Histamine intolerance and MTHFR: How are they related?

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

These amines are chemicals which occur naturally in certain foods and are usually well-tolerated. 

However, some people experience symptoms after ingestion. This may be due to a lack of diamine oxidase (DAO), an enzyme that breaks down histamine in the gut.

The highest concentrations of histamine are in the gut lining, the skin, and in the respiratory tract. Cells within these tissues called basophils and mast cells produce histamine when the body identifies a foreign substance. In fact, mast cells are the major producer of histamine 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.

Histamine intolerance (HIT) is caused by an accumulation of histamine in the body.³ This accumulation occurs due to a deficiency in certain enzymes required to metabolize histamine, allowing histamine to build up in plasma and cause adverse effects on the body.

Histamine activates histamine receptors, triggering a cascade of inflammatory mediators. This causes airways to contract, and increases vascular permeability and heart rate.⁴

Inability to metabolize histamine can result in sensitivity to high histamine levels in food. This sensitivity has been linked to various physiological responses and immune reactions, including inflammation, muscle cramping, vasodilation, and the release of inflammatory chemicals.

Histamine intolerance can cause a variety of symptoms that affect the skin, gastrointestinal system, cardiovascular system, mucus membranes, and respiratory functions. Symptoms of histamine intolerance⁵ may occur 30 minutes or longer after eating, although tolerance levels vary from person to person.

• Gastrointestinal: Abdominal pain, diarrhea, constipation, nausea, belching, bloating
• Cardiovascular: Headache, vertigo, palpitations
• Respiratory: Runny nose, nose congestion, sneezing and asthma
• Skin: Itching, rashes, redness, swelling, reddened eyelids

Although the MTHFR gene doesn’t directly cause histamine intolerance, MTHFR does play a major role in methylation, and proper methylation is critical to the function of DAO.

The MTHFR gene provides instructions for producing the MTHFR enzyme, which is required for converting folate (and folic acid) into the active form, methylfolate. Methylfolate and methionine are both required to produce S-adenosylmethionine (SAMe), the body’s main methyl donor. Many bodily systems are dependent on SAMe for this purpose. SAMe production relies on adequate stores of folate, vitamin B12, and choline.⁶

Around 50-80% of intracellular histamine is broken down by the enzyme histamine N-methyltransferase (HNMT). HMNT is mostly present in the respiratory, small intestinal, liver and kidney cells. It works by adding a methyl group from S-adenosyl-L-methionine, which then produces N-methylhistamine and subsequently M-methylimidazole acetic acid.⁷

Extracellular histamine is metabolized by diamine oxidase (DAO) through methylation. DAO is found in the gut, liver, kidney, placental and skin cells. It breaks down 15-30% of extracellular histamine in a process that requires vitamins B6, C and copper to function effectively.⁸

Clinical studies suggest that histamine intolerance can result from a number of biological malfunctions, including:

• DAO genetic mutations
• Impaired DAO or HNMT enzymes
• Gastrointestinal disorders or dysfunction (malabsorption inflammation, dysbiosis, infections)
• Nutrient deficiencies, particularly copper, vitamin C, and B6 (which can lead to decreased activity of DAO)[4]

Lifestyle causes may include:

• Diet: High-histamine foods such as sauerkraut, processed meat, fish, spinach, tomatoes, cocoa, eggplant, chicken, yogurt, soy, red wine are major causes of histamine reactions. Foods that promote mast cell histamine release may also trigger symptoms, particularly citrus, pineapple, bananas, strawberries, papaya, tomatoes, and artificial additives.
• Stress, alcohol, medications and xenobiotics that decrease DAO activity (or interfere with histamine metabolism) also affect histamine regulation.

If your tolerance for histamine is low, you are likely to react when you eat or drink something containing histamine.

The first step in managing your symptoms is to eat a low-histamine diet. Foods with the lowest amount of histamine are fresh, natural foods, including:

•  Fresh fruits and vegetables

•  Gluten-free grains (these are less likely to aggravate an irritated gut lining): amaranth, corn, millet, quinoa, rice, teff.

•  Fresh herbs

•  Fresh animal proteins: fish, chicken, beef, lamb.

•  Anti-inflammatory foods such as fatty fish, bone broth, berries

The levels of histamine in foods increase with fermentation and the degree of processing. Your histamine intolerance food list¹⁰ might include:

• Alcohol, especially red wine

• Avocado

• Dried fruits

• Eggplant

• Processed or smoked meats: salami, sausages, pepperoni, lunch meat, hot dogs

• Fermented beverages such as kombucha

• Fermented dairy products: yogurt, kefir, sour cream, buttermilk, cottage cheese, ricotta

• Fermented vegetables: miso, kimchi, sauerkraut, pickles, natto

• Fish and seafood, especially smoked, salted, canned

• Matured cheeses

• Beans and pulses such as chickpeas, soy

• Nuts prone to mold: peanuts, cashews, almonds

• Chocolates and other cocoa-based products

• Rice vinegar

• Instant or packaged meals

• Snacks and sweets with preservatives and artificial additives

• Soy sauce, tamari, coconut aminos, liquid aminos

Histamine is a neurotransmitter and has a variety of physiological roles in brain function. Acute stress increases the histamine turnover in the brain and also influences the hormones involved in the stress response.¹¹

Poor gut microbiome due to gastrointestinal symptoms may also contribute to a variety of cognitive and mood disorders via the gut-brain axis.

Effective techniques for stress management may include nutrition and exercise, along with strategies that improve cognitive and emotional functioning. Breathing, meditation and yoga have been clinically proven to reduce stress and anxiety when practiced regularly.

• DAO is essential for breakdown of histamine in the gastrointestinal system. Studies have shown that taking DAO supplements can help to prevent or alleviate histamine intolerance symptoms in patients.¹²
• Pyridoxal-5-phosphate (P-5-P, the active form of vitamin B6) may be useful in histamine-intolerant individuals as B6 is crucial for DAO activity.¹³
• Methylfolate - which is required for the production of SAMe - is often deficient in those with a MTHFR genetic mutation. Some of the best methylfolate supplements for those with histamine-related conditions due to MTHFR mutations include Methyl-Life® products (B-Methylated II, Methylated Multivitamin, Methylfolate 7.5+ or Methylfolate 15+.)