What Role Do Genes Play in Histamine Intolerance?

When one thinks of histamine and what it means, we often associate it with allergies, antihistamines, and some level of discomfort.

We have all experienced a histamine episode at some point in our lives which is a normal physiological reaction to our environment and the food we ingest. However, histamine intolerance is quite a different ball game and presents as a physical reaction or symptom to something we’ve come into contact with.

What is histamine?

Histamine is an organic nitrogenous compound that is mainly found in Mast cells. Mast cells are a type of white blood cell that is found mostly where the body interfaces with the environment, like the gut and skin. They are often described as the sentinels of the immune system; always on the lookout for environmental changes or insults to the body.

The histamine they release is involved in the immune response and plays a role in regulating the physiological function of the gut and acts as a neurotransmitter for the brain, spinal cord, and uterus.

Histamine is released if an allergen or pathogen is detected in the body. It is a powerful immune cell attracter and causes an influx of immune cells to the area where the allergen was first detected. Histamine causes this activation function by binding to histamine receptors on these immune cells which acts as an instruction for them to elicit an immune response. It is rapidly broken down after its release.

Ever wondered how antihistamines work? They bind to and block these histamine receptors so that histamine is not able to bind. The result (as you may have experienced) is rapid and significant symptomatic relief.

Histamine intolerance

Histamine is necessary in small amounts, however, when its production-break down cycle is disrupted in some way, adverse reactions may be experienced. Disequilibrium of histamine can exist if there is too much histamine produced by the mast cells, introduced into the body by certain foods, or if the body’s capacity to degrade histamine is diminished.

So, what you think is a food intolerance could actually be histamine intolerance. The symptoms can be both acute or chronic and show similarities to an IgE-mediated allergic response. These symptoms include:

• Heart: raised blood pressure, palpitations
• Digestive Tract: food intolerance, nausea, abdominal pain, diarrhea, bloating
• Skin: itchy skin, hives, flushing, rashes
• Lungs: Asthma-like wheezing, shortness of breath,
• Head, Brain, CNS: headache, migraine, anxiety, panic, confusion, depression.

High histamine foods

These symptoms may be exacerbated if you ingest high histamine-containing foods, these include:

• Smoked Meat Products
• Alcohol
• Pickled or Canned Foods – sauerkraut
• Matured Cheeses
• Vinegar
• Shellfish
• Beans and Pulses
• Salty Snacks, Sweets (with preservatives and artificial colorings)
• Nuts
• Chocolates (and other cocoa-based products)
• Ready Meals

That’s not all. Some foods are grouped as being ‘histamine liberators’. These are foods that themselves are low in histamines but cause histamine release in other foods. Unless you’ve been diagnosed as histamine intolerant, you don’t have to remove these from your diet. Histamine liberating foods include:

• Wheat Germ
• Cocoa and Chocolate
• Additives – benzoate, sulfites, nitrites, glutamate, food dyes
• Most Citric Fruits
• Nuts
• Papaya
• Tomatoes
• Beans and Pulses

Is histamine intolerance genetic?

Some individuals are unable to metabolize histamine in the intestine, resulting in sensitivity to normal or even low histamine levels in food ¹. Research has estimated that it affects 1–3% of the population ², a percentage that is likely to increase as more knowledge and diagnostic tools for histamine intolerance become available.

Two main histamine metabolic pathways are known in humans which involve the enzymes diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT). Both play important roles in breaking down and inactivating histamine after it has done its job.

Several studies have analyzed in-depth genetic variations or SNPs in genes encoding the DAO and HNMT enzymes, as well as the different histamine receptors. More than 50 SNPs in the DAO-encoding gene have been identified which can produce a protein with altered activity, leading to symptoms of histamine intolerance. To date, there is no direct evidence linking HNMT genetic variations to histamine intolerance.

So yes, histamine intolerance has a genetic component. We have created dedicated gene pages for the AOC1 genes and HNMT genes in our guide to nutrigenomics. As documented by the American Journal of Clinical Nutrition, both of these genes can play a role in histamine intolerance.

DAO

DAO is made in the cells of the small intestine and the upper large intestine to rapidly remove histamine from the intestine into the cells.  Once it gets processed by DAO and gets into the intestinal wall cells, HNMT inside the cells degrades the histamine. This prevents excess histamine from getting into the bloodstream. However, when too much histamine has been ingested or one or both of these enzymes are deficient, histamine gets into the bloodstream and causes the symptoms described above.

One study found DAO deficiency in 80% of 316 adult patients showing various symptoms associated with histamine intolerance (e.g. abdominal pain, urticaria, pruritus, diarrhea, vomiting, constipation, cough, and headache) ³. In another study focussing only on headache symptoms, DAO deficiency was reported in 23 of 27 patients (85%). Interestingly, a significant increase in DAO activity was detected after these patients followed a low-histamine diet for four weeks, which occurred together with remission or reduction in the frequency of headaches in almost 90% of individuals ⁴.

Interestingly, histamine intolerance is often seen in individuals with pre-existing gastrointestinal disorders such as IBD, IBS, coeliac, or SIBO which are conditions associated with either dysregulated gut microbiota diversity, poor barrier function, or gut-associated inflammation, all of which negatively impact DAO activity.

In female patients who exhibit estrogen dominance, histamine issues are often reported. This is because estrogen excess down-regulates DAO, leading to elevated levels of histamine, which in turn stimulates further estrogen production.

Supplements to boost DAO production

Vitamin C, Vitamin B6, zinc, and copper are all co-factors that are needed to produce DAO in the body. Therefore, a lack of any of these nutrients may decrease DAO activity and increase your sensitivity to histamine.

DAO can be replaced

If you are deficient in DAO because of genetic variations in your DAO gene, it can be replaced with DAO supplements to boost enzymatic activity.

Food-sourced anti-inflammatory compounds

Polyphenols such as grape seed extract, quercetin, pycnogenol, and omega-3 EPA can be particularly useful to include in your low-histamine diet. Polyphenols act directly on mast cells (main source of histamine), thereby reducing the release of histamine into the body. EPA, which is an anti-inflammatory nutrient can then act synergistically with either of these compounds to dampen the inflammatory response caused by histamine.

Increase the population of low-histamine bacteria in your gut

It is known that both pathogenic, as well as commensal bacteria, can make L-histidine decarboxylase (HDC) which is an enzyme that converts histidine into histamine. Additionally, pathogenic bacteria and excessive growth of some commensal bacteria can irritate and damage the gut lining which causes histamine release.

Therefore, testing gut flora populations is a good option if you’d like to investigate your histamine intolerance further.

Conclusion

The techniques and procedures to diagnose histamine intolerance are constantly improving. Tests that determine the DAO activity in blood or intestinal biopsy samples or on identifying genetic or metabolic urinary markers by noninvasive techniques are being assessed for efficacy ⁴.

Research is also underway to identify new sources of DAO enzyme, especially of plant origin, which is a vegan alternative to the porcine-derived DAO.