The 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 metabolising 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.

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.

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.

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.

To investigate the influences of cobalt (Co) and folic acid (FA) on growth performance and rumen fermentation, Holstein male calves (n 40) were randomly assigned to four groups according to their body weights. Cobalt sulphate at 0 or 0·11 mg Co/kg DM and FA at 0 or 7·2 mg/kg DM were used in a 2 × 2 factorial design. Average daily gain was elevated with FA or Co supplementation, but the elevation was greater for supplementing Co in diets without FA than with FA. Supplementing FA or Co increased DM intake and total-tract nutrient digestibility. Rumen pH was unaltered with FA but reduced with Co supplementation. Concentration of rumen total volatile fatty acids was elevated with FA or Co inclusion. Acetate percentage and acetate to propionate ratio were elevated with FA inclusion. Supplementing Co decreased acetate percentage and increased propionate percentage. Activities of xylanase and α-amylase and populations of total bacteria, fungi, protozoa, Ruminococcus albus, Fibrobacter succinogenes and Prevotella ruminicola increased with FA or Co inclusion. Activities of carboxymethyl-cellulase and pectinase increased with FA inclusion and population of methanogens decreased with Co addition. Blood folates increased and homocysteine decreased with FA inclusion. Blood glucose and vitamin B12 increased with Co addition. The data suggested that supplementing 0·11 mg Co/kg DM in diets containing 0·09 mg Co/kg DM increased growth performance and nutrient digestibility but had no improvement on the effects of FA addition in calves.

This study evaluated the effects of rumen-protected folic acid (RPFA) and betaine (BT) on growth performance, nutrient digestion and blood metabolites in bulls. Forty-eight Angus bulls were blocked by body weight and randomly assigned to four treatments in a 2 × 2 factorial design. BT of 0 or 0·6 g/kg DM was supplemented to diet without or with the addition of 6 mg/kg DM of folic acid from RPFA, respectively. Average daily gain increased by 25·2 and 6·29 % for addition of BT without RPFA and with RPFA, respectively. Digestibility and ruminal total volatile fatty acids of neutral-detergent fibre and acid-detergent fibre increased, feed conversion ratio and blood folate decreased with the addition of BT without RPFA, but these parameters were unchanged with BT addition in diet with RPFA. Digestibility of DM, organic matter and crude protein as well as acetate:propionate ratio increased with RPFA or BT addition. Ruminal ammonia-N decreased with RPFA addition. Activity of carboxymethyl cellulase, cellobiase, xylanase, pectinase and protease as well as population of total bacteria, protozoa, Fibrobacter succinogenes and Ruminobacter amylophilus increased with RPFA or BT addition. Laccase activity and total fungi, Ruminococcus flavefaciens and Prevotella ruminicola population increased with RPFA addition, whereas Ruminococcus albus population increased with BT addition. Blood glucose, total protein, albumin, growth hormone and insulin-like growth factor-1 increased with RPFA addition. Addition of RPFA or BT decreased blood homocysteine. The results indicated that addition of BT stimulated growth and nutrient digestion in bulls only when RPFA was not supplemented.

The functional effects of folate within C1 metabolism involve interrelationships with vitamin B12, vitamin B6 and riboflavin, and related gene–nutrient interactions. These B vitamins have important roles throughout life, from pregnancy, through childhood, to middle and older age. Achieving optimal nutritional status for preventing folate-related disease is challenging, however, primarily as a result of the poor stability and incomplete bioavailability of folate from natural food sources when compared with the synthetic vitamin form, folic acid. Thus, in European countries, measures to prevent neural tube defects (NTD) have been largely ineffective because of the generally poor compliance of women with folic acid supplementation as recommended before and in early pregnancy. In contrast, countries worldwide with mandatory folic acid fortification policies have experienced marked reductions in NTD. Low vitamin B12 status is associated with increased risk of cognitive dysfunction, CVD and osteoporosis. Achieving optimal B12 status can be problematic for older people, however, primarily owing to food-bound B12 malabsorption which leads to sub-clinical deficiency even with high dietary B12 intakes. Optimising B-vitamin intake may be particularly important for sub-populations with impaired folate metabolism owing to genetic characteristics, most notably the 677C→T variant in the gene encoding the enzyme methylenetetrahydrofolate reductase (MTHFR). This common folate polymorphism is linked with several adverse health outcomes, including stroke, however, recent evidence has identified its novel interaction with riboflavin (the MTHFR cofactor) in relation to blood pressure and risk of developing hypertension. This review addresses why and how the optimal status of folate-related B vitamins should be achieved through the lifecycle.

Periconceptional folic acid (FA) is known to have a protective effect in the prevention of neural tube defects (NTD), leading to global recommendations for FA supplementation before and in early pregnancy. Maternal folate throughout pregnancy may have other roles in offspring health, including neurodevelopment and cognitive performance in childhood. Folate is essential for C1 metabolism, a network of pathways involved in several biological processes including nucleotide synthesis, DNA repair and methylation reactions. The evidence reviewed here shows a conclusive role for offspring health of maternal folate nutrition in early pregnancy and probable benefits in later pregnancy. Folate-mediated epigenetic changes in genes related to brain development and function offer a plausible biological basis to link maternal folate with effects in offspring brain, albeit this research is in its infancy. Mandatory FA fortification of food has proven to be highly effective in decreasing NTD cases in populations where it has been implemented, but this policy is controversial owing to concerns related to potential adverse effects of over-exposure to FA. In the absence of population-wide fortification, and given the generally poor compliance with current FA recommendations, optimising folate status of mothers in very early pregnancy for protection against NTD remains challenging. Thus, current policy in the UK, Ireland and elsewhere in Europe for the prevention of NTD (based on periconceptional FA supplementation only), has proven to be largely ineffective. This review addresses the evidence and the controversies that surround this area, as well as identifying the challenges in translating policy into practice.

The possible roles of selected B vitamins in the development and progression of sarcopenia are reviewed. Age-related declines in muscle mass and function are associated with huge and increasing costs to healthcare providers. Falls and loss of mobility and independence due to declining muscle mass/function are associated with poor clinical outcomes and their prevention and management are attractive research targets. Nutritional status appears a key modifiable and affordable intervention. There is emerging evidence of sarcopenia being the result not only of diminished anabolic activity but also of declining neurological integrity in older age, which is emerging as an important aspect of the development of age-related decline in muscle mass/function. In this connection, several B vitamins can be viewed as not only cofactors in muscle synthetic processes, but also as neurotrophic agents with involvements in both bioenergetic and trophic pathways. The B vitamins thus selected are examined with respect to their relevance to multiple aspects of neuromuscular function and evidence is considered that requirements, intakes or absorption may be altered in the elderly. In addition, the evidence base for recommended intakes (UK recommended daily allowance) is examined with particular reference to original datasets and their relevance to older individuals. It is possible that inconsistencies in the literature with respect to the nutritional management of sarcopenia may, in part at least, be the result of compromised micronutrient status in some study participants. It is suggested that in order, for example, for intervention with amino acids to be successful, underlying micronutrient deficiencies must first be addressed/eliminated.

Folate is an essential B vitamin required for de novo purine and thymidylate synthesis, and for the remethylation of homocysteine to form methionine. Folate deficiency has been associated with placenta-related pregnancy complications, as have SNP in genes of the folate-dependent enzymes, methionine synthase (MTR) and methylenetetrahydrofolate dehydrogenase 1 (MTHFD1). We aimed to determine the effect of altered folate metabolism on placental cell proliferation, viability and invasive capacity and on progesterone and human chorionic gonadotropin (hCG) secretion. Human placental choriocarcinoma (JEG-3) cells cultured in low folic acid (FA) (2 nm) demonstrated 13 % (P<0·001) and 26 % (P<0·001) lower proliferation, 5·5 % (P=0·025) and 7·5 % (P=0·004) lower invasion capacity, and 5 to 7·5 % (P=0·004–0·025) lower viability compared with control (20 nm) or supplemented (100 nm) cells, respectively. FA concentration had no effect on progesterone or hCG secretion. Small interfering RNA (siRNA) knockdown of MTR gene and protein expression resulted in 17·7 % (P<0·0001) lower proliferation and 61 % (P=0·014) higher progesterone secretion, but had no effect on cell invasion and hCG secretion. siRNA knockdown of MTHFD1 gene expression in the absence of detectable changes in protein expression resulted in 10·3 % (P=0·001) lower cell proliferation, but had no effect on cell invasion and progesterone or hCG secretion. Our data indicate that impaired folate metabolism can result in lower trophoblast proliferation, and could alter viability, invasion capacity and progesterone secretion, which may explain in part the observed associations between folate and placenta-related complications.

Folic acid plays an essential role in DNA and methionine metabolism. Micro-organisms in the rumen can synthesise folates, but it has not been verified that these amounts are sufficient to achieve the best efficiency of dairy cows. However, the amount of folates synthesised in the rumen could possibly, to some extent, be affected by the forage:concentrate ratio. Degradation of orally supplemented folic acid in the rumen seems to be very high (about 97 %), as supplementation of folic acid hardly increases folate concentrations in the digesta at the duodenum. However, it must be considered that dietary supplements of folic acid higher than 0·5 mg/kg body weight increased serum folate concentrations in all available studies and milk folate concentrations in most studies. Additionally, milk production tended to be increased in some studies. Therefore, degradation of folic acid in the rumen may be overestimated as folates can be absorbed at the proximal duodenum. For future research it is necessary to consider the whole flow and the metabolic pathways of folates from the rumen to duodenum, blood, tissue, milk and transfer to calf to declare requirement values for cows. Consequently, the present review discusses current knowledge and emphasises areas for future research.

The folates are made up of a pterdine ring attached to a p-aminobenzoate and a polyglutamyl chain. The active form is tetrahydrofolate which can have C1 units enzymically attached. These C1 units (as a formyl group) are passed on to enzymes in the purine pathway that insert the C−2 and C−8 into the purine ring. A methylene group (−CH2−) attached to tetrahydrofolate is used to convert the uracil-type pyrimidine base found in RNA into the thymine base found in DNA. A further folate cofactor, i.e. 5-methyltetrahydrofolate, is involved in the remethylation of the homocysteine produced in the methylation cycle back to methionine. After activation to S-adenosylmethionine this acts as a methyl donor for the dozens of different methyltransferases present in all cells. Folate deficiency results in reduction of purine and pyrimidine biosynthesis and consequently DNA biosynthesis and cell division. This process is most easily seen in a reduction of erythrocytes causing anaemia. Reduction in the methylation cycle has multiple effects less easy to identify. One such effect is certainly on the nerve cells, because interruption of the methylation cycle causing neuropathy can also happen in vitamin B12 deficiency due to reduced activity of the vitamin B12-dependent enzyme methionine synthase (EC 2.1.1.13). In vitamin B12 deficiency, blocking of the methylation cycle causes the folate cofactors in the cell to become trapped as 5-methyltetrahydrofolate. This process in turn produces a pseudo folate deficiency in such cells, preventing cell division and giving rise to an anaemia identical to that seen in folate deficiency.