What is L-Methylfolate?

Methylfolate (5-MTHF) is a natural folate form that is directly bioavailable and therefore easy for the body to use. It does not require any extra metabolic steps to be absorbed and enter circulation once ingested. This makes it superior to folic acid, which needs to be activated before it can be used by the body. 5-MTHF does also not cause unmetabolized folic acid (UMFA) to raise in plasma, which has been associated with the risk of cancer, and autism spectrum disorder. 

What is Folate good for?

Folate is an essential, water-soluble B vitamin and as such plays an essential role for human body from preconception until old age. The vital functions of folate include:

  • Providing building blocks for DNA biosynthesis needed for cell growth, renewal, and function
  • Providing methyl groups for more than 100 cellular reactions such as DNA methylation which regulates gene expression by epigenetic mechanisms
  • Ensuring normal metabolism and plasma concentrations of the toxic amino acid homocysteine
  • Participating in the build-up of amino acids needed to produce cellular proteins 

Sufficient folate levels are crucial during all stages of life. For example, during pregnancy it reduces the risk of growth retardation and birth anomalies and in older adults it promotes health of the nervous system, hematopoietic system, cardiovascular system, gastrointestinal system, and bone.*

Recommended Intake of Folate

  • The recommended daily intake of folate for adults is 400 µg/day.
  • Recommended intake increases during pregnancy and lactation (500 – 800 µg/day) to support the needs of the fetus and infant, respectively.
  • Compared to adults, infants require higher amounts of folate per kg body weight.

Because folate is not produced by the human body, it must be obtained from dietary sources to maintain normal body functions. Folate is naturally present in some foods such as vegetables and animal foods such as meat and is added to foods and food supplements to enable a greater portion of the population to meet the daily requirements of this nutrient.

Meeting the daily recommended intake of folate via the natural diet can be challenging. For example, achieving 400 µg/day via the diet would require consumption of one kilogram of spinach or 500 grams of liver per day. In addition, folate exists as large complexes with polyglutamate in natural foods and proper absorption from the diet requires it to be released from these complexes. Release of folate from its polyglutamate binding could be a rate limiting step in the absorption process. Thus, the bioavailability of dietary folate is not as efficient as when folate is taken in free forms from fortified foods or food supplements. Approximately 5 to 10 mg of folate are stored in the human liver, an amount that is sufficient to support bodily needs for up to three months. If folate intake is insufficient or folate is not properly absorbed, a deficiency can develop within approximately three months.

Causes of Folate Insufficiency

Folate insufficiency can be related to the stage of life, lifestyle, and medical conditions or diseases. For example, it can develop during pregnancy and lactation, and can be found in infants and children as well as the elderly. In these cases, folate insufficiency is often the result of higher daily requirements or malabsorption.

Folate insufficiency can also be related to food selection such as the consumption of foods not fortified with folic acid. Medical conditions that affect the gastrointestinal system, the liver or kidneys may interfere with metabolism or absorption of folate. For example, infection with Helicobacter pylori, bariatric surgeries, ilial resections, alcoholism, or medications that influence the intestinal pH can all affect folate absorption. Conditions associated with reduced gastrointestinal motility such as obesity and Parkinson’s disease can influence folate absorption.

Relationship of Folate Insufficiency and Disease

Folate insufficiency is causally related to several diseases, the most well-known of which is anemia. Low folate is also related to pregnancy complications and poor outcomes such as neural tube defects. Folate deficiency may affect growth and development of infants and children, may cause infertility in men and women, and has been related to the risk of stroke, dementia, depression and bone fractures in the elderly, as well as cardiovascular diseases and fatty liver.

The Benefits of Folate Supplementation

Folate supplementation is an effective, safe, and inexpensive approach to promote better health, healthy aging, and to mitigate the risk of the disease and conditions. Supplementation using a liquid formulation containing a stable form of folate is particularly appealing for its convenience and ease of use for those with difficulty swallowing or reduced saliva volume. A liquid formulation can benefit people taking medications which influence gastrointestinal pH, those with malabsorption syndromes such as celiac or Crohn's disease, intestinal resection, inflammatory bowel disease, and those with reduced gastrointestinal motility.

Folic acid is a synthetic compound not present in nature. To be used by the body, folic acid must be metabolized in the liver via a series of conversions into 5-methyltetrahydrofolate (5-MTHF), the major physiological form of folate found in blood. After consuming folic acid, some unmetabolized folic acid (UMFA) remains in the circulation. 

References

  1. Pfeiffer CM, Sternberg MR, Fazili Z, Yetley EA, Lacher DA, Bailey RL, Johnson CL. 2015. Unmetabolized Folic Acid Is Detected in Nearly All Serum Samples from US Children, Adolescents, and Adults1–4. The Journal of Nutrition.145(3):520-531. https://doi.org/10.3945/jn.114.201210

2. Raghavan R, Selhub J, Paul L, Ji Y, Wang G, Hong X, Zuckerman B, Fallin MD, Wang X. 2020. A prospective birth cohort study on cord blood folate subtypes and risk of autism spectrum disorder. The American Journal of Clinical Nutrition.112(5):1304-1317. https://doi.org/10.1093/ajcn/nqaa208

3. Best KP, Green TJ, Sulistyoningrum DC, Sullivan TR, Aufreiter S, Prescott SL, Makrides M, Skubisz M, O'Connor DL, Palmer DJ. 2021. Maternal Late-Pregnancy Serum Unmetabolized Folic Acid Concentrations Are Not Associated with Infant Allergic Disease: A Prospective Cohort Study. The Journal of Nutrition.151(6):1553-1560. https://doi.org/10.1093/jn/nxab040

4. Troen AM, Mitchell B, Sorensen B, Wener MH, Johnston A, Wood B, Selhub J, McTiernan A, Yasui Y, Oral E,et al.2006. Unmetabolized Folic Acid in Plasma Is Associated with Reduced Natural Killer Cell Cytotoxicity among Postmenopausal Women. The Journal of Nutrition.136(1):189-194. https://doi.org/10.1093/jn/136.1.189

5. Paniz C, Bertinato JF, Lucena MR, DeCarli E, Amorim PMdS, Gomes GW, Palchetti CZ, Figueiredo MS, Pfeiffer CM, Fazili Z,et al.2017. A Daily Dose of 5 mg Folic Acid for 90 Days Is Associated with Increased Serum Unmetabolized Folic Acid and Reduced Natural Killer Cell Cytotoxicity in Healthy Brazilian Adults. The Journal of Nutrition.147(9):1677-1685. https://doi.org/10.3945/jn.117.247445

6. 2012. Stabilization of folic acid in liquid dosage form: formulation development, method validation and comparative analysis.[Internet]. Int J Pharmceuticaland Chemical Sciences:Available from:https://www.semanticscholar.org/paper/Stabilization-of-Folic-Acid-in-Liquid-Dosage-Form%3A-Vignesh-Sivakumar/6f481857ecdc102948ea0384b886715011a551bd