MTHFR and Histamine Levels: What's the Link | Methyl-Life®

Histamine is linked to allergic symptoms such as hay fever and skin rashes. While these reactions are often linked to food and environmental sensitivities, recent research suggested that histamine levels may also be influenced by the MTHFR mutation.

Histamine is a biologically active molecule known as an amine. It’s formed when the carboxyl group is removed from the amino acid histidine, a process known as decarboxylation.

The highest concentrations of histamine are in the gut lining, the skin, and the respiratory tract. Basophils and mast cells within these tissues secrete histamine when the body detects a pathogen or foreign substance, which becomes part of the immune response.

Mast cells are the major producer of histamine¹ and express many receptors on their surface. These receptors are activated through stimulants such as allergens, complement peptides, and neuropeptides, which cause the mast cells to release various inflammatory mediators, including histamine.

MTHFR is an enzyme required for numerous methylation processes in the body², including the conversion of folate to methyl-folate, DNA function, the repair of damaged cells, neurotransmitter production, the metabolism of B vitamins, and many others.  Methylation is also required for the proper functioning of the Histamine-N-Methyl-Transferase³ (HNMT) enzyme, which is critical for the processing of histamine.

Impaired methylation caused by mutations on the MTHFR gene can lead to a variety of health issues, including elevated homocysteine⁴, histamine intolerance, allergies and intolerances, hormonal imbalances, and more.

This article will explain the role of the MTHFR gene in histamine production and regulation and why a mutation may result in elevated histamine levels. We will also explain how different MTHFR variants can affect histamine levels and how someone with an MTHFR mutation can support their body’s methylation function through supplements.

One of the most important functions of the MTHFR gene is the conversion of homocysteine to methionine. Methionine⁵ is involved in detoxification, cell repair, the building of proteins, and healthy inflammatory response. It’s also necessary for producing glutathione, the body’s most important detoxification substance.

Methionine is broken down in the liver to create SAMe, a compound that helps produce and regulate hormones and maintain cell membranes. SAMe is also required to break down neurotransmitters and repair cellular damage.

SAMe is also an important cofactor of HNMT, the enzyme that processes and regulates histamine⁶ in the body. It also plays a key role in histamine detoxification. The HNMT enzyme works to add a methyl group to histamine so that the methylated histamine molecules can then be flushed out of the body in urine.

In short, the MTHFR helps regulate methylation,  which is essential to reduce intracellular histamine. This process requires vitamin B2 as a cofactor.

Methylation underpins many essential daily functions, from regulating cognitive function and supporting energy levels to detoxifying harmful substances from the body and supporting growth and repair.

Methylation occurs as a result of two important cycles - the folate cycle and the methionine cycle. Both of these are required to produce 5-MTHF and S-adenosyl methionine (SAMe), the body’s main methyl donor. SAMe is used in numerous bodily systems⁷ as it is required to donate a methyl group to various methyltransferase enzymes.

Methylation of neurotransmitters and hormones, such as dopamine, histamine, melatonin, and estrogen is necessary to facilitate their excretion.

The proper functioning of HNMT detoxifies histamine from the body, and this also depends on methylation. If methylation is impaired, the proper functioning of either HNMT or Catechol-O-Methyltransferase (COMT) is affected, and the body is less efficient at removing toxins⁸. This can lead to a significant build-up of histamine. At the same time, impaired function of the Diamine Oxidase (DAO) and Monoamine Oxidase (MAO) genes may impair detoxification further.

Methylation is also essential for the proper functioning of the COMT enzyme, which underpins the processing of estrogen in the liver⁹. 

Immune function¹⁰ is also dependent on methylation due to its role in regulating immune cell differentiation and maturation, antigen recognition, and the body’s immune response to antigens. 

Methylation is also involved in the production of phosphatidylcholine¹¹, which makes bile acids. Bile acids regulate the pH of the small intestine and help to digest certain food molecules. When insufficient, the pH of the small intestine rises, which is a major cause of small intestinal bacterial overgrowth (SIBO). Histamine intolerance is linked to a deficiency of the enzyme DAO and, therefore, the poor processing of histamine within the GI tract¹².

Although histamine levels are usually kept under control by rapid enzymatic detoxification, genetic variants such as MTHFR may increase histamine production or slow down¹³ its breakdown in the body. This can create a vicious cycle of high histamine, inflammation, and allergic symptoms.

Because SAMe relies on the proper function of the MTHFR enzyme, an MTHFR genetic mutation can impair the function of HMNT. The breakdown of histamine will be compromised, possibly leading to higher histamine levels and symptoms associated with histamine intolerance, such as skin conditions, digestive troubles, headaches, migraines, fatigue, and an irregular menstrual cycle.

Histamine is a key player in the allergic inflammatory cascade, and those with allergies tend to have a higher baseline histamine level, prolonging inflammatory signaling.

Impaired estrogen detoxification due to poor methylation can result in the accumulation of estrogen¹⁴, which in turn stimulates mast cells to release histamine.

Disruption of the HMNT gene has been shown to result in a significant increase in brain histamine¹⁵ concentration, demonstrating the essential role of HNMT in the brain’s detoxification system. Clinical studies have also suggested that single nucleotide polymorphisms of the human HNMT gene are associated with several brain disorders¹⁶ such as Parkinson’s disease and attention deficit hyperactivity disorder.

Abnormal variations of MTHFR can also be inherited as heterozygous (one variant) or homozygous (two variations).

Homozygous (two copies) of the MTHFR 677TT  leads to significantly reduced MTHFR enzyme function. At the same time, one copy of C677T and one of A1298C can also result in a significant reduction in MTHFR enzyme activity (up to 60%¹⁷)). Both variants lead to significantly lower levels of 5-MTHF, potentially impairing methylation further.

The A1298C polymorphism is generally thought to be less detrimental though studies on this form of MTHFR are ongoing.