Recommendations For Folate Intake Research Articles

Folate Transporters Are Found Throughout the Colon of Humans and Their mRNA Expression Appears to Be Unaffected by Low Dose Folic Acid Supplementation

ObjectivesA large depot of folate resides in the colon and can exceed dietary intake. Little is known about the capacity of the colon to absorb folate. We aimed to determine the expression of key folate transporters, reduced folate carrier (RFC) and proton-coupled folate transporter (PCFT), throughout the colon of healthy adults and the impact of low dose folic acid (FA) supplementation. MethodsIn this 16 wk open-labelled randomized control trial, healthy adults (n = 25) from a colonoscopy waiting list were randomized to receive daily a multivitamin plus a 400 μg FA (400FA, n = 12) or no FA supplement (0FA, n = 13). Subjects were provided with low FA bread and pasta and instructions how to follow a low FA containing diet. Six 24-hr diet recalls were administered throughout the study and blood samples were collected at baseline, 8 and 16 wk. At colonoscopy (16 wk), 4 tissue biopsies were collected from the terminal ileum, cecum, ascending and descending colon. Blood folates were determined by microbial assay; mRNA levels of folate transporters were assessed using qPCR. ResultsOne subject was removed from analysis due to missing data (0FA). No group differences in age, sex, BMI, dietary intake, vitamin B12, red blood cell (RBC) and plasma folate levels at baseline were observed. Mean ± SD FA supplement adherence was 92 ± 12% and 96 ± 9% at 8 and 16 wk, respectively. Subjects in the 400FA group had higher total folate intake (P < 0.05) and higher RBC and plasma folate levels (P < 0.01) at 8 and 16 wk compared to 0FA subjects. RBC values at 16 wk were 1764 ± 636 and 865 ± 190 nmol/L in the 400FA and 0FA group, respectively. RFC and PCFT were detected in terminal ileum and colon biopsies (n = 96) and their mRNA levels in each section did not differ between groups. However, expression of RFC was markedly higher than PCFT across all biopsy sections (P < 0.05) and highest in the terminal ileum, compared to the cecum, ascending and descending colon in both groups (P < 0.05). ConclusionsWe demonstrated expression of folate transporters, RFC and PCFT, throughout the human colon suggesting their potential contribution to overall folate absorption. mRNA expressions were not affected by a low dose FA supplement. A deeper understanding of how FA and folate status affect colonic transporter regulation may inform future revisions of folate intake recommendations. Funding SourcesNatural Sciences and Engineering Research Council.

Folate and Inflammation – links between folate and features of inflammatory conditions

Folate serves as a cofactor for one-carbon (1C) transfer reactions. These reactions are involved in the synthesis of DNA nucleotides, the amino acid methionine, and in the regulation of homocysteine (Hcy) levels. Emerging evidence suggests that these reactions have roles in the development and maintenance of inflammatory responses, with optimal folate availability having key importance in preventing endothelial dysfunction and DNA instability. Low folate levels are commonly observed in chronic inflammatory diseases, indicating that inadequate folate may be involved in the pathogenesis of inflammatory conditions or that chronic inflammation increases folate requirements. These findings highlight folate interventions as a potential treatment in inflammatory disorders. However, current understanding of folate and its influence on inflammatory phenotypes is limited. Evidence indicates that the relationship between folate and inflammation is dependent on several factors, including the timing of intervention, dosage, and interaction with environment and genes. These factors require further investigation before recommendations for folate intake can be made for the prevention and treatment of inflammation. This review outlines the emerging role of folate in inflammation and key factors that may influence this relationship.

Dietary choline and folate relationships with serum hepatic inflammatory injury markers in Taiwanese adults.

The relationships of dietary choline and folate intake with hepatic function have yet to be established in the Taiwanese population. We investigated the associations of choline and folate intake with hepatic inflammatory injury in Taiwanese adults. Blood samples and data on dietary choline components and folate intake from 548 Taiwanese adults without pathological liver disease were collected. Dietary intake was derived using a semiquantitative food-frequency questionnaire. Serum liver injury markers of alanine transaminase, aspartate transaminase, and hepatitis viral infection were measured. Elevated serum hepatic injury markers (>40 U/L) were associated with low folate and free choline intake (p<0.05). Folate intake was the most significant dietary determinant of serum aspartate transaminase concentration (beta=-0.05, p=0.04), followed by free choline intake (beta=-0.249, p=0.055). Folate intake exceeding the median level (268 μg/d) was correlated with a reduced rate of hepatitis viral infection (p=0.032) and with normalized serum aspartate transaminase (odds ratio [OR]=0.998, 95% confidence interval [CI]=0.996-1, p=0.042) and alanine transaminase (OR=0.998, 95% CI=0.007-1, p=0.019). Total choline intake exceeding the median level (233 mg/d) was associated with normalized serum aspartate transaminase (OR=0.518, 95% CI=0.360-0.745, p=0.018). The newly established relationships of dietary intake of total choline and folate with normalized hepatic inflammatory markers can guide the development of dietary choline and folate intake recommendations for Taiwanese adults.

Recommendations for folate intake in women: implications for public health strategies

Folate deficiency has been associated with anemia and other adverse outcomes in pregnancy such as neural tube defects. The current recommendations for prevention of such outcomes are difficult to achieve through diet only, and folic acid supplementation and food fortification are feasible public health strategies. However, it is necessary to determine the usual diet and supplement use among women of reproductive age, including an accurate assessment of other dietary micronutrients. In addition to the beneficial effects observed in randomized clinical trials, health risks to the population have also been widely evaluated and discussed in the scientific community: for a minority to benefit from fortification programs, many are exposed to high folic acid intake levels.

The association between serum folate and folate sub‐species with overall survival after breast cancer diagnosis

We studied the relationship between total serum folate and folate sub‐species, 5‐methyltetrahydrofolic acid (5MTHF), 5‐formyltetrahydrofolic acid (FOTS), pteroylglutamic acid (PGAS) and tetrahydrofolic acid (THFS) with overall survival after breast cancer diagnosis. Participants were post‐menopausal women diagnosed with breast cancer (n = 498) between 1994–1995 with a mean follow‐up of 80 months. Total serum folate and subspecies samples collected at or post diagnosis were measured by radio protein binding assay, and by isotope‐dilution LC/MS/MS methodology, respectively. In the Cox proportional multivariate hazards models [controlled for disease stage, age at diagnosis, body mass index (BMI), parity, ER/PR status, alcohol use and energy intake], we found that the relative risk of dying in the highest quartile for total serum folate levels was nearly 50% lower (RR: 0.56, 95% CI: 0.32–0.99) compared with all other groups (1st, 2nd and 3rd quartile). There was a borderline significant reduced risk of dying in the highest quartile of THFS, the bioactive form of folate, (RR: 0.61, 95% CI: 0.34–1.07) compared with the other quartiles. These results suggest that total folate concentrations at and/or after diagnosis were positively associated with survival after breast cancer diagnosis, and that of the folate sub‐species that contribute to total circulating folate levels, only THFS was associated with reduced risk of dying after breast cancer diagnosis, which has implications for dietary and supplemental folate intake recommendations.

Low-income women in California may be at risk of inadequate folate intake

Folate plays a major role in preventing neural tube defects in the developing fetus, as well as in reducing the risks of cardiovascular disease, certain types of cancer and some mental health problems. We assessed the folate intakes of socioeconomically disadvantaged women of childbearing age participating in California's Food Stamp Nutrition Education program. Of 195 women studied, 59% failed to meet the Institute of Medicine's folate intake recommendations for women capable of becoming pregnant. We found significant differences among the ethnic groups studied: 45% of Hispanic, 65% of white and 77% of black women did not meet the recommendation for synthetic folic acid intake. This study supports the need for developing targeted nutrition-education lessons focusing on the importance of adequate folate consumption.

Importance of folate in human nutrition.

From a public health perspective, some of the new insights into folic acid nutrition are of significance. Folate intake recommendations vary under different conditions. Intake of 350 microg is required to maintain plasma homocysteine levels, 650 microg for those with elevated plasma homocysteine, about 400 microg for women planning to become pregnant and 4000 microg for those with history of neural tube defect affected pregnancy. This raises the question whether the folate intake is adequate for the general population, particularly in the vulnerable groups or whether there is a need for scientists to take a fresh view of the requirements, recommended dietary intakes, and consider intervention measures which will have impact on the folate nutritional status. The recommendations should provide a margin of safety to allow for decreased intake, increased requirements, individual variability and bioavailability of natural food folates. The folate intake and nutriture in relation to India and other developing countries needs careful consideration to reduce anemia, neural tube defects and possibly impact on the high incidence of cardiovascular diseases.

Folate intake of the Dutch population according to newly established liquid chromatography data for foods

Determining folate intake is difficult because existing folate data in food-composition tables are scarce and unreliable. The purposes of this study were first to analyze 125 of the most important foods that contribute to folate intake in the Netherlands and second to estimate the folate intake of a representative sample of the population. We analyzed the folate content of foods by using a newly developed HPLC trienzyme method combined with an affinity chromatography cleanup step. These results were then used to estimate the folate intake of persons aged 1-92 y who participated in the second Dutch National Food Consumption Survey (DNFCS) in 1992 (n = 6218). For 35 important folate-containing foods, the mean relative folate contents measured by HPLC were 66%, 80%, and 77% of values for comparable foods included in the British food-composition table; the Ministry of Agriculture, Fisheries and Food table; and the US Department of Agriculture database, respectively. P values for comparison of relative values with 100% were 0.001, 0.171, and 0.144, respectively. The mean dietary folate intake of the DNFCS participants was 182 +/- 119 microg/d. Intake of supplement users (n = 86) was 344 microg/d, with 147 microg/d from supplements. On the basis of these findings, 42% of men and 54% of women do not meet current Dutch recommendations of 60 microg/d for children and 200 microg/d for adults. Total folate quantities in foods, analyzed by HPLC, are approximately 25% lower than amounts listed in recent food-composition tables estimated by use of the microbiological method. On the basis of these new data, approximately 50% of a representative Dutch population sample does not meet the current recommendations for folate intake.

Folate Status of Elderly Women following Moderate Folate Depletion Responds Only to a Higher Folate Intake

Dietary Reference Intakes (DRI) for folate for elderly women have been based primarily on data extrapolated from studies in younger women. This study was conducted to provide the first age-specific data in elderly women (60-85 y) from a controlled metabolic study on which to base folate intake recommendations. Subjects (n = 33) consumed a moderately folate-deplete (118 microg/d) diet for 7 wk, followed by repletion diets providing either 200 or 415 microg folate/d as diet plus folic acid (FA) or a combination of FA and orange juice (OJ) for 7 wk (n = 30). Comparisons among and within groups were made for serum folate (SF), RBC folate and plasma total homocysteine (tHcy) concentrations. SF concentrations decreased significantly (P < 0.001) during depletion (65 +/- 15%). Postrepletion, the adjusted SF concentration for subjects consuming 415 microg folate/d was significantly greater (P = 0.003) than for subjects consuming 200 microg folate/d. RBC folate concentrations decreased (P < 0.001) during depletion (21 +/- 10%) and further (P < 0.001) during repletion (5 +/- 14%). During depletion, plasma tHcy concentrations increased significantly (P < 0.001) and an inverse relationship between SF and plasma tHcy concentrations was observed in 94% of subjects (P < 0.001). Reversal of this inverse relationship was significant only for subjects consuming 415 microg folate/d (P < 0.001). Postrepletion, subjects consuming 200 microg folate/d had a significantly higher (P = 0.009) adjusted plasma tHcy concentration than subjects consuming 415 microg folate/d. These data in elderly women indicate that 415 microg/d folate, provided as a combination of diet, FA and OJ, or diet and FA, normalizes folate status more effectively than does 200 microg/d, thus providing age-specific data for future folate intake recommendations.

Thermolabile variant of 5, 10-methylenetetrahydrofolate reductaseassociated with low red-cell folates: implications for folate intake recommendations

The dietary reference values for folate, as for other nutrients, are targeted to the general and supposedly normal population, not people with special needs, such as those with genetic or metabolic abnormalities or diseases. However, 5-15% of general populations are homozygous for a thermolabile variant of 5,10-methylenetetrahydrofolate reductase (C677T) which causes mild hyperhomocysteinaemia and is positively associated with the development of vascular disease and the risk of neural-tube defects. If tissue-folate status is compromised in large sectors of the population by this or other genetic variants, the present dietary reference values may need to be changed. We identified the C677T genotype and measured red-cell folate concentrations in two groups of healthy women (pregnant, 242, not pregnant, 318). We then analysed the effect of genotype on red-cell folates, which are a reliable marker for tissue folate stores. In the pregnant group there were 20 TT homozygotes, 114 wild-type CC homozygotes, and 108 CT heterozygotes. In the non-pregnant group, the numbers were 41, 148, and 129. In both pregnant and non-pregnant groups, red-cell folate was significantly lower among TT homozygous than CC homozygous women (mean 252 [95% CI 202-317] vs 347 [321-372] micrograms/L, p = 0.002 for pregnant women; 284 [250-327] vs 347 [342-372] micrograms/L, p = 0.01 for non-pregnant women). Plasma folate was also significantly lower in TT homozygous than in CC homozygous women in the pregnant group (p = 0.009) but not in the non-pregnant group. These results suggest that a substantial minority of people in general populations may have increased folate needs. Future studies may show the presence of other common genetic variants that interact with particular nutrients and place doubts on the validity of assuming "normality" for nutrient requirements in any general population.