Vegan Guide to Folate (B9)

by

What we’ll do here is cover some basic information about folate or vitamin B9 as relates to plant-based eating.

First, I’ll answer some common questions for those of you who are in a rush:

  • Is folate vegan? Yes, unlike vitamin D (check out the article here) and vitamin B12, folate is found in numerous plant sources.1 As for supplements, folate can be derived from animals but tends to be produced via chemical synthesis.40 So, it’s typically considered vegan.
  • Are folate supplements (folic acid) vegan? Yes—folic acid is the form of folate in supplements and fortified foods.
  • What are some vegan sources of folate? Common plant-based sources of folate include spinach, legumes such as black-eyed peas, fortified breakfast cereals, asparagus, Brussels sprouts, and romaine lettuce.1 (See the chart below for more examples)
  • Are vegans commonly deficient in folate? No, not characteristically. According to NIH, those at risk for folate deficiency include people with alcohol use disorder, pregnant women and women of childbearing age, people with malabsorptive disorders, and people with what’s known as an MTHFR polymorphism.1
  • Does the vegan diet provide too much folate? No, folate is a water-soluble vitamin, so excesses of the vitamin get excreted. It is almost impossible to get too much folate from natural food sources in general.

What we’ll do next is take a closer look at plant sources of folate as well as some other basic info, such as the vitamin’s functions and deficiency symptoms.

Overview and Functions

Folate and vitamin B12 were discovered as a result of a frantic search for a cure for megaloblastic anemia—a type of anemia that was particularly prevalent in the late 1870s and early 1880s.

If the name folate sounds reminiscent of foliage, that’s because the vitamin was found in dark-green leafies.2The term “folic” is from the Latin folium meaning leaf. While it was initially found in greens, it actually occurs in a variety of foods.3,4

The terms folic acid and folate are not interchangeable. Folic acid, the form in supplements and fortified foods, refers to the vitamin’s oxidized form. Folate, however, refers to the compounds reduced form that’s naturally present in foods and biological tissues.

Folate is made up of three parts, each of which has to be present for it to exert vitamin activity. In case you’re interested:

  1. Pteridine or pterin (2-amino-4-hydroxypteridine)
  2. Para-aminobenzoic acid (PABA)
  3. Glutamic acid—metabolically active folate actually has multiple glutamic acid residues attached. These would be referred to as pteroylpolyglutamates.

Humans can actually synthesize all of the above components, but we lack the conjugase enzyme needed to couple pterin to PABA to make pteroic acid.

As with most vitamins, folate can take many forms in food. While there are a handful of variants commonly found in food, over 150 have been reported.5

The main pteroylpolyglutamates found in foods are 5-methyl tetrahydrofolate (THF) and 10-formyl THF—the forms that fulfill most metabolic roles.

Pteroylpolyglutamate is also the form of folic acid provided in fortified foods and supplements.

Coenzyme Roles: THF

THF functions as a coenzyme in the cytosol and mitochondria where it accepts one- or single-carbon units.6

The THF derivatives (the folate forms that do all the metabolic work) are as follows:

  • 5- and 10-formyl THF
  • 5-formimino THF
  • 5,10-methenyl THF
  • 5,10-methylene THF
  • 5-methyl THF

These forms are mostly interconvertible, but 5-methyl THF can’t undergo conversion back to 5,10-methylene THF.

Amino Acid Metabolism

Folate is involved in the metabolism of serine, histidine, glycine, and methionine.

  • Glycine and serine interconversion (5, 10-methylene THF)
  • Glycine breakdown (5, 10-methylene THF)
  • Glycine synthesis (5, 10-methylene THF)
  • Histidine breakdown (5-formimino THF)
  • Methionine synthesis (5-methyl THF)
Methionine Synthesis

Folate in the form of 5-methyl THF is used in methionine regeneration from homocysteine.

The reactions that convert methionine to homocysteine are as follows:

  1. First, methionine is converted to SAM (S-adenosyl methionine) via methionine adenosyltransferase.
  2. SAM is converted to SAH (S-adenosyl homocysteine) via a methyl group acceptor.
  3. Finally, the removal of the adenosyl group from SAH makes homocysteine.

As we’ll cover a bit later, we don’t want excessive homocysteine floating around in the bloodstream due to its association with CVD.

That’s where 5-methyl THF comes in.

Folate is used in the remethylation of homocysteine to regenerate methionine which lowers levels of homocysteine.

When levels of SAM are low, 5-methyl THF (the methyl donor) along with vitamin B12 (as methylcobalamin – the prosthetic group for methionine synthase aka homocysteine methyltransferase) team up in the following way:

  1. Vitamin B12 bound to methionine synthase snags the methyl group from 5-methyl THF generating methylcobalamin and THF.
  2. Methylcobalamin then donates a methyl group converting homocysteine to methionine.

SAM is a very important compound, due to its function as a methyl donor in many reactions in many processes including:

  • Myelin maintenance
  • DNA and RNA methylation
  • Synthesis of carnitine, polyamine, and catecholamines
  • Neural function

Again, SAM concentrations help regulate methionine metabolism including regenerating methionine from homocysteine. Concentrations increase in tandem with methionine levels, resulting in:

  • Stimulation of the transsulfuration pathway which irreversibly converts homocysteine to cystathionine via cystathionine synthase (a B6-dependent enzyme) and ultimately to cysteine.
  • Inhibition of methylene THF reductase, which decreases the availability of 5-methyl THF  and the remethylation of homocysteine.
DNA Synthesis and Cell Division

THF derivatives are involved in purine synthesis (10-formyl THF), pyrimidine synthesis (5, 10-methylene THF), and nucleotide metabolism.

For this reason, folate is essential for cell division and DNA synthesis. Which is why the synthesis of cells having short lifecycles (e.g. RBCs and enterocytes) are quickly affected by inadequate folate status.

The enzyme thymidylate synthetase uses folate as 5,10-methylene THF to convert dUMP (deoxyuridine monophosphate) to DHF (dihydrofolate) and dTMP (thymidylate).

Well, dTMP is needed for DNA synthesis in a rate-limiting reaction. Which is to say folate is needed for DNA replication. Folate deficiency can be disastrous. For example, inadequate folate status prevents the normal cell cycle from progressing ultimately causing DNA damage and strand breakage.7

Plant-Based Sources of Folate

  1. Greens. As for plant sources, folate is found most notably in dark green leafies like spinach, turnips, and collard greens. Spinach provides about 52.8 mcg or 15% DV per 1 cup.8
  2. Legumes. For example, pinto beans and black beans, lentils, lima beans, and kidney beans. Pinto beans (1/2 cup) provide 72 mcg or 18% DV.9
  3. Brussels sprouts. 1 cup provides 53.7 mcg or 13% DV.10
  4. Asparagus. 1 cup provides 69.7 mcg or 17% DV.11
  5. Broccoli. 1 cup, chopped, provides 57.3 mcg or 14% DV.12
  6. Okra. ½ cup provides 36.8 mcg or 9% DV.13
  7. Peanuts. 1 oz. provides 40.6 mcg or 10% DV.14
  8. Fruits. For example, strawberries, oranges, cantaloupe, and banana. 1 cup of strawberries provides 36.5 mcg or 9% DV.15
  9. Enriched bread. 1 large slice of commercially-prepared bread contains 33.3 mcg or 8% DV.16

Supplements

I mentioned above that folic acid is the form used in supplements and fortified foods. Often, synthetic nutrients are less effective than those found in whole foods (vitamin E, etc.). Well, folic acid is an exception, as it’s almost 100% bioavailable, especially if you consume it on an empty stomach.5

If consumed with natural sources of folate, the bioavailability of folic acid drops to about 85% which is still really good considering that folate bioavailability from a mixed diet is closer to 50%, on average, though it can vary from 10% to 98%.17,18

Select Folate Sources

Source: adapted from Office Of Dietary Supplements – Folate https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/

The DV used in the above chart is 400 mcg for adults and kids 4 years of age and older.19

This value will be changing to 400 mcg DFE per the updated Nutrition and Supplement Facts labels.20

Manufacturers will use the conversion factors: 1 mcg DFE = 1 mcg naturally occurring folate = 0.6 mcg folic acid. The new labels and DVs must appear on supplements and food products starting in January 2020, but they can be used now.38

The FDA doesn’t require labels to list folate unless a food has been fortified with it. Foods that provide 20% of the DV or more are considered high sources of folate, but foods providing lower amounts also contribute to a healthy diet. † Fortified as part of a fortification program.

The U.S. Department of Agriculture’s National Nutrient Database external link disclaimer has a giant list of foods and their nutrient content (including folate) that are arranged by food name and nutrient content.39

Recommended Daily Allowance (Needs)

Similar to niacin and vitamin A, folate recommendations are provided as dietary equivalents, in this case dietary folate equivalents (DFE). This is to account for the gap in bioavailability between folic acid (fortified foods/supplements) and the folate found in foods.

The adult RDA for folate is 400 μg DFE /day for both men and women.22

The equivalent for 1 DFE is as follow:22

  • Food folate: 1 μg
  • Folic acid via fortified food or supplement consumed w/meal: 0.6 μg
  • Folic acid supplement on an empty stomach: 0.5 μg

Alternately, you can use the formula that’s based on the assumption that folic acid in fortified food has 1.7 times the bioavailability of the folate found naturally in food, while supplemental folic acid taken on an empty stomach has about twice the bioavailability of natural folate.

This gives rise to the following formula: DFE = μg folate from food + (1.7 × μg folic acid).22

The need for most nutrients goes up a bit with pregnancy and lactation. Indeed, folate is no exception as the RDA rises to 600 μg DFE and 500 μg DFE per day for pregnancy and lactation, respectively.22

However, folate is unique in that recommendations also go up for women of childbearing age.

It’s long been thought that folic acid supplementation in the periconceptional period of pregnancy may decrease the incidence of neural tube defects. For this reason, the CDC suggests that women capable of becoming pregnant take 400 μg of synthetic folic acid/day.23


Source: Micronutrients in Health and Disease. Kedar Prasad – Crc – 2011

Deficiency Symptoms

In the short-term, folate deficiency results in anemia, while in the long term it can potentially result in a number of chronic conditions such as heart disease and perhaps even dementia.

Impaired DNA Synthesis

Megaloblastic Anemia

As for the former, folate deficiency is known to cause megaloblastic macrocytic anemia—a type of anemia that results in large and immature red blood cells that are fewer in number.

Precursor RBCs that exist in bone marrow start to display altered DNA synthesis and cell division, which results in RBCs that are immature and large (hence, macrocytic) that have a shorter life span.

With time, the large/immature RBCs start to increase in number while the healthy RBCs decrease. These defective cells are much less efficient in carrying oxygen, and thus diminish the blood’s capacity to transport oxygen.

Blood cells live about 90-120 days, so RBC folate concentrations diminish at about 3 to 4 months of low folate intake. At the 4 to 5 month mark, rapidly dividing cells (blood and GI tract) become megaloblastic.

Signs and symptoms of this type of anemia include:24

  • Headaches
  • Weakness, fatigue, and shortness of breath
  • Difficulty concentrating
  • Irritability
  • Heart palpitations

This type of anemia is fairly common in the US and can also result from vitamin B12 deficiency.

Other Complications

Impaired DNA synthesis affects all cells, not just RBCs. It’s just that RBCs and other rapidly dividing cells are the first to take a hit. Other body cells that have rapid cell turnover are those of the gastrointestinal tract.

Other manifestations of impaired DNA synthesis include:25

  • A bright red tongue
  • Thinning of the layers of the GI tract, and shortening of villi height.
  • Diarrhea
  • Impaired nutrient absorption (due to structural changes of the GIT).

Chronic Conditions

Alzheimer’s

It’s highly theoretical at this point, but another condition having a possible link to poor folate status is dementia, even Alzheimer’s.26

It seems that memory and capacity for abstract thinking can be significantly influenced by folate status. Correlations have been found between elevated plasma homocysteine concentrations and cognitive dysfunction and dementia.27

We know plasma homocysteine concentrations are affected by folate intakes, hence the connection.

Cancer

Folate deficiency and poor folate status have been implicated in the development of certain cancers (the initiation phase), specifically, cancers of the lungs and GI tract (especially colon cancer).28

It’s thought that, at the cellular level, folate deficiency may alter gene expression in a way that promotes cancer.

I mentioned early on that folate deficiency can lead to DNA strand breakage. Well, breaks in the chromosomes induced by folate deficiency are thought to result from hypomethylation of DNA.29

Heart Disease

Hyperhomocysteinemia is a potential complication of folate, B12, and B6 deficiencies due to the role these vitamins play in methionine and homocysteine metabolism. As such, plasma concentrations of homocysteine are inversely associated with intakes of folate, B12, and B6.30

These three vitamins are the focus of much attention these days for this reason as plasma homocysteine concentrations greater than 15 μmol/L are associated with premature heart disease, clogged arteries, and cerebral vascular diseases (e.g. stroke).

The actual mechanism by which high circulating homocysteine increases the risk of vascular disease is yet to be fully understood, but at present, it’s thought that hyperhomocysteinemia may cause damage in the following four ways:

  • Impairment of endothelial function.
  • Promotion of smooth muscle cell growth which may lead to vascular lesions.
  • Promotion of an autoimmune response.
  • Platelet aggregation, clotting, and adhesiveness.

Nailing down the exact mechanism is complicated. For example, supplementation with folic acid in folks with hyperhomocysteinemia improves endothelial function. Aha! But, not so fast. Supplementation with folic acid, B6, and B12 (in people with and without heart disease) normalizes homocysteine levels but fails to reliably reduce the risk of CVD and stroke.31-34

Whatever the mechanism, the association is of hyperhomocysteinemia to heart disease is pretty strong with a mere 5 μmol/L increase in serum homocysteine increasing the risk of heart disease by 20% to 30%.35

The Vegan Diet and Folate Status

Thankfully, there’s not a lot to say here as vegetarians and vegans tend to have relatively adequate intakes of folate.36

But, for heart health, it would be wise to keep an eye on folate intake as well as other B vitamins as vegans are known to have low intakes of B12.37

References

  1. Office Of Dietary Supplements – Folate https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/
  2. Chambers Concise Dictionary. Allied Publishers. 2004. p. 451. ISBN 9788186062364. Archived from the original on 8 September 2017.
  3. “Folate”. Micronutrient Information Center, Linus Pauling Institute, Oregon State University. 2014. Retrieved 17 March 2018.
  4. “Fact Sheet for Health Professionals – Folate”. National Institutes of Health. Archived from the original on 2 April 2011.
  5. Gropper, Sareen S.; Smith, Jack L.. Advanced Nutrition and Human Metabolism (Page 345).
  6. Gropper, Sareen S.; Smith, Jack L.. Advanced Nutrition and Human Metabolism (Page 347).
  7. Gropper, Sareen S.; Smith, Jack L.. Advanced Nutrition and Human Metabolism (Page 350).
  8. Spinach, Raw Nutrition Facts & Calories https://nutritiondata.self.com/facts/vegetables-and-vegetable-products/2626/2
  9. Beans, Pinto, Mature Seeds, Canned Nutrition Facts & Calories https://nutritiondata.self.com/facts/legumes-and-legume-products/4313/2
  10. Brussels Sprouts, Raw Nutrition Facts & Calories https://nutritiondata.self.com/facts/vegetables-and-vegetable-products/2362/2
  11. Asparagus, Raw Nutrition Facts & Calories https://nutritiondata.self.com/facts/vegetables-and-vegetable-products/2311/2
  12. Broccoli, Raw Nutrition Facts & Calories https://nutritiondata.self.com/facts/vegetables-and-vegetable-products/2356/2
  13. Okra, Cooked, Boiled, Drained, Without Salt Nutrition Facts & Calories https://nutritiondata.self.com/facts/vegetables-and-vegetable-products/2498/2
  14. Peanuts, All Types, Dry-roasted, Without Salt Nutrition Facts & Calories https://nutritiondata.self.com/facts/legumes-and-legume-products/4448/2
  15. Strawberries, Raw Nutrition Facts & Calories https://nutritiondata.self.com/facts/fruits-and-fruit-juices/2064/2
  16. Bread, White, Commercially Prepared (includes Soft Bread Crumbs) Nutrition Facts & Calories https://nutritiondata.self.com/facts/baked-products/4872/2
  17. McNulty H, Pentieva K. Folate bioavailability. Proc Nutr Soc. 2004; 63:529–36.
  18. Hannon-Fletcher M, Armstrong N, Scott J, et al. Determining bioavailability of food folates in a controlled intervention study. Am J Clin Nutr. 2004; 80:911–18.
  19. U.S. Food and Drug Administration. Guidance for Industry: A Food Labeling Guide  (14. Appendix F: Calculate the Percent Daily Value for the Appropriate Nutrients). 2013.
  20. U.S. Food and Drug Administration. Food Labeling: Revision of the Nutrition and Supplement Facts Labels. external link disclaimer2016.
  21. U.S. Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 27. Nutrient Data Laboratory Home Page, 2014.
  22. Food and Nutrition Board. Dietary Reference Intakes for Thiamin, Riboflavin, Niacin, Vitamin B6, Folate, Vitamin B12, Pantothenic Acid, Biotin, and Choline. Washington, DC: National Academy Press. 1998 pp. 196–305.
  23. Centers for Disease Control and Prevention (CDC). Recommendations for the use of folic acid to reduce the number of cases of spina bifida and other neural tube defects. MMWSR. 1992; 41:1–7.
  24. Gropper, Sareen S.; Smith, Jack L.. Advanced Nutrition and Human Metabolism (Page 351).
  25. Gropper, Sareen S.; Smith, Jack L.. Advanced Nutrition and Human Metabolism (Page 352).
  26. Ravaglia G, Forti P, Maioli F, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr. 2005; 82:636–43.
  27. Selhub J. Folate, vitamin B12 and vitamin B6 and one carbon metabolism. J Nutr Hlth Aging. 2002; 6:39–42.
  28. Su LJ, Arab L. Nutritional status of folate and colon cancer risk. Ann Epidemiol. 2001; 11:65–72.
  29. Mason JB. Folate, cancer risk, and the Greek god, Proteus: a tale of two chameleons. Nutr Rev. 2009; 67:206–12.
  30. Hankey, G.J. and Eikelboom, J.W. Homocysteine and vascular disease. Lancet, 354: 407, 1999.
  31. Abraham JM, Cho L. The homocysteine hypothesis: still relevant to the prevention and treatment of cardiovascular disease? Clin J Med 2010; 77:911–18.
  32. Manolescu BN, Oprea E, Farcasanu IC, et al. Homocysteine and vitamin therapy in stroke prevention and treatment: a review. Acta Biochimica Polonica. 2010; 57:467–77.
  33. DeBree A, Miero LA, Draijer R. Folic acid improves vascular reactivity in humans: a meta-analysis of randomized, controlled trials. Am J Clin Nutr. 2007; 86:610–07.
  34. Marti-Carvajal AJ, Sola I, Lathyris D, Salanti G. Homocysteine lowering interventions for preventing cardiovascular disease. Cochrane Database Syst Rev. 2009; CD006612.
  35. Wald DS, Law M, Morris JK. Homocysteine and cardiovascular disease: evidence on causality from a meta-analysis. BMJ. 2002; 325:1202–09.
  36. Draper, A., Lewis, J., Malhotra, N., and Wheeler, E. The energy and nutrient intakes of different types of vegetarian: a case for supplements? Brit. J. Nutr., 69: 3, 1993.
  37. Sanders, T.A.B. The nutritional adequacy of plant-based diets. Proc. Nutr. Soc., 58: 265, 1999.
  38. U.S. Food and Drug Administration. Food Labeling: Revision of the Nutrition and Supplement Facts Labels and Serving Sizes of Foods That Can Reasonably Be Consumed at One Eating Occasion; Dual-Column Labeling; Updating, Modifying, and Establishing Certain Reference Amounts Customarily Consumed; Serving Size for Breath Mints; and Technical Amendments; Proposed Extension of Compliance Dates.external link disclaimer 2017.
  39. U.S. Department of Agriculture, Agricultural Research Service. USDA National Nutrient Database for Standard Reference, Release 28.external link disclaimer Nutrient Data Laboratory Home Page, 2016.
  40. Jose L. Revuelta, Ruben M. Buey, Rodrigo Ledesma‐Amaro, and Erick J. Microbial biotechnology for the synthesis of (pro)vitamins, biopigments and antioxidants: challenges and opportunities. Microb Biotechnol. 2016 Sep; 9(5): 564–567.