What's the relation between histamine and gluten intolerance?

What's the relation between histamine and gluten intolerance?

A short while ago, I was alerted to research that is being conducted on histamine intolerance. The reason it piqued my interest was the remark on how perceived gluten intolerance may in reality be a case of histamine intolerance. The researchers that were interviewed spoke about probiotics being developed to 'cure' histamine intolerance.

Therefore, without further ado, an explanation on what histamine intolerance really is.

What is histamine?

Histamine is an extremely important bioactive chemical that is indispensable in the efficient functioning of many body systems. It is a neurotransmitter and is involved in the regulation of stomach acid, the permeability of blood vessels, muscle contraction, and brain function.
In humans, the highest histamine concentrations are found in the skin, lung, and stomach, with smaller amounts in the brain and heart.

Histamine is also essential in defending the body against invasion by potentially disease-causing agents such as bacteria, viruses and other foreign bodies.

Histamine is made and stored within white blood cells such as mast cells.
When the immune system is activated in response to foreign material entering the body, histamine is the first "defense chemical", or more correctly, inflammatory mediator released in the process called inflammation. Inflammation is the clinical evidence that the immune system is responding to a potential threat to the body. Histamine is always present when inflammation occurs, and excess histamine will result in symptoms that resemble inflammation.

In addition to its role in controlling vital body processes and defending against foreign invaders, histamine is a key mediator in the symptoms of an allergic reaction. Since allergy is essentially an inflammatory reaction, histamine, together with other protective inflammatory mediators is released in response to the allergen.
Allergens are components of living cells that in themselves are harmless, such as plant pollens, animal dander, mould spores, dust particles, dust mites, and foods. An allergic reaction to these "foreign but harmless" substances occurs when the immune system mistakes these innocuous materials for a potential threat.

How much histamine is excessive?

Everyone has a level of histamine that they tolerate without symptoms. Exceeding that level (called a person’s “limit of tolerance” or “tolerance threshold”) can result in symptoms.
Even healthy persons may develop severe headache, or flushing as a result of consuming massive amounts of histamine in a meal, but if ingested at lower concentrations only a few sensitive individuals will experience an adverse reaction. It has been speculated that the differences in the level of histamine that people can tolerate may be of genetic origin.
In addition, disease, various abnormal physiological conditions, hormone changes, especially in women at various stages in the menstrual cycle and at menopause, and medications, can reduce the tolerance threshold of any individual. People with a low tolerance threshold are designated “histamine intolerant”.

What causes an individual to be histamine intolerant?

Several abnormal physiological conditions may lead to histamine intolerance, in particular a defect in the process of histamine breakdown. Under normal physiological conditions excess histamine is degraded by two enzyme systems: histamine N-methyl transferase (HMT), and in the intestine by the mucosal enzyme diamine oxidase (DAO).
Of the two systems, it is deficiency in the DAO enzyme system that has received most attention as the probable cause of "histamine intolerance".

Under normal conditions, when histamine levels from any source rise above a certain level, these enzymes rapidly degrade the excess. However, when the rate of breakdown of excess histamine is insufficient to deal with the excess, the total level of histamine in the body rises. At a certain critical level, signs and symptoms occur that are the result of histamine coupling with histamine receptors on specific cells, producing a clinical picture that is often indistinguishable from allergy.

Symptoms of histamine excess

Whatever the source of histamine, when the total body level exceeds the enzymes' capacity to break it down, symptoms of histamine excess occur. Histamine intolerance manifests itself in a variety of signs and symptoms such as:

  • itching especially of the skin, eyes, ears, and nose (pruritus)
  • hives or urticaria
  • tissue swelling, especially of facial and oral tissues and sometimes the throat (angioedema)
  • drop in blood pressure (hypotension)
  • increased pulse rate (tachycardia)
  • symptoms resembling an anxiety or panic attack
  • chest pain
  • nasal congestion and runny nose
  • irritated, watery, reddened eyes (conjunctivitis)
  • some types of headaches that differ from those of migraine
  • fatigue, confusion, irritability
  • very occasionally loss of consciousness usually lasting for only one or two seconds
  • digestive tract upset, especially heartburn (indigestion/reflux)

Not all of these symptoms occur in any single individual, and the severity of symptoms varies, but the pattern of symptoms seems to be consistent for each person.

Histamine and eczema

In addition to the symptoms listed above, excess histamine can make some existing conditions worse. Eczema is an example. Eczema is an inflammatory condition in the skin, sometimes called atopic (allergic) dermatitis. When high histamine foods are consumed, people with less than efficient histamine tolerance may experience an increase in the severity of their eczema.

Histamine and anaphylaxis

There is some evidence to suggest that people who are prone to recurrent anaphylactic (severe allergic) reactions may be experiencing histamine intolerance in addition to their allergies. In such situations the histamine released in the allergic response quickly rises to a dangerously high level, leading to a situation that may be life-threatening.

Histamine and hormones

Histamine-intolerant women often suffer from the symptoms listed above, especially headaches and menstrual pain, during certain phases of their menstrual cycle. Histamine levels tend to fluctuate with the level of hormones, especially oestrogen, at ovulation and just prior to the onset of menstruation. In contrast, many women with both allergies and histamine intolerance find significant relief of their symptoms during pregnancy; this is because the placenta makes a great deal of DAO, the enzyme that breaks down histamine. The result is that the level of histamine no longer exceeds the woman’s tolerance threshold, and she remains blissfully free from her symptoms throughout her pregnancy. Unfortunately, the symptoms tend to recur once the DAO from the placenta is no longer available after the birth of her child.

Histamine and medications

Some medications can release histamine; others can reduce the effectiveness of the enzyme (diamine oxidase) that breaks down histamine. As a result, the level of histamine rises and may cause symptoms, even in a person who has shown no signs of histamine intolerance in the past. Common pain killers such as aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), some diuretics (“water pills”), antibiotics, and antidepressants are among the medications that can affect the functioning of DAO.

How can histamine intolerance be distinguished from food allergy?

Food allergy is a hypersensitivity reaction of the immune system that is caused when antibodies of the IgE type are produced against a specific food protein, called an allergen.
When the allergenic food is consumed by the person who is sensitised to it, that is whose immune system has produced IgE to the food on a previous occasion in an inappropriate attempt to protect the body from a perceived threat, inflammatory mediators are immediately released.
This results in the onset of symptoms usually within minutes of the food entering the body. So an allergic reaction to a food leads to the immediate appearance of symptoms, and in response to the mere presence of the allergen, however small the dose might be.
In contrast, symptoms of histamine intolerance, although they may be the same in type, take time to appear and are not evident immediately after histamine-rich foods and beverages are consumed. This is because the level of histamine needs to reach a certain critical level before the tissues respond.

Thus, a small amount of histamine will not cause a response – it is the total amount of histamine in the body, in excess of the body’s requirements, that causes the reaction. It is like filling a bucket with water. Everything is fine until the water level reaches the top of the bucket and overflows. Then your feet get wet! It is the overflowing of histamine that results in the symptoms. For this reason, tests designed to provoke and measure an immediate response will not detect histamine intolerance.
Often symptoms will appear several hours after consumption of histamine-rich foods, as the total level of histamine in the body gradually rises and overwhelms the enzymes’ capacities to break it down. Thus the association between cause and effect is often difficult to demonstrate in histamine intolerance.

Where does histamine come from?

Body cells and systems (intrinsic histamine)

Histamine is a biogenic or vasoactive amine that, in mammals, including humans, is produced primarily by the action of the enzyme histidine decarboxylase on the amino acid histidine.
Histidine is one of the 20 or so amino acids that combine together to make a protein.
Histidine decarboxylase is present in large quantities in leukocytes known as granulocytes, especially tissue mast cells and blood basophils.
In these cells it converts histidine to histamine. The newly formed histamine is then stored in structures within the cell in readiness for release in response to signals from a variety of body systems. In inflammation, whether produced in defending the body from injury or infection, or as a result of an allergic reaction, these signals come from lymphocytes, cytokines and antibodies. However, this is not the only source of histamine in our bodies.

Microorganisms in the large bowel

There are a large number of microorganisms that are capable of producing histamine. Many of the bacteria that live in the human large bowel produce histidine decarboxylase and are capable of converting the histidine in any protein that enters the bowel into histamine.
Therefore, the more microorganisms that produce histidine decarboxylase that are present in the colon, and the greater the amount of protein material that enters the bowel, the higher the level of histamine in the digestive tract. From here, histamine can be conveyed through the bowel wall to various sites in the body.

Histamine in natural foods (extrinsic histamine)

Another source of pre-formed histamine is the food we eat. Microorganisms capable of converting histidine to histamine exist ubiquitously in nature, so histamine can arise from various sources.
For example, histidine decarboxylase-producing bacteria colonise the gut of fish. As soon as a fish dies, the gut bacteria start to break down the tissue proteins, releasing histidine, which is then rapidly converted to histamine.
Since bacteria multiply rapidly, it is possible that the level of histamine in the ungutted fish can double every twenty minutes. The longer a fish remains ungutted after it dies, the higher the level of histamine in its tissues.
Furthermore, since shellfish are not gutted after harvesting, the bacteria in their gut will produce histamine as long as the fish remain uncooked.
Many a reaction to fish or shellfish has been blamed on allergy, when in reality it was a reaction to an exceedingly high level of histamine in an incorrectly processed fish.

Histamine in manufactured foods

There are a number of food manufacturing processes that depend on the production of amines and similar chemicals for the flavour and nature of the food. Any process that requires microbial fermentation will result in the production of relatively high levels of amines, especially histamine.
Cheese of all types, alcoholic beverages, vinegar, fermented vegetables such as sauerkraut, fermented soy products such as soy sauce, and processed meats such as pepperoni, bologna, salami, and frankfurters that are produced by a process of fermentation, all contain substantial levels of histamine.

Other food sources of histamine

Certain foods seem to contain high levels of histamine in conditions where microbial fermentation is an unlikely event. Histamine has been consistently detected in fruits such as citrus fruits, berries such as strawberry and raspberry, tomatoes, several types of tree fruits such as apricot, cherry and plums, and some vegetables, particularly aubergine, and pumpkin. Some preliminary research studies have indicated that histamine may be produced during ripening in tomatoes, and it may be that some, if not all fruits that go through a similar process produce histamine in the course of ripening. It remains for future research to explain this phenomenon.

How can diet help in reducing excess histamine?

The degree of improvement or resolution of the symptoms of histamine excess that can be achieved by diet alone will depend on whether the food sources of histamine can be reduced below a person's limit of tolerance. The histamine-restricted diet detailed below is designed to exclude all known food sources of histamine. However, some people will not achieve relief by diet alone because even by excluding all of the histamine-rich foods their total level of histamine still exceeds their enzymes’ capacity to break it down. In these cases taking antihistamines often helps.

A person with histamine intolerance will typically experience a constant fluctuation in the signs and symptoms of histamine excess in response to changing conditions.
For example, when a person is experiencing allergy to air-borne allergens such as seasonal pollens, the histamine released in the allergic response alone might put them into the symptom range.
In such a case, avoiding histamine-associated foods will no longer relieve their symptoms because their total level of histamine will remain above their limit of tolerance.
This explains the observation that during their "pollen allergy season" many people find themselves reacting to foods (usually histamine-rich foods) that they could normally eat with impunity.

Histamine intolerance test (HIT)

At this time there are no proven tests to diagnose histamine intolerance.
A trial of a low histamine diet is used to determine the presence of histamine intolerance. It is possible to measure blood DAO activity (one of the enzymes listed above), and histamine levels. These results do not seem to correlate with symptoms. Typical blood allergy tests or skin testing will not be positive, as HIT is not IgE mediated like true allergies.

It is important to remember that while considering HIT as a cause of symptoms you must evaluate for related disorders such as true allergies, mast cell disorders, inflammatory bowel disease, celiac disease, fructose malabsorption, small intestinal bacterial overgrowth, colitis, etc.

After the evaluation of related disorders, a diet eliminating high histamine foods may be pursued. If symptoms improve when histamine is lowered or eliminated from the diet you may be histamine intolerant.

Treatment for histamine intolerance

Treat any underlying disorder first. This may improve the histamine tolerance.
It is generally best to focus on dietary treatments, because this allows you to do as much as possible without medication.
But, histamine intolerance truly requires an integrative approach, as it often occurs in conjunction with other disorders that need to be addressed beyond dietary modifications.

Diet: A low histamine diet is the treatment of choice

This can be challenging if someone is already on a restricted diet such as a gluten-free or low FODMAP diet and should be done under the care of a health care practitioner so that proper nutritional intake is maintained.
The tolerance to histamine varies from person to person and the amount of histamine tolerated must be deduced by trial and error. Some people can only tolerate very small amounts and others can be more liberal.

What is important to note is that tolerance to histamine seems to improve once underlying issues are addressed. For example; if IBS (irritable bowel syndrome) or SIBO (small intestinal bacterial overgrowth) are treated, reactions to histamine often decrease. It is imperative to treat the underlying disorder in conjunction with dietary changes.

Once the elimination diet is completed one must individually assess tolerance to particular foods and liberalize the diet as tolerated so that optimum nutrition and lifestyle are attained.

Foods on a low histamine diet

Eat fresh food as much as possible
- fresh meat and fish (avoid canned meat and fish)
- fresh fruit, except strawberry, citrus
- fresh vegetables, except tomatoes, spinach, and cabbage
- grains: rice, corn, millet, oats, sorghum
- oils: Most cooking oils

Foods high in histamine

The histamine content of food varies depending on the duration of storage, ripeness or maturity, cooking, and processing.
Certain foods may also not be high in histamine yet are high in compounds known as histamine liberators which can trigger similar symptoms by increasing histamine levels.

The list below contains commonly accepted high histamine foods/histamine liberators. This list is by no means exhaustive. Available lists vary and consistent data is hard to find on the histamine content of foods.

Fermented and aged foods are some of the biggest culprits.

• alcohol: champagne, red wine, beer, white wine
• fermented or smoked meats/fish: sardine, mackerel, herring, tuna, salami
• pickled or canned foods: Sauerkraut, pickles, relishes, soy sauce
• fermented milk products: Yogurt, kefir, buttermilk
• aged cheeses: Parmesan, Gouda, Swiss, cheddar.
• fruit: dried fruit, strawberries, citrus
• vegetables: tomatoes and tomato products, spinach
• legumes: chickpeas, soybeans, peanuts
• other: cinnamon, chocolate
• grains: wheat
• histamine releasers: Citrus, papaya, pineapple, nuts, strawberries, egg white, additives
• DAO blockers: alcohol, black and green tea


7-8 hours a night helps everything!


Health issues and dietary restrictions are stressful and challenging. Seek out support from family, community, faith organizations, online support groups, local support groups. Avoid those who provide negative interactions. Negative interactions delay healing.


Any exercise is helpful. Aim for 30-60 minutes daily. Don’t feel bad if you only fit in 15 – it still helps!


The benefits of relaxation techniques cannot be emphasized enough. Breathing exercises or progressive muscle relaxation are easy, portable, and free. Yoga and meditation are great as well. Relaxation for you may also be reading, enjoying time with friends, or playing music.


Antihistamines, topical or oral steroids, plant-based creams, and lotions for rashes.


The following supplements are commonly used: vitamin C, vitamin B6, zinc, copper, magnesium, mangosteen, quercetin, DAO promoters and probiotic supplements.


Try a low histamine cookbook. It will make preparing meals easier, especially during the elimination phase.
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