The incidences of asthma, allergies, and eczema are rising! Interestingly, folic acid fortification could be the culprit, especially in those with MTHFR mutations. However, the results in humans have been mixed, suggesting that it is likely to be a contributing factor but not the sole cause. Read this post to learn more about how MTHFR, folate status and methylation may contribute to allergies.

What Causes Allergy?

Helper T cells (Th cells) help orchestrate the immune response to develop the right kinds of weapons for the invading pathogens. For example, Th1 cells fight against bacteria and viruses, Th2 cells fight against parasites, and Th17 cells fight against some yeasts and bacteria. 

Regulatory T cells (Treg) cells are also a type of helper T cells; but rather than activating the immune system, Treg cells antagonize Th1, Th2, and Th17 cells to ensure that they only fight against pathogens rather than attacking our own tissues or harmless things like pollen. Too low Treg and too high Th1, Th2, or Th17 can result in allergies and autoimmunity.

Everyone has genes that could activate any of these cells when the occasion calls for it. Environmental factors such as infections, nutrition, stress, and certain gut bacteria can activate or silent those genes through a process called “epigenetics.” 

Epigenetics helps determine which type of Helper T cells you will have more of based on your environment by marking (such as a methylating) specific genes. Sometimes, these epigenetic marks can even be transmitted to your children!

Currently, scientists are still trying to understand all the different factors that influence the epigenetics that lead to allergic diseases. For example, the Hygiene Hypothesis, which is based on comparing populations with low and high rates of allergies, posits that fewer infections and more cleanliness might explain the rising incidence of allergies in the developed world [1].

Another controversial factor that could be contributing to more people developing allergic diseases is the fortification of folic acid in foods. The conundrum here is that while folic acid prevents neural tube defects in newborns, it may also have unintended consequences.

Environmental factors influence epigenetics, including methylation, which increases allergic immune cells and reduces regulatory T cells. Folic acid may be one such environmental factor.

Folic Acid – The Double-Edged Sword

Folate deficiency can cause neural tube defects in newborns. As a result, there are public health campaigns to advocate for synthetic folic acid (henceforth referred to as “folic acid”) supplementation and food fortification. 

In 53 countries, including the United States, all wheat flours and many grain products are fortified with folic acid [2]. These campaigns have successfully reduced the incidences of neural tube defects.

However, folic acid is not harmless and too much of it is linked to many adverse health outcomes [3]. Excess folic acid intake above 250 micrograms/day can result in unmetabolized folic acid in the blood, which is now found in over 95% of Americans [4]. 

The excess folic acid can interfere with normal folate metabolism, resulting in folate deficiency due to lower methylfolate levels [5, 6]. Folic acid can, therefore, lower DNA methylation and interfering with normal epigenetics [7, 8, 9]. These changes in DNA methylation do get passed onto children, which may affect their health risks [10, 11].

If you have reduced MTHFR function, you are even more susceptible to problems from folic acid. In mice with 50% MTHFR function, high folic acid consumption (10x recommended doses) further reduces MTHFR and activity levels [5]. 

While the recommended daily intake of folic acid for women of reproductive age is about 400 micrograms [12], doctors may prescribe up to 5,000 micrograms (equivalent to 5 milligrams) for women with difficult pregnancies or undergoing fertility treatments [6]. In a case study, one such woman develops symptoms of folate deficiency while taking 5,000 micrograms/day of folic acid. Her symptoms included elevated homocysteine and the inability to get pregnant [13]. This was resolved within 5 days after giving her 500 mg of methylfolate!

Excessive synthetic folic acid can interfere with normal folate metabolism and result in folate deficiency, which may influence epigenetics.

Does Synthetic Folic Acid Cause Allergies?

In mice, if the pregnant mothers were fed with folic acid and their offsprings were subsequently exposed to an allergen, the babies would develop much more severe asthma than if the mothers were not fed with folic acid [14]. Interestingly, studies in humans are conflicting, making it a controversial topic.

These results may conflict with each other due to confounding factors—they used different or unreliable methods, such as relying on questionnaires to assess folic acid and food intake, or the lack of systematic measurement for methylfolate. In addition, other nutritional factors, such as vitamins B2 and B6, which were not measured, also influence folate needs and usage. 

Unfortunately, it is neither ethical nor feasible to do a strictly controlled experiment on maternal folate exposure in humans as we have done in mice, so it is only possible to observe and compare between self-reported populations. Therefore, it is not possible to remove all the confounding factors to clarify the results.

Complete folic acid fortification in the US since 1998 coincided with the rise in prevalence in allergic diseases. A study of 1394 children found that exposure to unmetabolized folic acid, but not methylfolate, in the womb is associated with childhood food allergy [15]. In addition, many large observational studies have associated maternal folic acid supplementation with childhood allergic diseases [16, 17, 18, 19, 20, 21].

However, as is typically the case for complex conditions that have multiple contributing factors, many other studies also found no association between folic acid use and allergic diseases [22, 23].

In order to reconcile these conflicting results and make the information applicable to you (an individual not a population), we will first review how this works biochemically and explain our thought process on different factors that affect your individual risk.

Excess folic acid may cause allergies in offsprings. However, observational studies in humans are conflicting, suggesting that folic acid alone is not the only factor that leads to allergies.

Folate and Your Immune System

Folate is important for expanding immune cell populations

The immune system needs folate to function correctly because folate is important for producing more cells (cell division). When a pathogen invades, your immune cells need to quickly expand in numbers in order to attack the pathogen. As a result, folate deficiency can compromise the immune system [24].

In elderly people who tend to be deficient in folate, folate supplementation improves their ability to fight off infections [25]. However, too much folic acid (over 400 micrograms/day) may impair the ability of the immune system to kill cancer cells [26].

Folate deficiency inhibits regulatory T cells

Regulatory T cells have a lot of folate receptors, suggesting that its function is sensitive to folate levels [27]. Folate deficiency can reduce the number of regulatory T cells, increasing the risks of allergies, autoimmunities, and food sensitivities [28]. 

Sensibly, low folate levels and the MTHFR C677T mutation, which impairs the ability to produce methylfolate, may increase the risk of allergic diseases [29, 30].

Folic Acid Changes DNA Methylation

While we know that folic acid alters DNA methylation in a way that may increase the risks of allergic diseases [31]. However, we need additional studies, especially in humans, to confirm this effect.

Folate is important for immune function and immune system balance. Folate deficiency can reduce regulatory T cells. In addition, folic acid alters DNA methylation.

Reconciling Conflicting Results – What to do:

When it comes to translating these results from large observational studies into individualized recommendations, consider that each human is unique. Here is our stance on this matter:

1) Avoid folic acid and use methylfolate instead

Methylfolate is the more bioavailable form of folate that is less likely to cause problems, regardless of MTHFR genotype.

2) Consider other predisposing factors

Remember that allergic diseases have many contributing factors, and not all of them have been identified. For example, family history is a known risk factor for childhood allergy, so the parents may want to be more careful about their folic acid intake than others if they or their other children have allergies [32]. 

3) Supplement based on lab tests

In addition, because both too little and too much folate can be harmful, we advocate for supplementation based on lab test results rather than blindly dosing folate. You can analyze your red blood cell and serum folate levels with LabTestAnalyzer.com to see if they are within optimal ranges. 

4) Pay attention to nutrient synergy when supplementing

Vitamins are typically present together in nature because they work together in the same pathway. Therefore, it is better to consume whole-food sources of vitamins, if possible. 

However, if your lab results show that you are suboptimal or deficient despite consuming a nutrient-dense diet, consider supplementing with a vitamin B complex that contains methylfolate. In fact, supplementing folic acid along with other B vitamins reduce the chance of having excess unmetabolized folic acid in the blood [33].

Takeaway

Synthetic folic acid should be avoided in favor of methylfolate to prevent excess folic acid in the blood.

Folate is important for immune function and maintaining the immune balance to prevent allergies and autoimmunity.

Excess synthetic folic acid, especially during pregnancy, may cause allergies in children. However, it is not the only cause of allergies. There may be other confounding factors that contribute to the conflicting human studies results.

About the Author

Nattha Wannissorn - PHD (MOLECULAR GENETICS) - Writer at Selfhacked

Nattha Wannissorn, PhD

PhD (Molecular Genetics)

Nattha received her Ph.D. in Molecular Genetics from the University of Toronto and her undergraduate degree in Molecular and Computational Biology from the University of Pennsylvania.

Aside from having spent 15 years in biomedical research and health sciences, Nattha is also a registered holistic nutritionist, a certified personal trainer, has a precision nutrition level 1 certification, and is a certified functional diagnostic nutrition practitioner. As a holistic practitioner with a strong science background, Nattha is an advocate of science literacy in health topics and self-experimentation.

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