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There are many links between the MTHFR enzyme and gene mutations (C677T and A1298C). If you are homozygous for either of the gene mutations or compound heterozygous (C677T + A1298C), histamine – and the related vaginal symptoms – may be an issue for you.
MTHFR enzyme and methylation
The MTHFR gene provides directions for the production of the MTHFR enzyme. The MTHFR enzyme breaks down folate and folic acid into the active form, L-methylfolate1.
L-methylfolate is required for methylation. If the conversion isn’t sufficient from folate or folic acid to L-methylfolate, you will not be methylating as much as you need to, though the extent varies between people.
HNMT enzyme and histamine
Methylation is required for the histamine-N-methyl-transferase (HNMT) enzyme to function. The HNMT enzyme degrades histamine2.
Thus, insufficient methylation means insufficient histamine degradation and a subsequent build-up of histamine in the body3. This excess histamine can result in vaginal, urinary tract and other symptoms.
COMT enzyme and histamine
Methylation is also required for the catechol-O-methyl-transferase (COMT) enzyme. The COMT enzyme is essential to liver clearance of oestrogen4.
A build-up of oestrogen results in mast cells being stimulated to produce more histamine5. Higher histamine levels then cause more oestrogen to be produced6, with a loop being created that worsens both oestrogen excess and histamine excess.
DAO enzyme and oestrogen
Oestrogen and the diamine oxidase (DAO) enzyme that degrades histamine have a complex, tissue-dependent relationship. Far from being simply suppressed, DAO is produced in very high amounts in some settings – the placenta makes huge quantities in pregnancy, for example7 – so the more reliable oestrogen–histamine link is oestrogen’s effect on mast cells, described above.
Methylation, histamine and SIBO
Methylation results in phosphatidylcholine, a major component of bile8. Bile acids play a major role in regulating the pH of the small intestine. Insufficient bile acids result in pH imbalances of the small intestine, a cause of small intestinal bacterial overgrowth (SIBO).
SIBO results in inflammation of the small intestine, which in turn releases histamine. The DAO enzyme can’t keep up, so the HNMT enzyme picks up the slack. If you’re not methylating properly, the HNMT enzyme becomes quickly overwhelmed due to less L-methylfolate.
Then, choline is used for methylation of homocysteine to methionine for producing SAM (a major methyl donor), leaving insufficient choline to make phosphatidylcholine and bile acids9.
Additionally, some bacteria produce histamine10.
And around it goes…
If you have MTHFR genetic mutations and histamine problems, working on methylation may be a key to recovery.
This article is general information and not a substitute for personalised medical advice. If you are dealing with ongoing vaginal or histamine symptoms, please see an experienced practitioner.
- Nazki FH, Sameer AS, Ganaie BA. Folate: metabolism, genes, polymorphisms and the associated diseases. Gene. 2014;533(1):11-20.
- Yoshikawa T, Nakamura T, Yanai K. Histamine N-methyltransferase in the brain. International Journal of Molecular Sciences. 2019;20(3):737.
- Maintz L, Novak N. Histamine and histamine intolerance. The American Journal of Clinical Nutrition. 2007;85(5):1185-1196.
- Dawling S, Roodi N, Mernaugh RL, Wang X, Parl FF. Catechol-O-methyltransferase (COMT)-mediated metabolism of catechol estrogens: comparison of wild-type and variant COMT isoforms. Cancer Research. 2001;61(18):6716-6722.
- Zierau O, Zenclussen AC, Jensen F. Role of female sex hormones, estradiol and progesterone, in mast cell behavior. Frontiers in Immunology. 2012;3:169.
- Bódis J, Tinneberg HR, Schwarz H, Papenfuss F, Török A, Hanf V. The effect of histamine on progesterone and estradiol secretion of human granulosa cells in serum-free culture. Gynecological Endocrinology. 1993;7(4):235-239.
- Maintz L, Schwarzer V, Bieber T, van der Ven K, Novak N. Effects of histamine and diamine oxidase activities on pregnancy: a critical review. Human Reproduction Update. 2008;14(5):485-495.
- Li J, Xin Y, Li J, Chen H, Li H. Phosphatidylethanolamine N-methyltransferase: from functions to diseases. Aging and Disease. 2023;14(3):879-891.
- Obeid R. The metabolic burden of methyl donor deficiency with focus on the betaine homocysteine methyltransferase pathway. Nutrients. 2013;5(9):3481-3495.
- Barcik W, Wawrzyniak M, Akdis CA, O’Mahony L. Immune regulation by histamine and histamine-secreting bacteria. Current Opinion in Immunology. 2017;48:108-113.
