Removing Folic Acid From Our Diet - Why It Matters, and To Whom It Matters Most
*This article is not medical advice. Before starting on any health related regimen, seek the advice of your Primary Care Physician or an M.D.
What Is Folic Acid
Its a synthetic stable form of B9. It was mandated to be put in all enriched flour in 1998 in the USA. The FDA mandated folic acid fortification of enriched cereal grain products, such as flour, bread, pasta, and rice, starting in 1998 to help prevent neural tube defects. This mandate requires these specific products to contain folic acid at levels ranging from 0.43 to 1.4 mg per pound. While mandatory for "enriched" products, other fortified foods are a result of voluntary fortification programs. CDC recommends all women capable of becoming pregnant get 400 micrograms (mcg) of folic acid daily. Getting 400 mcg of folic acid each day helps prevent some serious birth defects called neural tube defects (NTDs). Folic acid is more stable than folates found naturally in food. It is used in supplements and fortified foods, such as bread, pasta, some breakfast cereals, and some corn masa flour. A woman needs adequate folate in early pregnancy to properly form the neural tube, which becomes a baby's brain and spine. [1]
“The DHFR gene, not MTHFR, is the gene that processes folic acid into folates. The DHFR gene does other things too - like recycle BH2 back into BH4 [19] for use in various pathways including the production of serotonin, and dopamine. The DHFR gene in general, has low activity, and can become easily overloaded. In the case of high folic acid intake, this can be most problematic for those with lowered DHFR activity - in particular a mutation on location RS (rs70991108) [2]. When deletions are present on this location, these folks are much more susceptible to having elevated levels of Unmetabolized Folic Acid (UMFA) in their blood, especially with folic acid in intake above 500mcg/day. UMFA - results in a number of deleterious effects from blocking folate receptors themselves, to inhibiting the transport of important nutrients like B1 and B2. In on-line communities, people will exclaim that those with MTHFR mutations cannot process folic acid - they are both right and wrong. DHFR processes folic acid, but the buildup up UMFA - can mechanistically result in a B2 blockade - which is the cofactor for MTHFR!. Other studies point to a pseudo-deficiency in MTHFR after FA supplementation in mice.”
DHFR (Dihydrofolate Reductase) - NADPH Cofactor
DHFR converts synthetic folic acid (pteroylmonoglutamate) into tetrahydrofolate
DHFR catalyzes the reversible reduction of dihydrofolate (DHF) to tetrahydrofolate (THF) using NADPH as a cofactor.
This is an essential, rate-limiting step in folate metabolism that enables the continuous regeneration of tetrahydrofolate, the core cofactor for one-carbon transfer reactions
Dihydrofolate reductase; reduces DHF → THF for 1‑C metabolism (purines, thymidylate, Met). Dihydrofolate reductase catalyzes the reduction of Folic Acid (FA) to Dihydrofolate (DHF),. Dihydrofolate reductase converts dihydrofolate into tetrahydrofolate, a methyl group shuttle required for the de novo synthesis of purines, thymidylic acid, and certain amino acids. Dihydrofolate reductase deficiency has been linked to megaloblastic anemia. NADPH cofactor required. Uses non catalytic cysteine residues.
MTHFR - B2 Cofactor
Reduces 5,10‑methylene‑THF → 5‑methyl‑THF for methionine synthase/Re-methylation; C677T variants yield thermolabile enzyme with lower activity/stability. NADPH, and FAD required cofactors. Uses cysteine residues.
UMFA can create pseudo-MTHFR like deficiency [21].
Unmetabolized Folic Acid (UMFA)
In the 2007-2008 NHANES (National Health and Nutrition Examination Survey), UMFA was present in almost all serum samples! 95% of the US population surveyed had UMFA concentrations greater than 0.3 nmol/L in their blood [9].
In Ireland, with no mandatory fortification, UMFA was found to be widespread amongst the elderly [10].
Timeline of Folic Acid Supplementation Into Food
You can see when the UMFA started becoming a concern. It’s also apparent that the program works as expected when it comes to saving babies [11,12,13].
1992 – the US Public Health Service recommended that women of child-bearing age take 400 mcg of folic acid daily.
1998 – the US and Canada introduced mandatory folic acid fortification. In the US, grain products manufacturers were required to enrich every 100g of flour with 140mcg of folic acid
2007 – in Canada, the FA fortification program helped reduce NTDs by up to 46%
2015 – a US study estimates that about 1,326 babies born without NTDs would otherwise have been affected without the program
2020 – more than 80 countries have implemented a folic acid fortification program
What are the adverse effects of unmetabolized folic acid?
Both excessive FA intake and UMFA may mask a vitamin B12 deficiency. It may also hide pernicious anemia. UMFA isn’t directly responsible for a B12 deficiency, but its capacity to mask the deficiency can delay treatment. If left untreated, this deficiency can damage the heart, brain, nerves, and cause digestive issues [15].
UMFA might also be linked to reduced numbers and activity of natural killer cells, which may harm immune health. These cells are the first line of defense against tumor cells and viral infections [16].
However, an in-vitro study contradicts the findings above. Researchers say that natural killer cell function is NOT influenced by either folic acid or 5-MTHF [17].
Another study says UMFA may cause cancer to accelerate or speed up [10]. But there does not seem to be enough data to support this theory. For instance, a study that looked at 553 cases of breast cancer found that circulating UMFA is not associated with breast cancer risk [18].
Carriers of the DHFR del/del genotype (above) had worse memory scores and worse executive scores than did those with other genotypes. Finally, we observed an interaction such that carriers of the del/del genotype with high folate had significantly worse memory scores than those of both noncarriers with high-folate and del/del carriers with normal-folate. [20] This implies UMFA in the blood.
So far, we’ve come across a bunch of seemingly conflicting studies…
Moreover, there were no significant differences in the UMFA plasma concentration of women receiving 1.1mg vs 5mg of FA daily. This suggests that the body adapts to limit exposure to unmetabolized FA [7].
What Does UMFA Cause ? B1 and B2 Trouble
You can see from the above when we look at broad studies across populations that effects become less clear - what is needed is an understanding of the mechanics or mechanisms of action so those most likely to be adversely effected - can be isolated and the effects be understood more precisely. This takes an understanding of genetics and bio chemistry - very few are interested.
Inhibits folate receptors and transporters - FOLR1, SLC19A1, SLC46A1 [3]. If this is the case, then the folate we need - can be prevented from being properly used - so in a wierd way - too much folic acid - which was intended to make up for a lack of folate in modern diets - creates a potential folate deficiency.
There is a mechanistic probability (although no published research) that unmetabolized folic acid also impairs the absorption and or transport of other key nutrients, namely B1, B2:
B1 (SLC19a2, SLC19a2 inhibited). UMFA competitively inhibits transport because SLC19A1–3 family members have overlapping substrate domains for reduced folates and thiamine.
B2 (SLC52A1, SLC52A2, SLC52A3, etc) - needed as a cofactor for……drum roll…..MTHFR. High extracellular folate (esp. FA) reduces riboflavin uptake, via competitive transporter interaction or altered membrane potential. UMFA may impede import of FAD indirectly by altering folate redox balance and mitochondrial NADPH status. One of the transcription factors for SLC52A1 and SLC52A3, is SP1, and is methylation sensitive - so a methylation block can impair riboflavin transport.
Other UMFA - Other Genes Affected by UMFA [21]
Although plasma folate increased in FASD-fed mice, plasma homocysteine did not decrease
Folic Acid Supplementation (FASD) and Mthfr genotype had significant effects on hematologic parameters. The lower RBC count, hematocrit, and hemoglobin and the higher mean corpuscular volume, particularly in FASD Mthfr+/- mice, are consistent with reduced hematopoiesis, suggesting that FASD may impair nucleotide biosynthesis in addition to methylation reactions.
MTHFR protein levels were lowered by the Mthfr+/- genotype, as expected, and by FASD.
Although we confirmed that MTHFR activity is inhibited by folic acid in vitro, suggesting that UMFA might inhibit
MTHFR in tissues, UMFA in the liver was low and unlikely to have as great an effect as the expression and phosphorylation changes. Reduced methyl THF, SAM, and SAM/SAH ratio are consequences of lower MTHFR expression and follow the same diet/genotype pattern
A major consumer of liver SAM is methylation of phosphatidylethanolamine to phosphatidylcholine by PEMT. phosphatidylcholine synthesis via the CDP-choline pathway may be upregulated to compensate for reduced SAM concentration and Pemt expression, consistent with the reduction in Phosphatidyl Choline. Lower concentrations of phosphatidylethanolamine , phosphatidylcholine, SM, and LysoPtdCho in Mthfr+/- mice suggest that reduced methylation capacity due to MTHFR deficiency leads to greater use of betaine as a one-carbon donor and affects the choline-dependent synthesis of membrane phospholipids.
Mthfr+/- mice are particularly dependent on betaine-dependent homocysteine remethylation, consistent with the reduced betaine concentration in this study. However, the increased flux through betaine was insufficient to maintain SAM concentrations. Reduced Chdh expression suggests that capacity for betaine synthesis may not have met betaine demand. Altered Chdh expression may be a mechanism to spare choline for phosphatidylcholine synthesis via the CDP-choline pathway because PEMT expression is reduced. This is consistent with observations in humans as the rate of homocysteine remethylation may be reduced in patients with nonalcoholic steatohepatitis (NASH)
Reduced Nr1h4 in FASD-fed mice may have led to greater nuclear SREBP-1. FXR has also been shown to upregulate Ppara. Reduced expression of Ppara and its targets Scd1 and Fads2 is consistent with lower Nr1h4 expression. Expression of Pnpla2 (ATGL) was also lower in FASD-fed mice. ATGL catalyzes the first step of triglyceride hydrolysis to generate free fatty acids; triglyceride hydrolysis products upregulate PPARa signaling. Disruption of Pnpla2 prevents extraction of free fatty acids from lipid droplets, leading to severe steatosis and hepatic inflammation in mice. NR1H4 controls the bile salt export pump (BSEP/ABCB11) and thus effects detoxification.
Downregulation of CYP7A1 lowers cholesterol catabolism, raising cholesterol levels. Both FASD and the Mthfr+/- genotype significantly lowered Cyp7a1 expression. Greater methylation of Cyp7a1 CpGs in Mthfr+/- mice may have contributed to this effect. Reduced CYP7A1 may result in a buildup of intracellular cholesterol, leading to toxic effects such as altered membrane integrity.
Many of the dramatic effects on choline metabolites and gene expression were due to the combination of
MTHFR deficiency (+/-) and FASD. These findings suggest a 2-hit mechanism whereby MTHFR-deficient hepatocytes are less able to mitigate the effect of phospholipid and lipid disturbances, leading to hepatocyte injury. MTHFR deficiency in hepatocytes may set the stage for other insults (e.g., high-fat diets) that could also lead to NAFLD.
Summary
What if i told you, a number of people with this specific mutation (deletion) on DHFR, also responded poorly to doctored ordered folic acid supplementation, and also favorably to high dose Thiamine and Riboflavin supplementation ? B1 and B2 are critical nutrients across so many genes from the Krebs Cycle, Mitochondrial Electron Transport Chain, to being cofactors for the most critical anti oxidant genes, both in the cytosol and mitochondria. B2 is also a critical cofactor to make heme - perhaps one of the most important endogenous cofactors the body makes. FAD (one of the active forms of B2) is perhaps one of the most important cofactors - necessary to make nitric oxide, and also necessary to be imported into the mitochondria.
If we block folate receptors and transport - what critical processes are effected ? Methylation - required to remove many toxins, like heavy metals. And also needed for brain stem and spinal cord formation of the fetus. Add that onto all the processes needed to be supported by B1 and B2. All the phase 1 cyp450 genes need FAD (active b2), many of the redox/anti oxidant genes required FAD (active B2). If you dont have FAD (active b2), MTHFR doesnt work - you cant detox metals, etc. I could go on for soooo long. No folate, no methylation, no B1, no B2 and the systemic crash - would take too long to describe.
References:
CDCA 19-Base Pair Deletion Polymorphism in Dihydrofolate Reductase Is Associated with Increased Unmetabolized Folic Acid in Plasma and Decreased Red Blood Cell Folate. by Renee D Kalmbach, et. al. Journal of Nutrition. . 2008 Dec;138(12):2323–2327. doi: 10.3945/jn.108.096404. PMCID: PMC2855991 PMID: 19022952Folic Acid, Folinic Acid, 5 Methyl TetraHydroFolate Supplementation for Mutations That Affect Epigenesis through the Folate and One-Carbon Cycles. by Yves Menezo. Laboratoire CLEMENT, Avenue d’Eylau, 75016 Paris, France. Bourn Hall Clinic, Cambridge CB232TN, UK. Biomolecules 2022, 12(2), 197; https://doi.org/10.3390/biom12020197. Submission received: 20 December 2021 / Revised: 18 January 2022 / Accepted: 20 January 2022 / Published: 24 January 2022Reduced folate carrier transports thiamine monophosphate: an alternative route for thiamine delivery into mammalian cells. Rongbao Zhao, et. al. Am J Physiol Cell Physiology. 2002 Jun;282(6):C1512-7. doi: 10.1152/ajpcell.00547.2001. PMID: 11997266. DOI: 10.1152/ajpcell.00547.2001The emerging role of unmetabolized folic acid in human diseases: myth or reality? Obeid R, Herrmann W. Curr Drug Metab. 2012;13(8):1184-1195.Circulating Unmetabolized Folic Acid: Relationship to Folate Status and Effect of Supplementation, Carolyn Tam, Deborah O’Connor and Gideon Koren, Published19 Feb 2012General Information About Neural Tube Defects, Folic Acid, and Folate, taken from: https://www.cdc.gov/ncbddd/folicacid/faqs/faqs-general-info.htmlTaken from JN The Journal Of Nutrition, https://jn.nutrition.org/Taken from The American Journal of Clinical Nutrition, https://ajcn.nutrition.org/General Information About Neural Tube Defects, Folic Acid, and Folate, taken from: https://www.cdc.gov/ncbddd/folicacid/faqs/faqs-general-info.htmlFolic acid food fortification in Canada. Ray JG. Nutr Rev. 2004;62(6 Pt 2):S35-S39.Updated Estimates of Neural Tube Defects Prevented by Mandatory Folic Acid Fortification — United States, 1995–2011, Jennifer Williams, MSN, Cara T. Mai, DrPH, Joe Mulinare et al.Folate, Fact Sheet for Health Professionals, from; https://ods.od.nih.gov/factsheets/Folate-HealthProfessional/#en70Taken from The American Journal of Clinical Nutrition, https://ajcn.nutrition.org/Taken from JN The Journal Of Nutrition, https://jn.nutrition.org/Natural killer cell cytotoxicity is not regulated by folic acid in vitro, Sandra Hirsch, Dante Miranda… Nutrition, Volume 29, Issue 5, May 2013, Pages 772-776Circulating unmetabolized folic acid and 5-methyltetrahydrofolate and risk of breast cancer: a nested case-control study. Koenig, K.L., Scarmo, S., Afanasyeva, Y. et al. Eur J Clin Nutr 74, 1306–1315 (2020).Folate, folic acid and 5-methyltetrahydrofolate are not the same thing, Francesco Scaglione, Giscardo Panzavolta, Pages 480-488 | Received 12 Jul 2013, Accepted 13 Sep 2013, Published online: 04 Feb 2014Critical Role for Tetrahydrobiopterin Recycling by Dihydrofolate Reductase in Regulation of Endothelial Nitric-oxide Synthase Coupling RELATIVE IMPORTANCE OF THE DE NOVO BIOPTERIN SYNTHESIS VERSUS SALVAGE PATHWAYS. Mark J Crabtree, et. al. J Biol Chem. 2009 Aug 7;284(41):28128–28136. doi: 10.1074/jbc.M109.041483. PMCID: PMC2788863 PMID: 19666465Dihydrofolate reductase 19-bp deletion polymorphism modifies the association of folate status with memory in a cross-sectional multi-ethnic study of adults. By Dana Philip, et. al. . Am J Clin Nutrition. 2015 Nov;102(5):1279-88. doi: 10.3945/ajcn.115.111054. Epub 2015 Sep 9. PMID: 26354538. PMCID: PMC4625589. DOI: 10.3945/ajcn.115.111054High folic acid consumption leads to pseudo-MTHFR deficiency, altered lipid metabolism, and liver injury in mice By Christensen, et. al. . The American Journal of Clinical Nutrition Volume 101, Issue 3, March 2015, Pages 646-658. https://doi.org/10.3945/ajcn.114.086603