake prevents orofacial clefts (OFC) in the offspring. It has been suggested that other nutrients also play a role. We investigated the preconceptional intake of macronutrients (protein, fat, carbohydrate, fiber, and cholesterol), vitamins (vitamin A, retinol, ß-carotene, ascorbic acid, and ¿-tocopherol), minerals (calcium, phosphorus, iron, magnesium, and zinc) and food groups in mothers of OFC children and controls. At ~14 mo after the index pregnancy, 206 mothers of a child with a nonsyndromic OFC and 203 control mothers completed a FFQ on current food intake and a general questionnaire. After exclusion of pregnant and lactating mothers, mothers who reported a change in diet compared with the preconceptional period, and those for whom periconceptional folic acid supplement use was unclear, 182 OFC mothers and 173 control mothers were evaluated. Macronutrient, vitamin, mineral, and food group intakes were compared. After adjustment for energy, quintiles of dietary nutrient intake and odds ratios with 95% Cl were calculated. The preconceptional intake of all macronutrients, vitamins, minerals, and food groups with the exception of milk (products), potatoes, pies/cookies were lower in OFC mothers than in controls. The energy-adjusted intakes of vegetable protein, fiber, ß-carotene, ascorbic acid, ¿-tocopherol, iron, and magnesium were significantly lower in cases compared with controls. Increasing intakes of vegetable protein, fiber, ascorbic acid, iron, and magnesium decreased OFC risk. In conclusion, a higher preconceptional intake of nutrients predominantly present in fruits and vegetables reduces the risk of offspring affected by OFC.
Quantifying folate bioavailability: a critical appraisal of methods
Boonstra, A. ; Verhoef, P. ; West, C.E. - \ 2004
Current Opinion in Clinical Nutrition and Metabolic Care 7 (2004)5. - ISSN 1363-1950 - p. 539 - 545.
neural-tube defects - plasma homocysteine concentrations - deuterium-labeled monoglutamyl - coronary-heart-disease - folic-acid - relative bioavailability - supplemental folate - alzheimers-disease - controlled-trial - healthy women
Purpose of review Dietary reference intakes for folate rely on a good estimate of folate bioavailability from the general diet. In this review, current methods for quantifying the bioavailability of dietary folate and specific folate vitamers in humans are reviewed. Emphasis is on isotopic labeling techniques that have been developed during the past 15 years. Recent findings Most reported studies applied single-dose designs, in which blood or urine concentrations of folate are measured for several hours after oral folate administration. To obtain a measurable biochemical response, however, relatively high doses of folic acid are administered and individuals are often saturated with large doses of folic acid prior to study. The effect of this on folate absorption and metabolism is poorly understood. Therefore, study designs in which multiple oral doses are administered are preferred. Several such studies, both with unlabeled and isotopically labeled folic acid, are discussed. Although many studies have been performed on the bioavailability of specific folate compounds and of folate from single foods, reliable data in which the bioavailability of folate from total diets have been measured are currently lacking. Summary A multiple oral dose design is the best approach for measuring folate bioavailability because there are several serious drawbacks to designs based on the use of a single oral dose. Studies on folate bioavailability from total diets are urgently required in order to evaluate current recommendations for folate intake.
The Binding of Folic acid and 5-methyltetrahydrofolate to Folate-Binding Proteins during Gastric Passage Differs in a dynamic in vitro gastrointestinal model
Verwei, M. ; Arkbåge, K. ; Mocking, H. ; Havenaar, R. ; Groten, J. - \ 2004
The Journal of Nutrition 134 (2004)1. - ISSN 0022-3166 - p. 31 - 37.
neural-tube defects - red-cell folate - bovine-milk - cows milk - plasma homocysteine - vascular-disease - dairy-products - dietary-folate - bioavailability - prevention
Despite its low natural folate concentration, milk is responsible for 10-15% of the daily folate intake in countries with a high dairy consumption. Milk products can be considered as a potential matrix for folate fortification, e.g., with synthetic folic acid, to enhance the daily intake of folate. In untreated milk, the natural folate, 5-methyltetrahydrofolate (5-CH3-H(4)folate), is bound to folate-binding proteins (FBP). In this study, the extent of binding to FBP for folic acid and 5-CH3-H(4)folate was investigated in a dynamic in vitro model simulating human gastric passage. Protein binding of folic acid and 5-CH3-H(4)folate was characterized using gel-exclusion chromatography. Before gastric passage, folic acid and 5-CH3-H(4)folate were bound mainly to FBP (76-79%), whereas 7% was free. Folic acid remained bound to FBP to a similar extent after gastric passage. For 5-CH3-H(4)folate, the FBP-bound fraction gradually decreased from 79 to 5% and the free fraction increased from 7 to 93%. Although folic acid enters the proximal part of the intestine bound to FBP, 5-CH3-H(4)folate appears to be present mainly as free folate in the duodenal lumen. The stability of FBP was similar in both folate/FBP mixtures, i.e., 70% of the initial FBP content was retained after gastric passage. This study indicated that FBP are partly stable during gastric passage but have different binding characteristics for folic acid and 5-CH3-H(4)folate in the duodenal lumen. This could result in different bioavailability from folic acid- and 5-CH3-H(4)folate-fortified milk products.
Effects of cultivation conditions on folate production by lactic acid bacteria
Sybesma, W. ; Starrenburg, M. ; Tijsseling, L. ; Hoefnagel, M.H.N. ; Hugenholtz, J. - \ 2003
Applied and Environmental Microbiology 69 (2003)8. - ISSN 0099-2240 - p. 4542 - 4548.
gtp cyclohydrolase-i - neural-tube defects - folic-acid - streptococcus-lactis - lactococcus-lactis - enzymatic-synthesis - purification - homocysteine - biosynthesis - strain
A variety of lactic acid bacteria were screened for their ability to produce folate intracellularly and/or extracellularly. Lactococcus lactis, Streptococcus thermophilus, and Leuconostoc spp. all produced folate, while most Lactobacillus spp., with the exception of Lactobacillus plantarum, were not able to produce folate. Folate production was further investigated in L. lactis as a model organism for metabolic engineering and in S. thermophilus for direct translation to (dairy) applications. For both these two lactic acid bacteria, an inverse relationship was observed between growth rate and folate production. When cultures were grown at inhibitory concentrations of antibiotics or salt or when the bacteria were subjected to low growth rates in chemostat cultures, folate levels in the cultures were increased relative to cell mass and (lactic) acid production. S. thermophilus excreted more folate than L. lactis, presumably as a result of differences in the number of glutamyl residues of the folate produced. In S. thermophilus 5,10-methenyl and 5-formyl tetrahydrofolate were detected as the major folate derivatives, both containing three glutamyl residues, while in L. lactis 5,10-methenyl and 10-formyl tetrahydrofolate were found, both with either four, five, or six glutamyl residues. Excretion of folate was stimulated at lower pH in S. thermophilus, but pH had no effect on folate excretion by L. lactis. Finally, several environmental parameters that influence folate production in these lactic acid bacteria were observed; high external pH increased folate production and the addition of p-aminobenzoic acid stimulated folate production, while high tyrosine concentrations led to decreased folate biosynthesis
|Bioaccessibility of Folic Acid and (6S)-5-Methyltetrahydrofolate Decreases after the Addiction of Folate-Binding Protein to Yogurt as Studied in a Dynamic In Vitro Gastrointestinal Model
Arkbåge, K. ; Verwei, M. ; Havenaar, R. ; Witthöft, C. - \ 2003
The Journal of Nutrition 133 (2003). - ISSN 0022-3166 - p. 3678 - 3683.
neural-tube defects - small-intestine - cows milk - bovine-milk - 5-methyltetrahydrofolate - bioavailability - absorption - homocysteine - transport - diets
Milk products are only moderate sources of folate. Nevertheless, they are of interest due to their content of folate-binding proteins (FBP), which in some studies have been reported to increase folate bioavailability. The effect of FBP on folate bioavailability has been widely discussed. The aim of this study was to investigate the bioaccessibility of folic acid and (6S)-5- methyltetrahydrofolate (5-CH3-H(4)folate) from fortified yogurt using a dynamic in vitro gastrointestinal model (TIM). In addition, the effect of FBP on folate bioaccessibility and the stability of FBP added to yogurt during gastrointestinal passage were investigated. Folate bioaccessibility was 82% from yogurt fortified with folic acid and 5-CH3-H(4)folate. The addition of FBP to yogurt decreased (P <0.05) folate bioaccessibility. The lowering effect of FBP was more pronounced in yogurt fortified with folic acid (34% folate bioaccessibility) than from yogurt fortified with 5-CH3-H(4)folate (57% folate bioaccessibility). After gastrointestinal passage, 17% of the FBP in yogurt fortified with 5-CH3-H(4)folate and 34% of the FBP in yogurt fortified with folic acid were recovered. No difference in folate bioaccessibility was found between folate-fortified yogurt and folate-fortified pasteurized milk (P = 0.10), whereas the lowering effect of FBP was (P <0.05) greater in yogurt compared with pasteurized milk. In conclusion, based on the high bioaccessibility of folic acid and 5-CH3-H(4)folate, yogurt without active FBP can be considered to be an appropriate food matrix for folate fortification.
Folate bioavailibility: UK Food Standards Agency workshop report
Sanderson, P. ; McNulty, H.M. ; Mastroiacovo, P. ; McDowell, I.F.W. ; Melse, A. ; Finglas, P.M. ; Gregory III, J.F. - \ 2003
The British journal of nutrition 90 (2003)2. - ISSN 0007-1145 - p. 473 - 479.
neural-tube defects - glutamate carboxypeptidase-ii - cardiovascular-disease risk - framingham offspring cohort - randomized controlled trial - folic-acid - methylenetetrahydrofolate reductase - plasma homocysteine - 5,10-methylenetetrahydrofolate reductase - supp
The UK Food Standards Agency convened a group of expert scientists to review current research investigating folate bioavailability. The workshop aimed to overview current research and establish priorities for future research. Discrepancies were observed in the evidence base for folate bioavailability, especially with regard to the relative bioavailability of natural folates compared with folic acid. A substantial body of evidence shows folic acid to have superior bioavailability relative to food folates; however, the exact relative bioavailability still needs to be determined, and in particular with regard to mixed diets. The bioavailability of folate in a mixed diet is probably not a weighted average of that in the various foods consumed; thus the workshop considered that assessment of folate bioavailability of whole diets should be a high priority for future research.