Liver has multiple functions such as detoxification, metabolism, synthesis and storage. Folate is a water-soluble vitamin B9, which participates in one-carbon transfer reactions, maintains methylation capacity, and improves oxidative stress. Folic acid is a synthetic form commonly used as a dietary supplement. The liver is the main organ for storing and metabolizing folate/folic acid, and the role of folate/folic acid in liver diseases has been widely studied. Deficiency of folate results in methylation capacity dysfunction and can induce liver disorders. However, adverse effects of excessive use of folic acid on the liver have also been reported. This review aims to explore the mechanism of folate/folic acid in different liver diseases, promote further research on folate/folic acid, and contribute to its rational clinical application.

Previous research has suggested a potential link between folic acid supplementary therapy and gastric ulcers. To investigate this relationship further, we conducted a Mendelian randomization (MR) analysis using data from the UK Biobank. Our analysis primarily employed inverse variance-weighted (IVW) methods, including both fixed-effect and random-effect models. To ensure the robustness of our findings, additional methods such as the simple median, the weighted median, and the penalized weighted median were also applied. The MR analysis aimed to explore the causal effect of FA supplementary therapy on gastric ulcers. Seven single nucleotide polymorphisms (SNPs) at genetic loci associated with FA supplementary therapy were identified. Both the random-effect and fixed-effect IVW models indicated that genetically predicted FA supplementary therapy significantly reduced the risk of gastric ulcers (OR, 0.870; 95% CI, 0.826-0.917, p<0.001). This result was consistent across other methods, with similar outcomes observed using the simple median (OR, 0.835; 95% CI, 0.773-0.901, p<0.001), the weighted median (OR, 0.854; 95% CI, 0.794-0.919, p<0.001), and the penalized weighted median (OR, 0.849; 95% CI, 0.789-0.914, p<0.001). Leave-one-out sensitivity analysis confirmed that no individual SNP significantly drove the association between FA supplementary therapy and gastric ulcers. This MR study provides genetic evidence that FA supplementary therapy may decrease the risk of gastric ulcers.

The relationship between nutrition and ageing is complex. The metabolism and synthesis of micronutrients within the gut microbiome can influence human health but is challenging to study. Furthermore, studying ageing in humans is time-consuming and difficult to control for environmental factors. Studies in model organisms can guide research efforts in this area. This review describes how the nematode Caenorhabditis elegans can be used to study how bacteria and diet influence ageing and inform follow-on studies in humans. It is known that certain bacteria accelerate ageing in C. elegans. This age-accelerating effect is prevented by inhibiting folate synthesis within the bacteria, and we propose that in the human microbiome, certain bacteria also accelerate ageing in a way that can be modulated by interfering with bacterial folate synthesis. Bacterial-derived folates do not promote ageing themselves; rather, ageing is accelerated by bacteria in some way, either through secondary metabolites or other bacterial activity, which is dependent on bacterial folate synthesis. In humans, it may be possible to inhibit bacterial folate synthesis in the human gut while maintaining healthy folate status in the body via food and supplementation. The supplement form of folic acid has a common breakdown product that can be used by bacteria to increase folate synthesis. Thus, supplementation with folic acid may not be good for health in certain circumstances such as in older people or those with an excess of proteobacteria in their microbiome. For these groups, alternative supplement strategies may be a safer way to ensure adequate folate levels.

Folate, vitamin B12, vitamin B6 and riboflavin interact by functioning as cofactors within one-carbon metabolism (OCM), a network of interrelated cellular pathways essential for numerous biological processes, including the biosynthesis of DNA, amino acid interconversions and methylation reactions. The pathways of OCM are influenced by endocrine signals and genetic polymorphisms and are particularly responsive to relevant B-vitamin intakes. Physiological changes in healthy pregnancy, leading to a steady decline in B-vitamin status, add another layer of complexity to the regulation of OCM. Although significant advances have been made to improve our understanding of these pregnancy-related changes, no specific reference ranges yet exist for B-vitamin biomarkers in pregnancy to support normal fetal growth without depleting maternal stores. The lack of pregnancy-related criteria for adequacy of B-vitamin status is in turn a major limitation in identifying pregnant women most at risk of B-vitamin deficiency. Another challenge is that the evidence is very limited to provide a basis for establishing pregnancy-specific dietary recommendations for B-vitamins to support successful pregnancy outcomes. In terms of preventing adverse outcomes, periconceptional folic acid supplementation has a proven role, established more than 30 years ago, in protecting against neural tube defect-affected pregnancies and this has been the major focus of public health policy worldwide. This review evaluates the emerging evidence for the less well recognised role of B-vitamins in preventing hypertensive disorders in pregnancy and the intergenerational effects of B-vitamins on offspring neurodevelopment and cognitive performance during childhood. We also consider the underlying biological mechanisms.

Folic acid (FA) and iodine supplements are recommended by the Ministry of Health (MOH) for pregnant and/or lactating women in New Zealand (NZ)(1). Evidence suggests that many NZ women are not just taking FA and iodine in the form of a single-nutrient supplement (SNS) but are taking FA and iodine as part of a multivitamin supplement (MVS) which may or may not contain the recommended doses, and some are using a combination of both(2). No NZ study has examined the daily dose taken from both SNS and MVS for both FA and iodine across all time periods (2, 3). The aim of this study was to investigate what nutritional supplements containing FA and iodine were taken by postpartum NZ women, preconception, during the three trimesters of pregnancy and post-partum, and examine how well the women’s supplement use aligned with the NZ MOH recommendations. This cross-sectional observational study utilised data gathered on FA and iodine supplement use from an anonymous survey between February and August 2022. Descriptive statistics including frequency and percentages were reported. Folic acid and iodine weekly intakes from SNS and MVS were calculated by multiplying the amount of nutrient in each supplement, with the number of times per day taken, and the average number of days taken per week reported. A total of 584 women were included in the analysis. In addition to the SNS for FA (0.8mg and 5mg) and iodine (150 ug), women took 28 different MVS. Fifty-eight percent (preconception; 30% from SNS, 18% from MVS, and 10% from both) and 96% (1st trimester pregnancy; 61% from SNS, 17% from MVS, and 19% from both) of women took FA containing supplements. More than 75% of women reported taking iodine containing supplements during pregnancy (1st and 2nd trimesters: 93%, 3rd trimester: 89%) and postpartum (76%).Approximately 60% took SNS, 18% took only MVS and 14% took both. Based on the MOH recommendations, only 30% (preconception) and 62% (1st trimester) achieved sufficiency of FA supplementation at 0.8mg/day; 35% (preconception) and 69% (1st trimester) achieved sufficiency of FA at 5mg/day; around 50% women achieved sufficiency of iodine supplementation at 150 µg/day during pregnancy while only 37% during postpartum. The balance either took none, an insufficient dose or a dose that exceeded the recommended dose and many took them during non-recommended periods (FA after the 1st trimester; iodine preconception). Most women reported taking FA and/or iodine containing supplements at some point before, during and after their pregnancy. However, it is concerning that a large number of women do not seem to be adhering to the MOH recommendations for FA and iodine supplementation.

We previously showed that folic acid prescriptions for any indication were associated with lower rates of suicidal behaviour. Given that future randomised clinical trials are likely to focus on psychiatric disorders carrying elevated risk for suicide, we now report on the moderating effects of prior suicidal behaviour, psychiatric diagnoses and psychotropic medications on potential antisuicidal effects of folic acid. Data were obtained from the MarketScan Commercial Claims and Encounters databases that cover 164 million insured persons from 2005–2017, from which a cohort of 866 586 patients was derived. Analysis revealed no significant moderation effects on the antisuicidal effect of folic acid. These findings indicate that the potential benefit of folic acid for preventing suicidal behaviour is comparable in psychiatric populations at higher risk of suicide and that it may be additive to any benefit from psychotropic medications.

Folic acid supplementation is recommended during pregnancy to support healthy fetal development; (6S)-5-methyltetrahydrofolic acid ((6S)-5-MTHF) is available in some commercial prenatal vitamins as an alternative to folic acid, but its effect on blood folate status during pregnancy is unknown. To address this, we randomised sixty pregnant individuals at 8–21 weeks’ gestation to 0·6 mg/d folic acid or (6S)-5-MTHF × 16 weeks. Fasting blood specimens were collected at baseline and after 16 weeks (endline). Erythrocyte and serum folate were quantified via microbiological assay (as globally recommended) and plasma unmetabolised folic acid (UMFA) via LC-MS/MS. Differences in biochemical folate markers between groups were explored using multivariable linear/quantile regression, adjusting for baseline concentrations, dietary folate intake and gestational weeks. At endline (n 54), the mean values and standard deviations (or median, inter-quartile range) of erythrocyte folate, serum folate and plasma UMFA (nmol/l) in those supplemented with (6S)-5-MTHF v. folic acid, respectively, were 1826 (sd 471) and 1998 (sd 421); 70 (sd 13) and 78 (sd 17); 0·5 (0·4, 0·8) and 1·3 (0·9, 2·1). In regression analyses, erythrocyte and serum folate did not differ by treatment group; however, concentrations of plasma UMFA in pregnancy were 0·6 nmol/l higher (95 % CI 0·2, 1·1) in those supplementing with folic acid as compared with (6S)-5-MTHF. In conclusion, supplementation with (6S)-5-MTHF may reduce plasma UMFA by ∼50 % as compared with supplementation with folic acid, the biological relevance of which is unclear. As folate is currently available for purchase in both forms, the impact of circulating maternal UMFA on perinatal outcomes needs to be determined.

Over 30 years ago it was proven beyond doubt that folic acid supplementation of mothers in early pregnancy protects against neural tube defects (NTD) in their babies. Such conclusive scientific evidence led to clear recommendations for women worldwide to take 0⋅4 mg/d folic acid before conceiving and in early pregnancy, but implementing these into effective policy has been problematic. As a result, there has been no change in the incidence of NTD in Ireland, the UK or any other European country over the 25-year period that the current strategy, recommending periconceptional folic acid supplements to women, has been in place. Thus preventable NTD are not being prevented. Notably, in September 2021, the UK government announced that starch is to be fortified with folic acid on a mandatory basis. A similar decision is now urgently needed in Ireland, where rates of NTD are among the highest in the world. A policy of mandatory folic acid fortification of food would be highly effective in preventing NTD because it reaches all women, including those who have not planned their pregnancy. International evidence shows that wherever such a policy has been introduced, it has proved to be effective in reducing rates of NTD in that country. Apart from preventing NTD, the driver of policy in the area, other potential health benefits across the lifecycle can be anticipated from folic acid fortification. Urgent action is needed on implementation of mandatory food fortification with folic acid in Ireland so that mothers and their babies can benefit.

Age-related frailty and cognitive decline are complex multidimensional conditions that significantly impact the ability of older adults to sustain functional capacity and independence. While underlying causes remain poorly understood, nutrition continually emerges as one associated risk element. Many studies have addressed the importance of adequate nutrition in delaying the onset of these conditions, but the specific role of micronutrients is not well established. The consideration of pre-frailty as an outcome variable is also limited in the current literature. In this review, we focus on the potential value of maintaining micronutrient sufficiency to sustaining the health of the ageing population. Using data from the Irish longitudinal study on ageing, we consider several vitamins known to have a high prevalence of low status in older adults and their impact on pre-frailty, frailty and cognitive impairment. They include vitamin B12 and folate, both of which are associated with multiple biological mechanisms involved in long-term health, in particular in cognitive function; vitamin D, which has been associated with increased risk of musculoskeletal disorders, depression and other chronic diseases; and the carotenoids, lutein and zeaxanthin, that may help mitigate the risk of frailty and cognitive decline via their antioxidant and anti-inflammatory properties. We show that low concentrations of folate and carotenoids are implicated in poorer cognitive health and that the co-occurrence of multiple nutrient deficiencies confers greatest risk for frailty and pre-frailty in the Irish longitudinal study on ageing cohort. These health associations contribute to evidence needed to optimise micronutrient status for health in the older adult population.

This study aimed to explore the mediation effects of one-carbon metabolism (OCM) related nutrients on the association between MTHFR rs1801133 polymorphism and gestational diabetes mellitus (GDM). Folate, vitamin B12 and homocysteine (Hcy) were measured in the serum of 1254 pregnant women. Linear and logistic regressions were used to estimate the associations of OCM nutrients and MTHFR rs1801133 polymorphism with blood glucose levels and GDM risk. Mediation analysis was applied to test the mediation effects of folate, vitamin B12 and Hcy on the association of MTHFR rs1801133 polymorphism with blood glucose concentrations and GDM. Pregnant women with MTHFR rs1801133 CC genotype had higher serum folate (10·75 v. 8·90 and 9·40 ng/ml) and lower serum Hcy (4·84 v. 4·93 and 5·20 μmol/l) than those with CT and TT genotypes. Folate concentrations were positively associated with fasting plasma glucose (FPG), 1-h plasma glucose (1-h PG), 2-h plasma glucose (2-h PG) and GDM risk. Vitamin B12 levels were negatively correlated with FPG and GDM. Although no direct association was found between MTHFR rs1801133 genotypes and GDM, there were significant indirect effects of MTHFR rs1801133 CC genotype on FPG (β: 0·005; 95 % CI: 0·001, 0·013), 1-h PG (β: 0·006; 95 % CI: 0·001, 0·014), 2-h PG (β: 0·007; 95 % CI: 0·001, 0·015) and GDM (β: 0·006; 95 % CI: 0·001, 0·014) via folate. In conclusion, serum folate mediates the effect of MTHFR rs1801133 on blood glucose levels and GDM. Our findings potentially provide a feasible GDM prevention strategy via individualised folate supplementation according to the MTHFR genotypes.

Folate and vitamin B12 are essential for growth. Our objective was to estimate their long-term effects on linear growth in North Indian children. This is a follow-up study of a factorial designed, double-blind, randomised, placebo-controlled trial in 1000 young children. Starting at 6–30 months of age, we gave folic acid (approximately 2 RDA), vitamin B12 (approximately 2 RDA), both vitamins or a placebo daily for 6 months. Six years after the end of supplementation, we measured height in 791 children. We used the plasma concentrations of cobalamin, folate and total homocysteine to estimate vitamin status. The effect of the interventions, the association between height-for-age z-scores (HAZ) and baseline vitamin status, and the interactions between supplementation and baseline status were estimated in multiple regression models. Mean (sd) age at follow-up was 7·4 (0·7) years (range 6 to 9 years). There was a small, non-significant effect of vitamin B12 on linear growth and no effect of folic acid. We observed a subgroup effect of vitamin B12 supplementation in those with plasma cobalamin concentration < 200 pmol/l (P for interaction = 0·01). The effect of vitamin B12 supplementation in this group was 0·34 HAZ (95 % CI 0·11, 0·58). We found an association between cobalamin status and HAZ in children not given vitamin B12 (P for interaction = 0·001). In this group, each doubling of the cobalamin concentration was associated with 0·26 (95 % CI 0·15, 0·38) higher HAZ. Suboptimal vitamin B12 status in early childhood seemingly limits linear growth in North Indian children.

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.

Periconceptional folic acid supplementation is effective in the prevention of neural tube defects (NTDs). The aim of the present study was to determine the level of knowledge about the benefits of preconceptional folic acid supplementation in a sample of women of childbearing age and its associated factors. A cross-sectional community-based study design was carried out on a total of 441 women of childbearing age. Questionnaires included knowledge of preconception of folic acid supplements and socio-demographic characteristics. The χ2 was used to compare categorical data. Multivariate logistic regression was used to isolate the predictive variables and examined individually by calculating the adjusted odds ratio. Statistical significance is declared as P < 0·05. We found that 35·1 % (n 155) knew preconceptional folic acid supplementation could prevent NTDs, and 3·8 % (n 17) knew the right time to take preconceptional folic acid supplementation and only 1·7 % (n 7) who had a history of NTDs. Attended secondary education (OR 2·7; 95 % CI 1·1, 6·0, P = 0·017), governmental employee (OR 3·5; 95 % CI 2·3, 17·8, P < 0·001), current pregnancy status (OR 3·0; 95 % CI 2·1, 4·2, P = 0·043), history of visiting the antenatal care service during pregnancy (OR 2·9; 95 % CI 1·07, 7·8, P = 0·03), history of taking folic acid supplement (OR 4·5; 95 % CI 2·9, 7·1, P < 0·001) were associated. More than half of the participant women did not know about preconception of folic acid supplements that reduce the risk of NTDs. Identification of the level of knowledge on preconception of folic acid may allow for targeted educational or other interventions to further encourage folic acid use.

This study examined the influences of coated folic acid (CFA) and coated riboflavin (CRF) on bull performance, nutrients digestion and ruminal fermentation. Forty-eight Angus bulls based on a randomised block and 2 × 2 factorial design were assigned to four treatments. The CFA of 0 or 6 mg of folic acid/kg DM was supplemented in diets with CRF 0 or 60 mg riboflavin (RF)/kg DM. Supplementation of CRF in diets with CFA had greater increase in daily weight gain and feed efficiency than in diets without CFA. Supplementation with CFA or CRF enhanced digestibility of DM, organic matter, crude protein, neutral-detergent fibre and non-fibre carbohydrate. Ruminal pH and ammonia N content decreased and total volatile fatty acids concentration and acetate to propionate ratio elevated for CFA or CRF addition. Supplement of CFA or CRF increased the activities of fibrolytic enzymes and the numbers of total bacteria, protozoa, fungi, dominant fibrolytic bacteria and Prevotella ruminicola. The activities of α-amylase, protease and pectinase and the numbers of Butyrivibrio fibrisolvens and Ruminobacter amylophilus were increased by CFA but were unaffected by CRF. Blood concentration of folate elevated and homocysteine decreased for CFA addition. The CRF supplementation elevated blood concentrations of folate and RF. These findings suggested that CFA or CRF inclusion had facilitating effects on performance and ruminal fermentation, and combined addition of CFA and CRF had greater increase in performance than CFA or CRF addition alone in bulls.

We evaluated the association between maternal prenatal folic acid supplementation/dietary folate intake and motor and cognitive development in 2-year-old offspring using data from the Japan Environment and Children’s Study database. Neurodevelopment of 2-year-old offspring were evaluated using the Kyoto Scale of Psychological Development 2001. In total, data of 3839 offspring were analysed. For folic acid supplementation, a multiple regression analysis showed that offspring of mothers who started using folic acid supplements before conception had a significantly lower developmental quotient (DQ) in the postural-motor DQ area than offspring of mothers who did not use them at any time throughout their pregnancy (partial regression coefficient (B) −2·596, 95 % CI −4·738, −0·455). Regarding daily dietary folate intake from preconception to early pregnancy, a multiple regression analysis showed that the group with ≥ 200 µg had a significantly higher DQ in the language-social area than the group with <200 µg. The DQ was higher in the ≥ 400 µg group (B 2·532, 95 % CI 0·201, 4·863) than the 200 to <400 µg group (B 1·437, 95 % CI 0·215, 2·660). In conclusion, our study showed that maternal adequate dietary folate intake from preconception to early pregnancy has a beneficial association with verbal cognition development in 2-year-old offspring. On the other hand, mothers who started using folic acid supplements before conception had an inverse association with motor development in 2-year-old offspring. There were no details on the amount of folic acid in the supplements used and frequency of use. Therefore, further studies are required.

This was a longitudinal study utilising the Irish Longitudinal Study on Ageing (n 3849 aged ≥ 50 years) and investigated the relationship between blood plasma folate and B12 levels at baseline (wave 1) and incident depressive symptoms at 2 and 4 years (waves 2 and 3). A score ≥ 9 on the Center for Epidemiological Studies Depression Scale-8 at wave 2 or 3 was indicative of incident depressive symptoms. B12 status profiles (pmol/l) were defined as < 185, deficient low; 185 to < 258, low normal; > 258–601, normal and > 601 high. Folate status profiles (nmol/l) were defined as ≤ 10·0, deficient low; > 10–23·0, low normal; > 23·0–45·0, normal; >45·0, high. Logistic regression models were used to analyse the longitudinal associations. Both B12 and folate plasma concentrations were lower in the group with incident depressive symptoms v. non-depressed (folate: 21·4 v. 25·1 nmol/l; P = 0·0003; B12:315·7 v. 335·9 pmol/l; P = 0·0148). Regression models demonstrated that participants with deficient-low B12 status at baseline had a significantly higher likelihood of incident depression 4 years later (OR 1·51, 95 % CI 1·01, 2·27, P = 0·043). This finding remained robust after controlling for relevant covariates. No associations of folate status with incident depression were observed. Older adults with deficient-low B12 status had a 51 % increased likelihood of developing depressive symptoms over 4 years. The findings highlight the need to further explore the low-cost benefits of optimising vitamin B12 status for depression in older adults.