Vitamin B12 intake and status and cognitive function in elderly people
Doets, E.L. ; Wijngaarden, J.P. van; Szczecinska, A. ; Dullemeijer, C. ; Souverein, O.W. ; Dhonukshe-Rutten, R.A.M. ; Cavelaars, A.J.E.M. ; Veer, P. van 't; Brzozowska, A.M. ; Groot, C.P.G.M. de - \ 2013
Epidemiologic Reviews 35 (2013)1. - ISSN 0193-936X - p. 2 - 21.
randomized controlled-trial - incident alzheimers-disease - placebo-controlled trial - task-force consensus - folic-acid - methylmalonic acid - older-people - serum vitamin-b-12 - dietary-folate - holo-transcobalamin
Current recommendations on vitamin B12 intake vary from 1.4 to 3.0 µg per day and are based on the amount needed for maintenance of hematologic status or on the amount needed to compensate obligatory losses. This systematic review evaluates whether the relation between vitamin B12 intake and cognitive function should be considered for underpinning vitamin B12 recommendations in the future. The authors summarized dose-response evidence from randomized controlled trials and prospective cohort studies on the relation of vitamin B12 intake and status with cognitive function in adults and elderly people. Two randomized controlled trials and 6 cohort studies showed no association or inconsistent associations between vitamin B12 intake and cognitive function. Random-effects meta-analysis showed that serum/plasma vitamin B12 (50 pmol/L) was not associated with risk of dementia (4 cohort studies), global cognition z scores (4 cohort studies), or memory z scores (4 cohort studies). Although dose-response evidence on sensitive markers of vitamin B12 status (methylmalonic acid and holotranscobalamin) was scarce, 4 of 5 cohort studies reported significant associations with risk of dementia, Alzheimer's disease, or global cognition. Current evidence on the relation between vitamin B12 intake or status and cognitive function is not sufficient for consideration in the development of vitamin B12 recommendations. Further studies should consider the selection of sensitive markers of vitamin B12 status.
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.
High folic acid increases cell turnover and lowers differentiation and iron content in human HT29 colon cancer cells
Pellis, E.P.M. ; Dommels, Y.E.M. ; Venema, D.P. ; Polanen, A. van; Lips, E. ; Baykus, H. ; Kok, F.J. ; Kampman, E. ; Keijer, J. - \ 2008
The British journal of nutrition 99 (2008)4. - ISSN 0007-1145 - p. 703 - 708.
low-density-lipoprotein - folate-deficiency - colorectal-cancer - gene-expression - dna methylation - mismatch repair - dietary-folate - apoptosis - disease - risk
Folate, a water-soluble B vitamin, is a cofactor in one-carbon metabolism and is essential for DNA synthesis, amino acid interconversion, methylation and, consequently, normal cell growth. In animals with existing pre-neoplastic and neoplastic lesions, folic acid supplementation increases the tumour burden. To identify processes that are affected by increased folic acid levels, we compared HT29 human colon cancer cells exposed to a chronic supplemental (100 ng/ml) level of folic acid to cells exposed to a normal (10 ng/ml) level of folic acid, in the presence of vitamin B12 and other micronutrients involved in the folate¿methionine cycle. In addition to higher intracellular folate levels, HT29 cells at 100 ng folic acid/ml displayed faster growth and higher metabolic activity. cDNA microarray analysis indicated an effect on cell turnover and Fe metabolism. We fully confirmed these effects at the physiological level. At 100 ng/ml, cell assays showed higher proliferation and apoptosis, while gene expression analysis and a lower E-cadherin protein expression indicated decreased differentiation. These results are in agreement with the promoting effect of folic acid supplementation on established colorectal neoplasms. The lower expression of genes related to Fe metabolism at 100 ng folic acid/ml was confirmed by lower intracellular Fe levels in the cells exposed to folic acid at 100 ng/ml. This suggests an effect of folate on Fe metabolism
Folate and colo-rectal cancer risk
Sanderson, P. ; Stone, E. ; Young-In Kim, K. ; Mathers, J. ; Kampman, E. ; Downes, C.S. ; Muir, K.R. ; Baron, J.A. - \ 2007
The British journal of nutrition 98 (2007)6. - ISSN 0007-1145 - p. 1299 - 1304.
potential chemopreventive agents - unmetabolized folic-acid - genomic dna methylation - dietary-folate - postmenopausal women - promoter methylation - adenoma recurrence - cigarette-smoking - colonic neoplasia - rat colon
The UK Food Standards Agency convened a group of expert scientists to review current research investigating folate and colo-rectal cancer risk. The workshop aimed to examine current research and establish research priorities. The timing of folate exposure with respect to carcinogenesis, as well as the dose and form of folate, were considered key issues for future research. Also, the need to study further the influence of genetically defined subgroups was highlighted for future research.
Folic Acid and Vitamin B-12 Supplementation Does Not Favorably Influence Uracil Incorporation and Promoter Methylation in Rectal Mucosa DNA of Subjects with Previous Colorectal Adenomas
Donk, M. van den; Pellis, E.P.M. ; Crott, J.W. ; Engeland, M. van; Friederich, P. ; Nagengast, F.M. ; Bergeijk, J. van; Boer, S.Y. van; Mason, J.B. ; Kok, F.J. ; Keijer, J. ; Kampman, E. - \ 2007
The Journal of Nutrition 137 (2007)9. - ISSN 0022-3166 - p. 2114 - 2120.
methylenetetrahydrofolate-reductase - folate supplementation - dietary-folate - colon-cancer - s-adenosylmethionine - c677t polymorphism - vascular-disease - tumor-suppressor - common mutation - breast-cancer
Adequate folate availability is necessary to sustain normal DNA synthesis and normal patterns of DNA methylation and these features of DNA can be modified by methylenetetrahydrofolate reductase (MTHFR) C677T genotype. This study investigated the effect of MTHFR C677T genotype and daily supplementation with 5 mg folic acid and 1.25 mg vitamin B-12 on uracil misincorporation into DNA and promoter methylation. Subjects (n = 86) with a history of colorectal adenoma and MTHFR CC or TT genotype were randomly assigned to receive folic acid plus vitamin B-12 or placebo for 6 mo. Uracil misincorporation and promoter methylation of 6 tumor suppressor and DNA repair genes were assessed in DNA from rectal biopsies at baseline and after the intervention. The biomarkers did not differ between the treated group and the placebo group after 6 mo compared with baseline. The uracil concentration of DNA increased in the treated group (5.37 fmol/µg DNA, P = 0.02), whereas it did not change in the placebo group (P = 0.42). The change from baseline of 4.01 fmol uracil/µg DNA tended to differ between the groups (P = 0.16). An increase in promoter methylation tended to occur more often in the intervention group than in the placebo group (OR = 1.67; P = 0.08). This study suggests that supplementation with high doses of folic acid and vitamin B-12 may not favorably influence uracil incorporation and promoter methylation in subjects with previous colorectal adenomas. Because such alterations may potentially increase the risk of neoplastic transformation, more research is needed to fully define the consequences of these molecular alterations
Effect of increase vegetable and fruit consumption on plasma folate and homocysteine concentrations
Bogers, R.P. ; Dagnelie, P.C. ; Bast, A. ; Leeuwen, M. van; Klaveren, J.D. van; Brandt, P.A. van den - \ 2007
Nutrition 23 (2007)2. - ISSN 0899-9007 - p. 97 - 102.
folic-acid - controlled-trial - dietary-folate - heart-disease - metaanalysis - humans - bioavailability - questionnaire - carotenoids - validity
OBJECTIVE: We assessed the effects of an intervention aimed at increasing the consumption of fruits and vegetables on plasma folate and homocysteine concentrations. METHODS: Seventy-one healthy non-smoking women (mean +/- SD 41 +/- 4 y of age) were randomized to an intervention or a control group. Participants in the intervention group (n = 36) received weekly packets containing fruits and vegetables free of charge and were asked to consume a daily amount of >/=200 g of vegetables and two pieces of fruit (the Dutch recommended intake level) over a period of 1 mo. Control subjects did not receive any intervention. RESULTS: Compared with the control group, reported fruit and vegetable intakes in the intervention group increased by 133 g/d (95% confidence interval [CI] 87-179, P <0.001) for fruits and juice and 64 g/d (95% CI 37-91, P <0.001) for vegetables and estimated folate intake from fruits and vegetables increased by 40 mug/d (95% CI 22-58, P <0.001). However, no effect was observed on plasma folate concentrations (intervention effect 0.3 nmol/L, 95% CI -1.8 to 2.8, P = 0.77) or homocysteine concentrations (intervention effect 0.26 mumol/L, 95% CI -0.34 to 0.87, P = 0.39). CONCLUSION: The results suggest that 4 wk of increased fruit and vegetable consumption to the recommended amounts may be insufficient to change plasma folate and homocysteine concentrations.
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
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.
Folic acid and 5-methyltetrahydrofolate in fortified milk are bioaccessible as determined in a dynamic in vitro gastrointestinal model
Verwei, M. ; Arkbåge, K. ; Havenaar, R. ; Berg, H. van den; Witthöft, C. ; Schaafsma, G. - \ 2003
The Journal of Nutrition 133 (2003)7. - ISSN 0022-3166 - p. 2377 - 2383.
folate-binding-protein - neural-tube defects - red-cell folate - cows milk - plasma homocysteine - small-intestine - dietary-folate - bovine-milk - bioavailability - prevention
Dairy products are a potential matrix for folate fortification to enhance folate consumption in the Western world. Milk folate-binding proteins (FBP) are especially interesting because they seem to be involved in folate bioavailability. In this study, folate bioaccessibility was investigated using a dynamic computer-controlled gastrointestinal model [TNO gastrointestinal model (TIM)]. We used both ultrahigh temperature (UHT)-processed milk and pasteurized milk, differing in endogenous FBP concentrations and fortified with folic acid or 5-methyltetrahydrofolate (5-CH3-H(4)folate). To study FBP stability during gastrointestinal passage and the effect of additional FBP on folate bioaccessibility, FBP-fortified UHT and pasteurized milk products were also tested. Folate bioaccessibility and FBP stability were measured by taking samples along the compartments of the gastrointestinal model and measuring their folate and FBP concentrations. Folate bioaccessibility from folic acid-fortified milk products without additional FBP was 58-61%. This was lower (P <0.05) than that of the 5-CH3-H(4)folate-fortified milk products (71%). Addition of FBP reduced (P <0.05) folate bioaccessibility from folic acid-fortified milk (44-51%) but not from 5-CH3-H(4)folate-fortified milk products (72%). The residual FBP levels in the folic acid- and 5-CH3-H(4)folate-fortified milk products after gastrointestinal passage were 13-16% and 0-1%, respectively, of the starting amounts subjected to TIM. In conclusion, milk seems to be a suitable carrier for folate, because both folic acid and 5-CH3-H(4)folate are easily released from the matrix and available for absorption. However, our results suggest that folic acid remains partly bound to FBP during passage through the small intestine, which reduces the bioaccessibility of folic acid from milk in this model.