Dietary Folate Research Articles

Anti-inflammatory effects of 6S-5-methyltetrahydrofolate‐calcium on RAW264.7 cells and zebrafish

Aim6S-5-methyltetrahydrofolate is the predominant form of dietary folate in circulation and is used as a crystalline form of calcium salt (MTHF-Ca). Reports revealed that MTHF-Ca was more safe than folic acid, a synthetic and highly stable version of folate. Folic acid has been reported to have anti-inflammatory effects. The study's objective was to assess the anti-inflammatory effect of MTHF-Ca in vitro and in vivo. Main methodsIn vitro, the ROS production was assessed by H2DCFDA, and nuclear translocation of NF-κB were evaluated by the NF-κB nuclear translocation assay kit. Interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-alpha (TNF-α) were assessed using ELISA. In vivo, ROS production was assessed by H2DCFDA, neutrophils and macrophages recruitment were evaluated in tail transection-induced and CuSO4-induced zebrafish inflammation models. Expression of inflammation related genes were also investigated based on CuSO4-induced zebrafish inflammation model. Key findingsMTHF-Ca treatment decreased LPS-induced ROS production, inhibited nuclear translocation of NF-κB and decreased the levels of IL-6, IL-1β and TNF-α in RAW264.7 cells. In addition, MTHF-Ca treatment inhibited ROS production, suppressed the recruitment of neutrophils and macrophages, and reduced the expression of inflammation related genes, including jnk, erk, nf-κb, myd88, p65, tnf-α, and il-1b in zebrafish larvae. SignificanceMTHF-Ca may play an anti-inflammatory role by reducing the recruitment of neutrophils and macrophages and keeping the low levels of proinflammatory mediators and cytokines. MTHF-Ca may have a potential role in the treatment of inflammatory diseases.

Tolerability of capecitabine in difference racial/ethnic groups.

e18833 Background: Capecitabine (cap) is an oral chemotherapy agent used for treatment of solid malignancies. The recommended dose of cap generally ranges from 1000mg/m2 to 1250mg/m2 twice daily, but many patients require a dose reduction during treatment due to AE. It is unclear whether patients of different race have better tolerability of cap than others. In Asian populations for example, potential differences in tolerance have been attributed to low dietary folate intake. Race is a social construct; however it has been used to identify groups of patients within a population. We aimed to understand the tolerability of cap among patients of different racial/ethnic groups. Methods: In this retrospective chart review, we studied patients treated with cap at Tufts Medicine (three centers in MA, USA) between 2017-2021. Patients treated with cap alone, concurrent with other chemo, or concurrent with radiation for solid tumors were included. Patients were excluded if race/ethnicity data was not available. We collected demographic information, cap dose, AE, and dose reductions during the treatment period. Dose intensity (DI) was calculated (Total administered cap dose during treatment period (mg)/Recommended cap dose (mg/m2) * BSA (m2)). ANOVA was used to determine difference between groups. Results: 202 patients were included: 134 (66.3%) White, 35 (17.3%) Asian, 22 (10.9%) African American/Black, and 11 (5.4%) other race. 10 (5%) identified as Hispanic ethnicity. Most common cancer types treated were 46 (22.8%) breast, 44 (21.8%) colon, and 39 (19.3%) rectal. Average DI by race/ethnicity is outlined in Table 1. There was no statistically significant difference in DI among patients of different racial groups (p = 0.232). AEs leading to dose reduction or cap discontinuation occurred in 93 (46%) of patients, the most common outlined in Table 1. Conclusions: We found no significant difference in cap DI or toxicity among patients of different racial groups. The study is limited by the small sample size and that it is retrospective. The patients presented are racially diverse but live in one geographic area, which could impact environmental factors such as dietary folate intake. Our findings suggest that there is no difference in tolerated DI among all patients. Clinicians should not empirically reduce the dose of cap based on race and should assess tolerance on an individual basis. [Table: see text]

Association of Early Pregnancy Perfluoroalkyl and Polyfluoroalkyl Substance Exposure With Birth Outcomes

Prenatal perfluoroalkyl and polyfluoroalkyl substances (PFAS) have been linked to adverse birth outcomes. Previous research showed that higher folate concentrations are associated with lower blood PFAS concentrations in adolescents and adults. Further studies are needed to explore whether prenatal folate status mitigates PFAS-related adverse birth outcomes. To examine whether prenatal folate status modifies the negative associations between pregnancy PFAS concentrations, birth weight, and gestational age previously observed in a US cohort. In a prospective design, a prebirth cohort of mothers or pregnant women was recruited between April 1999 and November 2002, in Project Viva, a study conducted in eastern Massachusetts. Statistical analyses were performed from May 24 and October 25, 2022. Plasma concentrations of 6 PFAS compounds were measured in early pregnancy (median gestational week, 9.6). Folate status was assessed through a food frequency questionnaire and measured in plasma samples collected in early pregnancy. Birth weight and gestational age, abstracted from delivery records; birth weight z score, standardized by gestational age and infant sex; low birth weight, defined as birth weight less than 2500 g; and preterm birth, defined as birth at less than 37 completed gestational weeks. The cohort included a total of 1400 mother-singleton pairs. The mean (SD) age of the mothers was 32.21 (4.89) years. Most of the mothers were White (73.2%) and had a college degree or higher (69.1%). Early pregnancy plasma perfluorooctanoic acid concentration was associated with lower birth weight and birth weight z score only among mothers whose dietary folate intake (birth weight: β, -89.13 g; 95% CI, -166.84 to -11.42 g; birth weight z score: -0.13; 95% CI, -0.26 to -0.003) or plasma folate concentration (birth weight: -87.03 g; 95% CI, -180.11 to 6.05 g; birth weight z score: -0.14; 95% CI, -0.30 to 0.02) were below the 25th percentile (dietary: 660 μg/d, plasma: 14 ng/mL). No associations were found among mothers in the higher folate level groups, although the tests for heterogeneity did not reject the null. Associations between plasma perfluorooctane sulfonic acid and perfluorononanoate (PFNA) concentrations and lower birth weight, and between PFNA and earlier gestational age were noted only among mothers whose prenatal dietary folate intake or plasma folate concentration was in the lowest quartile range. No associations were found among mothers in higher folate status quartile groups. In this large, US prebirth cohort, early pregnancy exposure to select PFAS compounds was associated with adverse birth outcomes only among mothers below the 25th percentile of prenatal dietary or plasma folate levels.

DNA methylation as a biomarker for cardiometabolic disease risk

Abstract Funding Acknowledgements Type of funding sources: None. Cardiovascular disease (CVD) is the leading cause of death in most countries [1]. Risk factors known to predispose to the development of CVD include increasing age, male gender, diabetes mellitus, high blood cholesterol, tobacco smoking, high blood pressure (hypertension), obesity, physical inactivity, and family history [2]. Elevated plasma homocysteine is also an independent risk factor for CVD [2,3]. The mechanism by which elevated homocysteine contributes to CVD risk is not well understood, but it is well-established that dietary folate and vitamin B supplementation can reduce serum homocysteine levels by facilitating remethylation of homocysteine to methionine [4]. DNA methylation can modulate gene expression in response to exposure to various substances, such as nutrients, smoking, and environmental chemicals.Variation in healthy aging and lifespan is ascribed more to various non-genetic factors than to inherited genetic determinants, and a major goal in aging research is to reveal the epigenetic basis of aging. The remethylation cycle is essential for the systemic methyl donor supply, which is used for important biological processes, such as cytosine-5 methylation of genomic DNA, an epigenetic modification that plays an important role in maintaining genomic stability, chromatin structure, and in controlling transcriptional capacity [2,4]. Methodology/Principal Findings In this prospective study, we examined both gender patients, aged 40-50 years. Relationship between prevalence of Cardiometabolic risk factors (metabolic syndrome, oxidative stress and arterial hypertension) or its predisposing conditions (hypertrigliceridemia, dislipedimia, inusline resistance, D vitamin hipovitaminosis)) and DNA hydroximethylation was investigated. Hydroxymethylation measurement was done using a gold standard technique (liquid chromatography + mass spectrometry), the biological age equivalent was calculated by LC-MS in laboratories Reunis, to verify the potential value of DNA methylation as a CVD biomarker. Results Generally, 296 both gender patients were analyzed regarding metabolic syndrome and oxidative stress, age group 40-50 years (Me=47,1). MethylAge (DNA-hydroxymethylation) in analyzed group has average age 40,1 years old. DNA Hydroxymethylation is higher in those individuals, who has increased waist circumference, as well as, statistically significant correlation was observed between MethylAge waist circumference, metabolic syndrome and hypertriglyceridemia (p<0,05). Conclusion The evidence that the age-related changes in DNA methylation play a role in aging comes from studies of anti-aging interventions (e.g., caloric restriction, iron deficiency, dyslipidemia). Our data showed a link between premature biological ageing and waist circumference, hypertrigliceridimia. Hydroxymethylation of DNA is a good epigenetic marker for aging and risk assessment, especially in alliance with AGEs and oxidative stress research.

Folate Intake and Ovarian Cancer Risk among Women with Endometriosis: A Case-Control Study from the Ovarian Cancer Association Consortium.

Although folate intake has not been associated with an increased risk of ovarian cancer overall, studies of other cancer types have suggested that high folate intake may promote carcinogenesis in precancerous lesions. Women with endometriosis (a potential precancerous lesion) have an increased risk of developing ovarian cancer; however, whether high folate intake increases risk in this group is unknown. We conducted a pooled analysis of six case-control studies from the Ovarian Cancer Association Consortium to investigate the association between folate intake and risk of ovarian cancer among women with and without self-reported endometriosis. We included 570 cases/558 controls with and 5,171/7,559 without endometriosis. We used logistic regression to estimate odds ratios (OR) and 95% confidence intervals for the association between folate intake (dietary, supplemental, and total) and ovarian cancer risk. Finally, we used Mendelian randomization (MR) to evaluate our results using genetic markers as a proxy for folate status. Higher dietary folate intake was associated with an increased risk of ovarian cancer for women with endometriosis [OR, 1.37 (1.01-1.86)] but not for women without endometriosis. There was no association between supplemental folate intake and ovarian cancer risk for women with or without endometriosis. A similar pattern was seen using MR. High dietary folate intake may be associated with an increased risk of ovarian cancer among women with endometriosis. Women with endometriosis with high folate diets may be at increased risk of ovarian cancer. Further research is needed on the potential cancer-promoting effects of folate in this group.

Does maternal genetic liability to folate deficiency influence the risk of antiseizure medication-associated language impairment and autistic traits in children of women with epilepsy?

BackgroundPrenatal exposure to antiseizure medication (ASM) may lead to low plasma folate concentrations and is associated with impaired neurodevelopment. ObjectivesTo examine whether maternal genetic liability to folate deficiency interacts with ASM-associated risk of language impairment and autistic traits in children of women with epilepsy. MethodsWe included children of women with and without epilepsy and with available genetic data enrolled in the Norwegian Mother, Father, and Child Cohort Study. Information on ASM use, folic acid supplement use and dose, dietary folate intake, child autistic traits, and child language impairment was obtained from parent-reported questionnaires. Using logistic regression, we examined the interaction between prenatal ASM exposure and maternal genetic liability to folate deficiency expressed as polygenic risk score of low folate concentrations or maternal rs1801133 genotype (CC or CT/TT) on risk of language impairment or autistic traits. ResultsWe included 96 children of women with ASM-treated epilepsy, 131 children of women with ASM-untreated epilepsy, and 37,249 children of women without epilepsy. The polygenic risk score of low folate concentrations did not interact with the ASM-associated risk of language impairment or autistic traits in ASM-exposed children of women with epilepsy compared with ASM-unexposed children aged 1.5–8 y. ASM-exposed children had increased risk of adverse neurodevelopment regardless of maternal rs1801133 genotype {adjusted odds ratio [aOR] for language impairment aged 8 y was 2.88 [95% confidence interval (CI): 1.00, 8.26] if CC and aOR 2.88 [95% CI: 1.10, 7.53] if CT/TT genotypes}. In children of women without epilepsy aged 3 y, those with maternal rs1801133 CT/TT compared with CC genotype had increased risk of language impairment (aOR: 1.18; 95% CI: 1.05, 1.34). ConclusionsIn this cohort of pregnant women reporting widespread use of folic acid supplements, maternal genetic liability to folate deficiency did not significantly influence the ASM-associated risk of impaired neurodevelopment.

Folate and vitamin B12 usual intake and biomarker status by intake source in United States adults aged ≥19 y: NHANES 2007–2018

BackgroundFolate and vitamin B12 are important biomarkers of nutritional status of populations. ObjectivesThis study aims to estimate folate and vitamin B12 usual intakes among United States adults and examine folate and vitamin B12 biomarker status by intake source. MethodsWe analyzed data for United States adults aged ≥19 y from National Health and Nutrition Examination Survey 2007–2018 (n = 31,128), during which time voluntary corn masa flour (CMF) fortification was started. Usual intake was estimated using the National Cancer Institute method. Folate intake included folate from natural foods and folic acid from 4 sources: enriched cereal grain products (ECGPs), CMF, ready-to-eat cereals (RTEs), and folic acid–containing supplements (SUP). Vitamin B12 intake was mainly from food and supplements. ResultsThe median natural food folate intake (222 μg dietary folate equivalents (DFE)/d) was below the estimated average requirement (EAR) of 320 μg DFE/d. The proportions of those who consumed folic acid from ECGP/CMF only, ECGP/CMF + RTE, ECGP/CMF + SUP, and ECGP/CMF + RTE + SUP were 50%, 18%, 22%, and 10%, respectively. Median usual folic acid intakes (μg/d) were 236 (IQR: 152, 439) overall and 134, 313, 496, and 695 in the ECGP/CMF only, ECGP/CMF + RTE, ECGP/CMF + SUP, and ECGP/CMF + RTE + SUP folic acid consumption groups, respectively. Overall, 2.0% (95% CI: 1.7%, 2.3%) of adults, all of whom used folic acid supplements, consumed greater than the tolerable upper intake level (UL) of 1000 μg/d folic acid. The median usual vitamin B12 intake (μg/d) was 5.2 for vitamin B12 supplement nonusers and 21.8 for users. Consumption of RTE and/or supplements with folic acid was associated with higher serum and red blood cell folate concentrations. Vitamin B12 supplement users had significantly higher serum vitamin B12 concentrations. ConclusionsFolic acid fortification plays a critical role in helping United States adults meet the folate EAR. At current fortification levels, United States adults who do not consume supplements do not have the usual folic acid intake exceeding the UL.

Abstract A44: The influence of dietary one-carbon metabolites on gut dysbiosis during pre-malignant hematopoiesis

Abstract TET2 loss-of-function mutations induce a pre-malignant state known as clonal hematopoiesis of indeterminate potential (CHIP). CHIP occurs in approximately 10% of people over 65 years of age and confers a 10-fold greater risk of developing hematological malignancy. Several environmental factors, including radiation, sleep deprivation, atherosclerosis, and diet, have been associated with the expansion of pre-malignant clones in CHIP patients. Tet2-deficiency in mice has also been shown to trigger a pro-inflammatory state with increased intestinal permeability and accelerated myeloid expansion. Gut microbes exert an influence on host disease progression through the synthesis of many compounds including short-chain fatty acids (SCFAs), which promote gut barrier integrity. Dietary levels of one-carbon metabolites and cofactors, including methionine and folate, have been found to alter gut microbial composition in disease-free adults and influence SCFA production in the gut in murine models. Given the connection between diet, SCFAs and gut permeability, we sought to determine the impact of dietary one-carbon metabolites on gut microbial composition and function in a murine model of pre-malignant hematopoiesis. We performed competitive bone marrow transplantation assays in mice fed diets with altered one-carbon metabolite supplementation, such as high and low folate or methionine. We found that differential supplementation with these one-carbon metabolites did not influence the competitiveness of Tet2-deficient hematopoietic cells, however, increased dietary methionine promoted a myeloid lineage differentiation bias and an elevation in circulating pro-inflammatory cytokines. After 8 months of dietary treatment, fecal samples were collected, and shotgun sequencing was performed to examine the role of one-carbon metabolite levels on gut microbial diversity. Alterations in dietary methionine and folate caused significant changes to gut microbial composition in Tet2-deficient mice. High folate or methionine supplementation led to a decrease in the ratio of Firmicutes to Bacteroidetes and high folate supplementation was also associated with decreased alpha diversity and a decrease in SCFA-producing bacteria in the gut. These studies highlight the potential influence of dietary one-carbon metabolites on the microbiome and inflammatory microenvironment of pre-malignant hematopoiesis. Citation Format: Peter Lyon, Praveen Singh, Byron Fang, Victoria Strippoli, Sabita Roy, Luisa Cimmino. The influence of dietary one-carbon metabolites on gut dysbiosis during pre-malignant hematopoiesis [abstract]. In: Proceedings of the AACR Special Conference: Acute Myeloid Leukemia and Myelodysplastic Syndrome; 2023 Jan 23-25; Austin, TX. Philadelphia (PA): AACR; Blood Cancer Discov 2023;4(3_Suppl):Abstract nr A44.

Dietary Folic Acid Supplementation Inhibits HighFat DietInduced Body Weight Gain through Gut Microbiota-Associated Branched-Chain Amino Acids and Mitochondria in Mice.

The effects of folic acid on body weight gain in obesity and gut microbiota-associated branched-chain amino acids (BCAAs) and mitochondrial function were investigated. Three- to four-wk-old male C57BL/6J conventional (CV) and germ-free (GF) mice were fed a high-fat diet (HD), folic acid-supplemented HD (FSHD) and a normal-fat diet (ND) for 25 wk. In CV mice, the HD-induced increases in body weight and plasma BCAA concentrations, downregulated expression of genes related to BCAA catabolism (Bcat2, Bckdha, or Ppm1k), mitochondrial biogenesis (Pgc-1α, Cox1, Nd1 or Nd6), fusion (Mfn1, Mfn2 or Opa1) and mitophagy (Pink1 or Park2), and upregulated expression of the fission-associated gene Drp1 in epididymal fat were reversely corrected with FSHD feeding. In contrast, the expression of these genes in the liver was the opposite under HD feeding or folic acid supplementation. In GF mice, plasma BCAA concentrations were much less affected by HD feeding and were reduced by FSHD feeding, with almost no alterations in the expression of genes associated with BCAA catabolism and mitochondrial function. Further analysis indicated a correlation between adipose and hepatic Mt C/N and plasma BCAA concentrations, and the latter had a close association with specific gut bacteria. Therefore, dietary folic acid supplementation differentially affected body weight gain, BCAA catabolism, and mitochondrial dynamics and metabolism under HD feeding between CV and GF mice, suggesting that gut bacteria-altered BCAAs and mitochondria might partially share the responsibility for the beneficial effects of dietary folic acid on obesity.

Ischaemic stroke with multi-focal venous and arterial thrombosis due to hyperhomocysteinemia: anabolic androgenic steroid use and MTHFR c.667 C > T variant – a case report

BackgroundSeverely elevated serum homocysteine is a rare cause of ischaemic stroke and extra-cranial arterial and venous thrombosis. Several factors can lead to mild elevation of homocysteine including dietary folate and B12 deficiency, and genetic variants of the methylenetetrahydrofolate reductase (MTHFR) enzyme. The use of Anabolic androgenic steroid (AAS) is under-reported, but increasingly linked to ischaemic stroke and can raise homocysteine levels.Case ReportWe present a case of a man in his 40s with a large left middle cerebral artery (MCA) territory ischaemic stroke and combined multifocal, extracranial venous, and arterial thrombosis. His past medical history was significant for Crohn’s disease and covert use of AAS. A young stroke screen was negative except for a severely elevated total homocysteine concentration, folate and B12 deficiencies. Further tests revealed he was homozygous for the methylenetetrahydrofolate reductase enzyme thermolabile variant (MTHFR c.667 C > T). The etiology of this stroke was a hypercoagulable state induced by raised plasma homocysteine. Raised homocysteine in this case was likely multifactorial and related to chronic AAS use in combination with the homozygous MTHFR c.677 C > T thermolabile variant, folate deficiency and, vitamin B12 deficiency.ConclusionIn summary, hyperhomocysteinemia is an important potential cause of ischaemic stroke and may result from genetic, dietary, and social factors. Anabolic androgenic steroid use is an important risk factor for clinicians to consider, particularly in cases of young stroke with elevated serum homocysteine. Testing for MFTHR variants in stroke patients with raised homocysteine may be useful to guide secondary stroke prevention through adequate vitamin supplementation. Further studies looking into primary and secondary stroke prevention in the high-risk MTHFR variant cohort are necessary.

Associations between Maternal Nutrition and the Concentrations of Human Milk Oligosaccharides in a Cohort of Healthy Australian Lactating Women.

Human milk oligosaccharides (HMOs) are complex glycans associated with positive infant health outcomes. The concentrations of HMOs in the milk of lactating women are associated with substantial intra- and inter-individual differences and may be influenced by maternal physiological and/or nutrition-related factors. The primary aim of this study was to explore potential influences of short-term maternal diet and current body composition on HMO profiles in mature human milk. Milk samples were collected at 3-4 months postpartum from 101 healthy Australian women using standardised procedures, and analysed for macronutrients (lactose, fat, and protein). In addition, HMO concentrations were analysed using liquid-chromatography mass-spectrometry (LC-MS). Maternal dietary data were collected using three validated 24-h dietary recalls, and the body composition of a subgroup of mothers was assessed by DEXA scans (n = 30). Most (79%) of the women were secretor-positive. Individual nutrients were not significantly correlated with HMO concentrations after correction for multiple comparisons (p > 0.05), except for dietary folate intake. DEXA scans revealed no associations between HMO profiles and maternal body composition during established lactation. The study findings suggest a lack of clear and consistent associations between maternal nutrition and HMO concentrations in mature human milk from healthy lactating women with adequate dietary intake. The prevailing influence of genetic variation in lactating mothers may overshadow any impact of maternal nutritional and/or physiological status on HMO composition in mature human milk.

High dietary folate and low vitamin B12 in parental diet disturbs the epigenetics of imprinted genes MEST and PHLDA2 in mice placenta

To elucidate the dietary effects of vitamin B12 and folic acid on fetal and placental epigenetics, different dietary combinations of folic acid and low vitamin B12 (four groups) were fed to the animals (C57BL/6 mice), and mating was carried out within each group in the F0 generation. After weaning for 3 weeks in the F1 generation each group is divided into two sub-groups, while one group of mice was continued on the same diet (sustained group), the other was shifted to a normal diet (transient group) for 6–8 weeks (F1). Mating was carried out again within each group, and on day 20 of gestation, the maternal placenta (F1) and fetal tissues (F2) were isolated. Expression of imprinted genes and various epigenetic mechanisms, including global and gene-specific DNA methylation and post-translational histone modifications, were studied. Evaluation of mRNA levels of MEST and PHLDA2 in placental tissue revealed that their expression is maximally influenced by vitamin B12 deficiency and high folate conditions. The gene expression of MEST and PHLDA2 was found significantly decreased in the F0 generation, while over-expression was seen in BDFO dietary groups of F1 generation. These dietary combinations also resulted in DNA methylation changes in both generations, which may not play a role in gene expression regulation. However, altered histone modifications were found to be the major regulatory factor in controlling the expression of genes in the F1 generation. The imbalance of low vitamin B12 and high folate leads to increased levels of activating histone marks, contributing to increased gene expression.

Dietary folate intake and its association with longitudinal changes in cognition function

Folate (vitamin B9) is an essential co-factor for one-carbon metabolism. Controversial evidence has emerged regarding the association between folate and cognitive performance. The aim of the study was to investigate the association between baseline dietary folate intake and cognitive decline in a population exposed to mandatory fortification during a median follow-up of 8 years. Multicenter, prospective cohort study involving 15,105 public servants aged 35-74 years old, both sexes, from The Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Baseline dietary intake was assessed by a Food Frequency Questionnaire (FFQ). Six cognitive tests were performed in the three waves to assess memory, executive function and global cognition. Linear mixed-effects models were used to assess the association between dietary folate intake at baseline and changes in cognition over time. Data from 11,276 participants were analyzed. The mean (SD) age was 51.7 (9) years, 50% were women, 63% were overweight/obese, and 56% had graduated from college or more. Overall dietary folate intake was not associated with cognitive decline; neither vitamin B12 intake was a modifier of this association. General dietary supplements and specifically multivitamins use did not affect these findings. Natural food folate group was associated with a slower rate of global cognitive decline (β (95% CI): 0.001 (0.000; 0.002), P=0.015). There was no association between fortified food group and cognition scores. Overall dietary folate intake was not associated with cognitive function in this Brazilian population. However, folate naturally occurring in food sources may slow global cognitive decline.

Folate Supplementation in Women with Pre-Existing Diabetes.

Folate supplementation in the periconceptual period is the standard of care for the prevention of neural tube defects. To support dietary folate intake, some countries have introduced mandatory folic acid fortification of food products. Robust evidence supports the additional use of a low-dose folic acid supplement (0.4 mg/day) in all women from 2-3 months preconception until the end of the 12th week of gestation. For women with pre-existing diabetes, high-dose folic acid supplementation (5 mg/day) is recommended in some, but not all international guidelines. The recommendation is made based on consensus opinion and reflects the increased risk of neural tube defects in pregnant women with pre-existing diabetes. However, there is limited evidence to clarify the high-risk groups that benefit from high-dose folic acid versus those that do not. There are also some data to suggest that high-dose folic acid may be harmful to mothers and offspring, although this issue remains controversial. This narrative review explores the evidence that supports the recommendation for women with pre-existing diabetes to take high-dose folic acid in the periconceptual period. It explores the potential benefits of high-dose supplemental folate beyond the prevention of neural tube defects, and also the potential adverse impacts of high-dose folate use. These topics are considered with a specific focus on the issues that are pertinent to women with pre-existing diabetes. Based on the available evidence, a pragmatic approach to the use of folic acid supplements in women with pre-existing diabetes during the periconception period is suggested. The need for comprehensive preconception care that optimises glycaemic control and addresses other modifiable risk factors before pregnancy is emphasized.

Dose-response association between dietary folate and niacin intakes with diabetes among Chinese adults: a cross-sectional study

BackgroundThe aim of this study was to examine the relationship between dietary intake of folate and niacin and diabetes risk in Chinese adults.MethodsThis is a cross-sectional study. Demographic and anthropometric data along with information on dietary intake of vitamins were collected, and eligible participants were recruited to complete the questionnaire. A binary logistic regression analysis was conducted to examine the association between dietary intake of vitamins and diabetes risk, with adjustment for potential confounders. Non-linear dose-response relationships between dietary intake of folate and niacin and diabetes risk were also evaluated using adjusted restricted cubic splines.ResultsOf the 3106 eligible participants, 15.9% had diabetes. Median folate was significantly higher in diabetic patients than in controls (32.030 vs. 27.600 gμ), while median niacin was significantly lower (7.000 vs. 7.900 mg). After controlling for potential confounders, binary logistic regression analysis showed that each unit increase in folate intake was associated with a 1.002-fold increase in the risk of developing diabetes (odds ratio (OR) = 1.002; 95% confidence interval (CI) 1.000–1.004; P = 0.022), while each unit increase in niacin intake was associated with a 3.5% reduction in diabetes risk (OR = 0.965; 95% CI 0.944–0.986; P = 0.001). The plots of restricted cubic splines presented an atypical inverted U-shaped association between dietary intake of folate and diabetes risk.ConclusionsDiabetic patients had a low intake of vitamins, especially the B vitamins. Dietary intake of folate and niacin tended to be independently associated with the risk of diabetes. Nevertheless, this study is observational and a large-scale randomized controlled trial is yet to be conducted, which will add to the evidence of the study results.

Micronutrient supplement intakes among collegiate and masters athletes: A cross-sectional study.

In our cross-sectional study, we evaluated micronutrient supplementation intake among Collegiate and Masters Athletes. We conducted a cross-sectional study to assess micronutrient supplementation consumption in Collegiate and Masters Athletes, comparing sex and sport classification within each respective group. Micronutrient supplement consumption data were measured using a Food Frequency Questionnaire. A two-way analysis of variance was used to explore the differences among Collegiate and Masters Athletes' supplement intakes of the following vitamins and minerals: vitamins A, B6, B12, C, E, D, and calcium, folate, iron, magnesium niacin, riboflavin, selenium, thiamine, and zinc. When significant differences were found, a Bonferroni post hoc test was performed to identify specific group differences. The significance level was set a priori at p < 0.05. A total of 198 athletes (105 females and 93 males) were included in the study. Participants were 36.16 ± 12.33 years of age. Collegiate male athletes had significantly greater vitamin A [1,090.51 ± 154.72 vs. 473.93 ± 233.18 mg retinol activity equivalents (RAE)/day] (p < 0.036), folate [337.14 ± 44.79 vs. 148.67 ± 67.50 mcg dietary folate equivalents (DFE)/day] (p < 0.027), and magnesium (65.35 ± 8.28 vs. 31.28 ± 12.48 mg/day) (p < 0.031) intakes compared to Collegiate female athletes. Collegiate CrossFit Athletes (940.71 ± 157.54 mg/day) had a significantly greater vitamin C intake compared to Collegiate General Athletes (156.34 ± 67.79 mg/day) (p < 0.005), Collegiate Triathletes (88.57 ± 148.53 mg/day) (p < 0.027), Collegiate Resistance Training Athletes (74.28 ± 143.81 mg/day) (p < 0.020), and Collegiate Powerlifters (175.71 ± 128.63 mg/day) (p < 0.044). Masters females had significantly greater calcium intakes compared to Masters males (494.09 ± 65.73 vs.187.89 ± 77.23 mg/day, respectively) (p < 0.002). Collegiate Runners (41.35 ± 6.53 mg/day) had a significantly greater iron intake compared to Collegiate Powerlifters (4.50 ± 6.53 mg/day) (p < 0.024). Masters Swimmers (61.43 ± 12.10 mg/day) had significantly greater iron intakes compared to Masters General Athletes (13.97 ± 3.56 mg/day) (p < 0.014), Masters Runners (17.74 ± 2.32 mg/day) (p < 0.03), Masters Triathletes (11.95 ± 3.73 mg/day) (p < 0.008), Masters CrossFit Athletes (15.93 ± 5.36 mg/day) (p < 0.043), Masters Rowers (9.10 ± 3.36 mg/day) (p < 0.003), and Masters Cyclists (1.71 ± 9.88 mg/day) (p < 0.011). Masters Powerlifters (47.14 ± 9.65 mg/day) had significantly greater zinc intakes compared to Masters General Athletes (9.57 ± 2.84 mg/day) (p < 0.015), Masters Runners (10.67 ± 1.85 mg/day) (p < 0.017), Masters Triathletes (10.24 ± 2.98 mg/day) (p < 0.020), Masters Rowers (9.33 ± 2.68 mg/day) (p < 0.013), and Masters Cyclists (1.43 ± 7.88 mg/day) (p < 0.019). There were no other significant differences among the other micronutrient supplement intakes between the sexes or among the sport classification. We reported significant differences among female and male Collegiate and Masters Athletes. Additionally, we reported significant differences among Collegiate and Masters Athletes sport classifications. Further research should examine both dietary and micronutrient supplement intake among Collegiate and Masters Athletes to examine the extent that athletes exceed the Recommended Dietary Allowances (RDA), and the potential effects on health and performance.

Selecting a dietary supplement with appropriate dosing for 6 key nutrients in pregnancy

BackgroundMost pregnant women in the United States (US) are at risk of inadequate intake of key nutrients during pregnancy from foods alone. Current dietary supplement practices reduce risk of inadequacy for only some nutrients and induce excessive intake of other nutrients. ObjectivesOur study aimed to estimate the doses of supplementation needed to help most pregnant women achieve the recommended intake without exceeding upper limits for key prenatal nutrients and to identify US dietary supplements providing these doses. MethodsWe conducted 24-h dietary recalls in 2450 pregnant participants aged 14–50 y from 2007 to 2019. We estimated the usual intake of vitamins A and D, folate, calcium, iron, and ω-3 FAs from foods alone. We calculated the target doses of supplementation needed to shift 90% of participants to consume above the estimated average requirement and keep 90% below the tolerable upper limit. We identified products in the Dietary Supplement Label Database providing these target doses of supplementation. ResultsThe target dose for supplementation was ≥198 mcg retinol activity equivalents of total vitamin A (with ≤2063 mcg preformed retinol); 7–91 mcg vitamin D; 169–720 mcg dietary folate equivalents of folic acid; 383–943 mg calcium; 13–22 mg iron; and ≥59 mg ω-3 FAs. Out of 20,547 dietary supplements (including 421 prenatal products), 69 products (33 prenatal) contained all 6 nutrients; 7 products (2 prenatal) contained target doses for 5 nutrients. Only 1 product (not a prenatal) contained target doses for all 6 nutrients, but it currently costs ∼USD200/mo and requires 7 tablets per daily serving. ConclusionsAlmost no US dietary supplements provide key nutrients in the doses needed for pregnant women. Affordable and convenient products that fill the gap between food-based intake and estimated requirements of pregnancy without inducing excess intake are needed to support pregnant women and their offspring. Am J Clin Nutr 20XX;xx:xx–xx.

Reduced methionine synthase expression results in uracil accumulation in mitochondrial DNA and impaired oxidative capacity.

Adequate thymidylate [deoxythymidine monophosphate (dTMP) or the "T" base in DNA] levels are essential for stability of mitochondrial DNA (mtDNA) and nuclear DNA (nDNA). Folate and vitamin B12 (B12) are essential cofactors in folate-mediated one-carbon metabolism (FOCM), a metabolic network which supports synthesis of nucleotides (including dTMP) and methionine. Perturbations in FOCM impair dTMP synthesis, causing misincorporation of uracil (or a "U" base) into DNA. During B12 deficiency, cellular folate accumulates as 5-methyltetrahdryfolate (5-methyl-THF), limiting nucleotide synthesis. The purpose of this study was to determine how reduced levels of the B12-dpendent enzyme methionine synthase (MTR) and dietary folate interact to affect mtDNA integrity and mitochondrial function in mouse liver. Folate accumulation, uracil levels, mtDNA content, and oxidative phosphorylation capacity were measured in male Mtr+/+ and Mtr+/- mice weaned onto either a folate-sufficient control (C) diet (2 mg/kg folic acid) or a folate-deficient (FD) diet (lacking folic acid) for 7 weeks. Mtr heterozygosity led to increased liver 5-methyl-THF levels. Mtr+/- mice consuming the C diet also exhibited a 40-fold increase in uracil in liver mtDNA. Mtr+/- mice consuming the FD diet exhibited less uracil accumulation in liver mtDNA as compared to Mtr+/+ mice consuming the FD diet. Furthermore, Mtr+/- mice exhibited 25% lower liver mtDNA content and a 20% lower maximal oxygen consumption rates. Impairments in mitochondrial FOCM are known to lead to increased uracil in mtDNA. This study demonstrates that impaired cytosolic dTMP synthesis, induced by decreased Mtr expression, also leads to increased uracil in mtDNA.

Long-term dietary folic acid supplementation attenuated aging-induced hippocampus atrophy and promoted glucose uptake in 25-month-old rats with cognitive decline

The brain has high energy demand making it sensitive to changes in energy fuel supply. Aging shrinks brain volume, decreases glucose uptake availability of the brain, and finally, causes cognitive dysfunction. Folic acid supplementation delayed cognitive decline and neurodegeneration. However, whether folic acid affects brain energy metabolism and structural changes is unclear. The study aimed to determine if long-term dietary folic acid supplementation could alleviate age-related cognitive decline by attenuating hippocampus atrophy and promoting brain glucose uptake in Sprague-Dawley (SD) rats. According to folic acid levels in diet, 3-months old male SD rats were randomly divided into four intervention groups for 22 months in equal numbers: folic acid-deficient diet (FA-D) group, folic acid-normal diet (FA-N) group, low folic acid-supplemented diet (FA-L) group, and high folic acid-supplemented diet (FA-H) group. The results showed that serum folate concentrations decreased and serum homocysteine (Hcy) concentrations increased with age, and dietary folic acid supplementation increased serum folate concentrations and decreased Hcy concentrations at 11, 18, and 22 months of intervention. Dietary folic acid supplementation attenuated aging-induced hippocampus atrophy, which was showed by higher fractional anisotropy and lower mean diffusivity in the hippocampus, increased brain 18F-Fluorodeoxyglucose (18F-FDG) uptake, then stimulated neuronal survival, and alleviated age-related cognitive decline in SD rats. In conclusion, long-term dietary folic acid supplementation alleviated age-related cognitive decline by attenuating hippocampus atrophy and promoting brain glucose uptake in SD rats.

Dietary Folate Deficiency Promotes Lactate Metabolic Disorders to Sensitize Lung Cancer Metastasis through MTOR-Signaling-Mediated Druggable Oncotargets

Lactate metabolism plays a pivotal role in cancers but is often overlooked in lung cancer (LC). Folate deficiency has been linked to lung cancer development, but its impact on lactate metabolism and cancer malignancy is unclear. To investigate this, mice were fed either a folate-deficient (FD) or control diet and intrapleurally implanted with lung cancer cells pre-exposed to FD growth medium. Results showed that FD promoted lactate over-production and the formation of tumor oncospheroids (LCSs) with increased metastatic, migration, and invasion potential. Mice implanted with these cells and fed an FD diet developed hyperlactatemia in blood and lungs. This coincided with increased expression of hexokinase 2 (HK2), lactate dehydrogenase (LDH), and decreased expression of pyruvate dehydrogenase (PDH). Pre-treatment of the FD-LCS-implanted mice with the mTORC1 inhibitor, rapamycin, and the anti-metabolic drug metformin abolished FD/LCS-activated mTORC1 and its targets including HIF1α, HK2, LDH, and monocarboxylate transporters (MCT1 and MCT4), which coincided with the reduction in lactate disorders and prevention of LC metastasis. The findings suggest that dietary FD promotes lactate metabolic disorders that sensitize lung cancer metastasis through mTOR-signaling-mediated targets.