Folate in Human Health and Disease

Abstract

Folate, a water‐soluble B vitamin, and its synthetic form folic acid (FA) used in fortification and supplements, are critical to human health due to their role in one‐carbon transfer reactions required for biological methylation and nucleotide biosynthesis. As such, folate deficiency has been linked to a variety of adverse health outcomes such as megaloblastic anaemia, neural tube defects, coronary heart disease and cancer among others. Corollary to this, FA supplementation has garnered a considerable amount of interest as an ideal functional food component for disease prevention. Although the benefits of FA supplementation in treatment of megaloblastic anaemia and in prevention of neural tube defects are well established, the effects of FA supplementation on other disease outcomes remain largely equivocal. In addition, an emerging body of evidence has raised concern regarding potentially serious adverse health effects of excessive FA intake, which warrant further studies. Key Concepts: Folate, a water‐soluble B vitamin, and its synthetic form folic acid used in fortification and supplements, are critical to one‐carbon transfer reactions required for DNA synthesis and biological methylation reactions. Dietary folate intake is the main source of folate for humans; inadequate dietary intake, impaired absorption or metabolism of folate, and increased folate demand and utilisation may result in deficiency. Folate deficiency has been associated with various adverse health effects including megaloblastic anaemia, neural tube defects and other congenital disorders, adverse pregnancy outcomes, neuropsychiatric disorders and cognitive decline, coronary heart disease, stroke and development of some cancers. Folic acid supplementation is effective in treatment of folate‐deficiency associated megaloblastic anaemia and in prevention of neural tube defects. The primary objective of periconceptional folic acid supplementation and mandatory folic acid fortification of the food supply, typically wheat, implemented in North American in 1998, is to prevent neural tube defects. It appears that folic acid fortification has led to up to 50% reduction in the rates of neural tube defects in North America. Folate requirements are increased throughout pregnancy due to rapid growth of the uterus, placenta and foetus, and during lactation as to maintain an adequate folate supply in breast milk for infants. Folate appears to play a dual modulatory role in colorectal carcinogenesis depending on the dose and the stage of cell transformation at the time of folate exposure. Animal studies conducted in colorectal cancer models have shown that folic acid supplementation prevents the development of cancer in normal tissues but promotes the progression of established (pre)neoplastic lesions. Animal studies have also suggested that supraphysiological supplemental doses of folic acid supplementation may promote, rather than prevent cancer development. However, folic acid intervention trials in humans have produced inconsistent results. Although folate deficiency and raised plasma homocysteine levels have been associated with increased risk of coronary heart disease in observational studies; clinical trials have reported largely null effects of folic acid supplementation on the secondary prevention of coronary heart disease. Folate status may play an important role in regulation of epigenetic determinants of gene expression such as DNA methylation relating to its critical role in the provision of S ‐adenosylmethionine, the primary methyl donor in most biological methylation reactions. Excessive folic acid intake from fortified foods and supplements has been linked to certain adverse health effects including masking of vitamin B 12 deficiency and tumour‐progression.

Folic Acid Homeostasis and Its Pathways Related to Hepatic Oxidation in Adolescent Rats Exposed to Binge Drinking

“…FA is taken up from the diet and bio-transformed mainly in the liver by the enzyme dihidrofolate reductase (DHFR). It functions as a coenzyme in reactions of one-carbon transfer, needed for the biosynthesis of several essential molecules [ 4 ]. Adequate intake of FA is vital for metabolism, cellular homeostasis and DNA synthesis [ 5 ].…”

Effectiveness of Folic Acid Supplementation Recommendations among Polish Female Students from the Podkarpackie Region

“…Folate deficiency is associated with various adverse health effects, including complications of pregnancy, such as neural tube defects, intrauterine growth restriction and recurrent pregnancy loss [ 36 ]. This may be caused by an insufficient dietary folate intake, impaired folate absorption or metabolism, as well as increased demand for folates, for instance during pregnancy [ 37 ]. It is estimated that young non-pregnant women in Poland (aged 18–35) take about 127–315 mcg of folic acid per person per day [ 38 ].…”

Current Status of Folic Acid Supplementation on Colorectal Cancer Prevention

“…Folate is essential for proper cell division and normal growth and development and hence plays a crucial role in human health and disease [20,29]. Folate deficiency has been linked to macrocytic anemia, congenital defects including neural tube defects, adverse pregnancy and birth outcomes, coronary heart disease and stroke, cognitive dysfunction, and certain cancers [20,21,29].…”

“…Folate deficiency has been linked to macrocytic anemia, congenital defects including neural tube defects, adverse pregnancy and birth outcomes, coronary heart disease and stroke, cognitive dysfunction, and certain cancers [20,21,29]. In contrast to observational epidemiologic studies, which have generally supported the inverse association between folate status and cardiovascular disease risk, the overwhelming majority of randomized clinical trials and their meta-analyses or pooled analyses have shown a null effect of folic acid supplementation on coronary heart disease [30,31].…”

“…High intakes and blood levels of folate and folic acid have been linked to several adverse health outcomes, although unequivocal evidence to support these purported associations is lacking [20,29]. These include masking of vitamin B 12 deficiency primarily in elderly [58]; decreased natural killer cell cytotoxicity [56]; resistance to antifolate drugs used against arthritis [59][60][61], malaria [62], and cancer [63,64]; an increased risk of insulin resistance and obesity and asthma in children born to folic acid-supplemented mothers [65]; accelerated progression of diabetic nephropathy [66]; an increased risk of cognitive impairment in elderly with suboptimal vitamin B 12 status [67,68]; aberrant patterns and dysregulation of DNA methylation [69]; and the promotion of progression of existing precancerous lesions or cancer [1,2,15,16].…”