Impact Of Folic Acid Supplementation Research Articles

Mendelian randomization to evaluate the effect of folic acid supplement on the risk of Alzheimer disease.

We conducted a study to evaluate the impact of folic acid supplementation on the risk of Alzheimer disease (AD). A Mendelian randomization (MR) analysis model assessed the causal effects of folic acid supplementation on AD, utilizing data from recent genome-wide association studies. Effect estimates were scrutinized using various methods: inverse-variance weighted (IVW), simple mode, weighted mode, simple median, weighted median, penalized weighted median, and the MR-Egger method. The sensitivity analysis assessed heterogeneity and pleiotropy of individual single nucleotide polymorphisms (SNPs) using the IVW method with Cochran Q statistics and MR Egger intercept, respectively. Additionally, a leave-one-out sensitivity analysis determined potential SNP-driven associations. Both fixed-effect and random-effect IVW models in the MR analysis revealed a reduced risk of AD associated with folic acid supplementation (odds ratio, 0.930; 95% CI, 0.903-0.958, P < .001; odds ratio, 0.930; 95% CI, 0.910-0.950, P < .001) based on 7 SNPs as instrumental variables. The reverse MR analysis indicated no causal association between AD and folic acid supplementation. This study, utilizing genetic data, suggests that folic acid supplementation may potentially reduce the risk of AD and provides novel insights into its etiology and preventive measures.

Impact of folic acid supplementation on ischemia‒reperfusion-induced kidney injury in rats: folic acid prophylactic role revisited

Folic acid (FA), with its anti-inflammatory and antioxidant properties, may offer protection against ischemia–reperfusion (IR) injury. This study investigated whether FA safeguards rat kidneys from IR by targeting high mobility group box-1 (HMGB1), a key inflammatory mediator. Fifty adult male Wistar rats were randomly allocated into four groups: control, IR, IR + FA pretreatment, and FA alone. Compared to controls, IR significantly impaired renal function and elevated levels of malondialdehyde, HMGB1, NF-κB, and caspase 3. FA pretreatment effectively reversed these detrimental changes, protecting renal function and minimizing tissue damage. The FA-alone group showed no significant differences compared to the control group, indicating no adverse effects of FA treatment. Mechanistically, FA inhibited HMGB1 expression and its downstream activation of NF-κB and caspase 3, thereby quelling inflammation and cell death. FA shields rat kidneys from IR-induced injury by suppressing HMGB1-mediated inflammation and apoptosis, suggesting a potential therapeutic avenue for IR-associated kidney damage.

Impact of folic acid supplementation on the epigenetic profile in healthy unfortified individuals – a randomized intervention trial

ABSTRACT Folate is an essential mediator in one-carbon metabolism, which provides methyl groups for DNA synthesis and methylation. The availability of active methyl groups can be influenced by the uptake of folic acid. We conducted a randomized intervention trial to test the influence of folic acid supplementation on DNA methylation in an unfortified population in Germany. A total of 16 healthy male volunteers (age range 23–61 y) were randomized to receive either 400 μg (n = 9) or 800 μg (n = 7) folic acid supplements daily for 8 weeks. Infinium Human Methylation 450K BeadChip Microarrays were used to assay site-specific DNA methylation across the genome. Microarray analyses were conducted on PBL DNA. We estimated several epigenetic clocks and mean DNA methylation across all autosomal probes on the array. AgeAccel was estimated as the residual variation in each metric. In virtually all participants, both serum and red blood cell (RBC) folate increased successively throughout the trial period. Participants with a larger increase in RBC folate had a larger increase in DNAmAge AgeAccel (Spearman Rho: 0.56, p-value = 0.03). No notable changes in the methylome resulting from the folic acid supplementation emerged. In this population with adequate folate levels derived from diet, an increase in RBC folate had a modest impact on the epigenetic clock predicting chronologic age.

Maternal Folic Acid Supplementation during Pregnancy Prevents Hepatic Steatosis in Male Offspring of Rat Dams Fed High-Fat Diet, Which Is Associated with the Regulation of Gut Microbiota.

Maternal dietary patterns during pregnancy have been demonstrated to impact the structure of the gut microbiota in offspring, altering their susceptibility to diseases. This study is designed to elucidate whether the impact of folic acid supplementation during pregnancy on hepatic steatosis in male offspring of rat dams exposed to a high-fat diet (HFD) is related to gut-liver axis homeostasis. In this study, female rats were administered a HFD and simultaneously supplemented with 5 mg/kg folic acid throughout their pregnancy. Histopathological examination showed that folic acid supplementation effectively ameliorated hepatic lipid accumulation and inflammatory infiltrate in male offspring subjected to a maternal HFD. Maternal folic acid supplementation reduced the abundance of Desulfobacterota and the Firmicutes/Bacteroidota (F/B) ratio in male offspring. The expression of tight junction proteins in the colon was significantly upregulated, and the serum LPS level was significantly reduced. Furthermore, there was a notable reduction in the hepatic expression of the TLR4/NF-κB signaling pathway and subsequent inflammatory mediators. Spearman's correlation analysis revealed significant associations between hepatic inflammation-related indices and several gut microbiota, particularly Desulfobacterota and Lactobacillus. With a reduction in hepatic inflammation, the expression of PPAR-α was upregulated, and the expression of SREBP-1c and its downstream lipid metabolism-related genes was downregulated. In summary, folic acid supplementation during pregnancy modulates gut microbiota and enhances intestinal barrier integrity in male offspring of HFD dams. This helps reduce the LPS leakage and suppress the expression of TLR4/NF-κB pathway in the liver, thereby improving lipid metabolism disorders, and alleviating hepatic steatosis.

Non-Isolated Neural Tube Defects with Comorbid Malformations Are Responsive to Population-Level Folic Acid Supplementation in Northern China.

Simple SummaryNeural tube defects are severe congenital malformations of the central nervous system. Some cases also have comorbid malformations in other organ systems, which cause morbidity and mortality in affected individuals. Although folic acid is effective in preventing neural tube defects, whether folic acid prevents those cases which have comorbid malformations, or only isolated neural tube defects is unknown. In this study, we described the epidemiology of neural tube defects with comorbid malformations and assessed the impact of folic acid supplementation. We found the prevalence of neural tube defects with comorbid malformations decreased after population-level folic acid supplementation in northern China. Malformations of various organ systems are more common in people with neural tube defects, suggesting common etiology. For fetuses with NTDs, clinicians are also suggested to consider screening for possible comorbid congenital malformations. Objective: Comorbid congenital malformation of multiple organs may indicate a shared genetic/teratogenic causality. Folic acid supplementation reduces the population-level prevalence of isolated neural tube defects (NTDs), but whether complex cases involving independent malformations are also responsive is unknown. We aimed to describe the epidemiology of NTDs with comorbid malformations in a Chinese population and assess the impact of folic acid supplementation. Study Design: Data from five counties in Northern China were obtained between 2002 and 2021 through a population-based birth defects surveillance system. All live births, stillbirths, and terminations because of NTDs at any gestational age were recorded. NTDs were classified as spina bifida, anencephaly, or encephalocele. Isolated NTDs included spina bifida cases with presumed secondary malformations (hydrocephalus, hip dislocation, talipes). Non-isolated NTDs were those with independent concomitant malformations. Results: A total of 296,306 births and 2031 cases of NTDs were recorded from 2002–2021. A total of 4.8% of NTDs (97/2031) had comorbid defects, which primarily affected the abdominal wall (25/97), musculoskeletal system (24/97), central nervous system (22/97), and face (15/97). The relative risk of cleft lip and/or palate, limb reduction defects, hip dislocation, gastroschisis, omphalocele, hydrocephalus, and urogenital system defects was significantly greater in infants with NTDs than in the general population. Population-level folic acid supplementation significantly reduced the prevalence of both isolated and non-isolated NTDs. Conclusion: Epidemiologically, non-isolated NTDs follow similar trends as isolated cases and are responsive to primary prevention by folic acid supplementation. Various clinically-important congenital malformations are over-represented in individuals with NTDs, suggesting a common etiology.

Folic acid supplementation in pregnant women with hepatitis B surface antigen improves infant hepatitis B surface antibody mediated by infant IL-4.

Immunoprophylaxis has not completely eliminated hepatitis B virus (HBV) infection due to hyporesponsiveness to hepatitis B vaccine (HepB). We explored the impact of folic acid supplementation (FAS) in pregnant women with positive hepatitis B surface antigen (HBsAg) on their infant hepatitis B surface antibody (anti-HBs) and the mediation effect of infant interleukin-4 (IL-4). We recruited HBsAg-positive mothers and their neonates at baseline. Maternal FAS was obtained via a questionnaire, and neonatal anti-HBs and IL-4 were detected. Follow-up was performed at 11-13 months of age of infants, when anti-HBs and IL-4 were measured. We applied univariate and multivariate analyses. A mediation effect model was performed to explore the mediating role of IL-4. A total of 399 mother-neonate pairs were enrolled and 195 mother-infant pairs were eligible for this analysis. The infant anti-HBs geometric mean concentrations in the maternal FAS group were significnatly higher than those in the no-FAS group (383·8 mIU/ml, 95 % CI: 294·2 mIU/ml to 500·7 mIU/ml v. 217·0 mIU/ml, 95 % CI: 147·0 mIU/ml to 320·4 mIU/ml, z = -3·2, P = 0·001). Infants born to women who took folic acid (FA) within the first trimester were more likely to have high anti-HBs titres (adjusted β-value = 194·1, P = 0·003). The fold change in IL-4 from neonates to infants partially mediated the beneficial influence of maternal FAS on infant anti-HBs (24·7 % mediation effect) after adjusting for confounding factors. FAS during the first trimester to HBsAg-positive mothers could facilitate higher anti-HBs levels in infants aged 11-13 months partly by upregulating IL-4 in infants.

The modifying effect of the MTHFR genotype on the association between folic acid supplementation and pulse wave velocity: Findings from the CSPPT

In a subgroup analysis of the China Stroke Primary Prevention Trial, we aimed to explore the impact of folic acid supplementation on arterial stiffness and assess the modifying effect of the methylenetetrahydrofolate reductase (MTHFR) gene in Chinese patients with hypertension. This prospective study enrolled 2529 hypertensive Chinese patients. Participants were randomized to receive treatment with either a combination of enalapril and folic acid or enalapril. Brachial-ankle pulse wave velocity (PWV) was measured by trained medical staff using PWV instruments at both baseline and exit visits, approximately 5years after enrollment. This trial was registered with clinicaltrials.gov (NCT00794885). During the follow-up, change in folate was significantly and independently correlated with change in ba-PWV in study patients (β=-1.31, P<0.001). Individuals with CC genotype had a significantly greater PWV response to folic acid supplementation than did carriers of the T allele (β=-2.79, P<0.001 for CC homozygotes compared with β=-0.56, P=0.464 for TT homozygotes). The positive effect of folic acid on improved PWV was modified by the MTHFR genotype (P for interaction=0.034). In a subgroup of Chinese hypertensive patients who had received 5-year antihypertensive therapy, increases in folate status were associated with higher reductions in PWV, and individuals with the CC genotype showed greatest PWV response to folic acid supplementation.

Impact of folic acid supplementation during pregnancy on cognitive performance of children at age 11 years: preliminary results from the FASSTT Offspring study

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New Perspective on Impact of Folic Acid Supplementation during Pregnancy on Neurodevelopment/Autism in the Offspring Children - A Systematic Review.

It has been conclusively established that folic acid supplementation prior to and during early pregnancy (up to 12 weeks of gestation) can prevent neural tube defects (NTDs). We hypothesized that folate effects may extend from neuro-structural defects to alterations in neuro-behavioural and emotional skills including autism spectrum disorders (ASDs) and other developmental disorders. The objective of this review was to comprehensively evaluate evidence on the impact of folic acid on neurodevelopment other than NTDs. We conducted an online search of relevant literature compiled by the National Library of Medicine from Medline and EMBASE (searched on Dec 31, 2014: http://www.ncbi.nlm.nih.gov/entrez/query/fcgi and http://www.elsevier.com/online-tools/embase). We first created 3 files (search restricted to English literature) using the following key words: 1) folate or folic acid (171322 papers identified by this search); 2) maternal or pregnancy or pregnant or gestation or gestational or prenatal or antenatal or periconception or periconceptional (1349219 papers identified by this search); and 3) autism or autism spectrum disorders or developmental delay or development or neurodevelopment or mental or cognitive or language or personal-social or gross motor or fine motor or behaviour or intellectual or intelligence or Bayley Scale (8268145 papers identified by this search). We then merged the 3 files and reviewed the papers that addressed these three issues simultaneously. A total of 22 original papers that examined the association between folic acid supplementation in human pregnancy and neurodevelopment/autism were identified after the screening, with 15 studies showing a beneficial effect of folic acid supplementation on neurodevelopment/autism, 6 studies showed no statistically significant difference, while one study showed a harmful effect in > 5 mg folic acid supplementation/day during pregnancy. Folic acid supplementation in pregnancy may have beneficial effects on the neurodevelopment of children beyond its proven effect on NTDs.

Impact of Folic Acid Supplementation on Single- and Double-Stranded RNA Degradation in Human Colostrum and Mature Milk

Sufficient intake of folic acid is necessary for normal embryogenesis, fetal, and neonatal development. Folic acid facilitates nucleic acid internalization, and protects cellular DNA from nuclease degradation. Human milk contains enzymes, antimicrobial proteins, and antibodies, along with macrophages, that protect against infections and allergies. However, little to no information is available on the effects of folic acid supplementation on degradation of nucleic acids in human milk. In the present study, we aimed to determine the RNase activity (free and inhibitor-bound) in colostrum and mature milk, following folic acid supplementation. The study design included a total of 59 women, 27 of whom received 400 μg of folic acid daily periconceptionally and after. Folic acid supplementation increased the free RNase and polyadenylase activity following lactation. However, the increased RNase activity was not due to de novo enzyme synthesis, as the inhibitor-bound (latent) RNase activity was significantly lower and disappeared after one month. Folic acid reduced RNase activity by using double-stranded RNA as substrate. Data suggests that folic acid supplementation may improve viral RNAs degradation and mRNA degradation, but not dsRNA degradation, preserving in this way the antiviral defense.

Folate and Alzheimer: when time matters

Folate is necessary for DNA and mtDNA integrity and via folate/B12-dependent methionine cycle for methylation of multiple substrates (epigenetic DNA and enzymes) and methylation of homocysteine. During embryogenesis, folate deficiency is a risk factor for neural tube defects and late in life for cognitive decline and Alzheimer's dementia (AD). It induces several Alzheimer pathomechanisms like oxidative stress, Ca(++) influx, accumulation of hyperphosphorylated tau and β-amyloid. But impact of folic acid supplementation on prevention or delay of dementia is a matter of debate. Six out of seven randomized controlled trials (RCT) with B vitamin intervention periods between 2 and 5.4 years reported about cognitive benefits in the supplemented groups mainly for those subjects with high homocysteine or low folate levels at baseline. This review tries to demonstrate the connection between folate deficiency and AD, analyses selected epidemiologic studies and RCT on folate/B12/homocysteine with long-observation periods (≥ 2 years RCT; ≥ 4 years observational) and attempts to find explanations for the controversy in literature like short follow-up, heterogeneity of subjects concerning age, recruitment, baseline cognition, inclusion criteria and probably "misleading"(not representative for the past) folate/B12/homocysteine levels due to not reported short-term use of multivitamins or food-fortification. Population-based studies-epidemiologic and interventional-starting in the fourth decade would provide the best information about the impact of folate on later development of AD. Mandatory folate fortification areas will be important future field studies for-like neural tube defects-hopefully declining AD incidence and disproving safety concerns.

EFFECT OF FOLIC ACID SUPPLEMENTATION IN PATIENTS WITH CHRONIC HEART FAILURE: PP.1.13

Background: Patients with chronic heart failure (CHF) are characterized by endothelial dysfunction, partly due to increased oxidative stress. Since folic acid exerts potential antioxidant activity, the present study was designed to evaluate the impact of folic acid supplementation on endothelial function, as well as on markers of chronic inflammation and oxidative-stress. Methods and Results: 20 patients with CHF were included in this randomized, double blind, placebo-controlled study to receive folic acid (5 mg/day) or placebo for 1 month, on top of standard optimal therapy. Despite a significant increase in plasma folate levels (from 6.9 ± 3.2 to 163.2 ± 147.7 ng/ml, p < 0.01) and a significant reduction in homocystein plasma concentration (from 14.8 ± 3.5 to 12.0 ± 2.0 mmol/L p = 0.011) in the folate-group, endothelial function, as assessed non-invasively by flow mediated vasodilatation, was not significantly affected (from 3.8 ± 1.7% to 4.1 ± 2.1%, p = 0.64). Oxidative stress and inflammation parameters did not change significantly after folate substitution. However, 4 weeks of treatment with 5 mg folic acid significantly decreased diastolic blood pressure (DBP) as compared to baseline from 76.1 ± 12.2 to 69.5 ± 7.2mmHg; p = 0.03). A not-significant decrease in systolic blood pressure (SBP) was also observed (from 115 ± 10.5 to 111 ± 12.8mmHg; p = 0.06). There was no change in blood pressure after placebo (SBP from 113.8 ± 8.9 to 116 ± 5.1mmHg, p = 0.36 DBP from 68.9 ± 7.2 to 71.0 ± 6.9mmHg p = 0.13). Conclusion: Chronic treatment with folic acid (5 mg/day) over one month did not improve endothelial function and oxidative as well as inflammatory parameters in patients with CHF. However a significant reduction in arterial blood pressure has been observed.

Maternal folic acid supplementation to dams on marginal protein level alters brain fatty acid levels of their adult offspring

Studies on fetal programming of adult diseases have highlighted the importance of maternal nutrition during pregnancy. Folic acid and long-chain essential polyunsaturated fatty acids (LC-PUFAs) have independent effects on fetal growth. However, folic acid effects may also involve alteration of LC-PUFA metabolism. Because marginal deficiency of LC-PUFAs during critical periods of brain growth and development is associated with risks for adult diseases, it is highly relevant to investigate how maternal supplementation of such nutrients can alter brain fatty acid levels. We examined the impact of folic acid supplementation, conventionally used in maternal intervention, on brain essential fatty acid levels and plasma corticosterone concentrations in adult offspring at 11 months of age. Pregnant female rats from 4 groups (6 in each) were fed with casein diets either with 18 g protein/100 g diet (control diet) or treatment diets that were marginal in protein (MP), such as 12 g protein/100 g diet supplemented with 8 mg folic acid (FAS/MP), 12 g protein/100 g diet without folic acid (FAD/MP), or 12 g protein/100 g diet (MP) with 2 mg folic acid. Pups were weaned to a standard laboratory diet with 18 g protein/100 g diet. All male adult offspring in the FAS/MP group showed lower docosahexaenoic acid ( P < .05) as compared with control adult offspring (6.04 ± 2.28 vs 10.33 ± 0.86 g/100 g fatty acids) and higher n-6/n-3 ratio ( P < .05). Docosahexaenoic acid levels in FAS/MP adult offspring were also lower ( P < .05) when compared with the MP group. Plasma corticosterone concentrations were higher ( P < .05) in male adult offspring from the FAS/MP group compared with control as well as the MP adult offspring. Results suggest that maternal folic acid supplementation at MP intake decreased brain docosahexaenoic acid levels probably involving corticosterone increase.

Folate and the face: evaluating the evidence for the influence of folate genes on craniofacial development.

Genetics has been thought to play a crucial role in the etiology of non-syndromic cleft lip and palate (CL/P) for over 60 years, but we are still no closer to finding contributing genes. The main hindrance to the progress of CL/P genetic research is the complex multifactorial nature of the disorder with environmental factors playing a significant, if not equally important role. Thus, CL/P is the likely outcome of several developmental and biochemical events that may be different in different individuals or families. Because of the known advantages of folate therapy during pregnancy and the developmental problems that may occur when diets are folate deficient, recent research has looked toward a possible genetic explanation for susceptibility to low folate status. Several gene variants have been identified which, when combined with an inadequate diet, may impede human development, but it still remains to be seen whether these are a major contributor to CL/P. Here we review some of the current viewpoints and the possible impact of folic acid supplementation on clefting incidence.

Impact of Folic Acid Supplementation in the United States

Impact of Folic Acid Supplementation in the United States

Impact of folic acid supplementation in the United States: markedly diminished high maternal serum AFPs

Objective: Folic acid supplementation of breads and grains was implemented in the United States in 1998 to try to reduce the incidence of neural tube defects (NTDs). Complete birth registry outcome data will take several years to accumulate. Here we sought to use high maternal serum alpha-fetoprotein (MSAFP) values as a surrogate for likelihood of NTDs, both before and after folic acid supplementation. Methods: From 1997 and 2000, 61,119 AFP values were assessed for MOM at Quest Diagnostics Laboratory, Teterboro, NJ. Patients were characterized by MOM value. Results: Comparative data show a 42% decrease of patients with MOMs of 3.00+ (1.7% –1.33%). Further categorization revealed similar decreases. n ≤2.75 2.76–4.00 4.00+ n % n % n % 1997 27,020 26,330 97.4 488 1.80 202 0.75 2000 34,099 33,511 98.3 409 1.20 179 0.52 % decrease 61,119 59,841 — 897 33% 381 30% Conclusions: The introduction of folic acid supplementation has produced a profound decrease in the number of high AFPs, reflective of a decreased incidence of NTDs. This represents a highly successful public health policy for birth defect prevention.

Folic acid and human malformations: a summary and evaluation

A large body of evidence gathered over the past 30 or more years has led to the firmly established belief that deficiency of the vitamin folic acid is a cause of congenital malformations of neural tube closure. Beginning with studies showing folic acid levels of mothers of children with such defects to be low, this belief has been solidified by epidemiologic studies revealing that this consequence is prevented by maternal supplements of the vitamin from early pregnancy. The present article reviews this evidence for the purpose of examining the claims of the efficacy of folic acid in this respect. This seems to be an advantageous moment to do so, because no clear impact of folic acid supplementation and fortification on the prevalence of neural tube defects has as yet been documented; and furthermore a pause seems to have been reached in such studies. It is felt that a historical, i.e. a chronologic approach will best describe the findings, and therefore they will be considered as they unfolded.