Histamine Intolerance- What Is It?

According to the World Allergy Organization, adverse reactions to food without an immunological basis are termed nonallergic food hypersensitivity, in order to clearly differentiate them from food allergies initiated by a specific immune mechanism.  Nonallergic food hypersensitivity is commonly known as food intolerance, which means a response triggered by a food or any of its components at a dose normally tolerated by the healthy population. 

Currently almost 20% of the Westernized world’s population suffers from some type of food intolerance, with lactose intolerance being the most common, followed closely by histamine and fructose intolerance. 

The biological cellular response of histamine intolerance is different than an actual allergic reaction.  Even if some of the symptoms are similar.

Histamine is a biogenic amine synthesized from L-histidine (an essential amino acid).  Histamine is involved in several regulatory functions important to our biochemistry and physiology, including brain communication, response to injury, and release of stomach acid to help with digestion.

Histamine is broken down and cleared by DAO (diamine oxidase) and HNMT (histamine methyltransferase).  HNMT deactivates histamine intracellularly, while DAO functions extracellularly, in particular, in the gastrointestinal tract.  DAO is found in the small intestine and ascending colon and regulates histamine absorption and breakdown. 

 Like lactase deficiency, histamine intolerance is thought to mostly be caused by decreased intestinal DAO (diamine oxidase) enzyme activity.  This decrease in intestinal DAO results in higher levels of histamine in the gut and body with resulting symptoms.  These symptoms include gastrointestinal and extra-intestinal complaints depending on which histamine receptors are activated. 

This depiction shows the diverse signs and symptoms that can occur due to histamine attaching to its various receptors throughout the body.  Gastrointestinal symptoms related to histamine intolerance include diarrhea, bloating, and abdominal pain.  Common extra-intestinal symptoms include headaches, nasal congestion, fatigue, itchiness, rashes, flushing, and swelling.

(Shulpekova et al., 2021)

Histamine intolerance originates in the gut.

Histamine intolerance is not about how much histamine a person is consuming but rather how the gastrointestinal balance is dysregulated to cause overproduction/overaccumulation of histamine.   If gastrointestinal permeability is altered (from intestinal dysfunction, dysbiosis, atrophy, etc.), DAO production is decreased.  A decrease in DAO production in turn causes over-accumulation of the histamine ingested.  If DAO does not metabolize histamine in the gut, the overaccumulated histamine not only can act locally causing symptoms, but can systemically spread resulting in other histamine reactions.  The more the intestinal permeability/dysfunction, the less DAO activity.

Patients with histamine intolerance have been found to have decreased diversity of the gut microbiome with increased levels of Roseburia and Proteobacteria, and decreased levels of Bifodobacteria.  This is the cause of histamine intolerance, not the result.  Elevation of Proteobacteria, and reduction of Bifidobacteria, in the gut microbiome is a sign of dysbiosis and considered a marker for epithelial dysfunction.  Patients also demonstrate increased levels of zonulin.  Zonulin is a sign of gut permeability, also known as “leaky gut”.   

Reduced DAO activity has been seen in Crohn’s disease, generalized colonic inflammation, and ulcerative colitis.  Over half of non-responsive celiac disease patients are estimated to have histamine intolerance. 

Genetic polymorphisms and medications can also reduce DAO activity.  Genetic changes in the DAO enzyme (called SNPs or polymorphisms) alter the kinetics of the enzyme, reducing its enzymatic activity.  Having a polymorphism doesn’t mean you will have expression of the altered gene resulting in histamine intolerance.  However, it does mean you are pre-disposed, particularly if your environment (food, stress, toxin exposure, hormones, gut function) is affecting the expression of the gene or production of DAO in the gastrointestinal tract.

Drugs that reduce DAO activity include:

• Non-steroidal anti-inflammatory drugs (ibuprofen, aspirin)

• Antidepressants (Cymbalta, Effexor, Prozac, Zoloft)

• Antihypertensives

• Muscle relaxants

• Narcotics

• Immune modulators (Humira, Enbrel, Plaquenil)

• Antiarrhythmics (propranolol, metoprolol, Cardizem, Norvasc)

• Antihistamines (Allegra, Zyrtec, Benadryl)

• Histamine (H2) blockers (Tagamet, Pepcid, Zantac)

Decreased DAO activity can also be seen with copper, vitamin B6, magnesium, and vitamin C deficiencies.

Estrogen downregulates DAO, so in times when estrogen is higher than progesterone, women can experience increased symptoms.  This includes ovulation, premenstrual, and, for some women, perimenopause, and menopause.

Elevated levels of gastrointestinal histamine can also be seen from GI bleeding (breakdown of histidine from hemoglobin), sepsis, intestinal obstruction or inflammation, and breakdown from particular gut microbiota. 

Treating histamine intolerance begins with treating the gut. 

In intestinal diseases, the degree of DAO deficiency directly correlates with the severity of mucosal damage and intestinal permeability. 

The reduction of ingested histamine with a histamine-reduced diet is helpful by allowing your intestinal lining to heal, resulting in decreased inflammation and symptoms.  DAO activity has been shown to increase when histamine-rich foods are eliminated from the diet.

Histamine-rich foods

• Fish and meat

  • Animal products contain histidine.  If they are not preserved quickly after slaughter/caught (or if stored in the refrigerator), bacteria on the surface will degrade the histidine to histamine.

• Leftovers, canned, or already prepared meals

• Sugar sweetened beverages

• Ketchup

• Over ripe fruit

• Fermented foods

  • The bacteria responsible for the fermentation process can also metabolize histidine to histamine. 

    • Dairy products (aged cheeses, sour cream, yogurt, kefir)

    • Yeast products (serves as a catalyst for histamine generation)

    • Soy products (miso, soy sauce, tempeh)

    • Fermented beverages (wine, beer, kombucha, champagne)

    • Processed, cured meats

    • Sourdough

    • Fermented vegetables (sauerkraut, pickles)

Histamine levels in foods vary depending on how ripe, matured, or hygienic the foods are.

As much as it is possible, only buy and eat fresh products.

Cooking food does not get rid of the histamine already produced.

Histamine liberating foods

• Tomatoes

• Eggplant

• Spinach

• Vinegar

• Avocado

• Brussel sprouts

• Walnuts

• Peanuts

• Chocolate

• Citrus fruit

• Wheat germ

• Additives (colors, preservative, sodium benzoate)   

DAO blockers

• Alcohol

• Black tea

• Energy drinks

• Green tea

• Mate tea

Foods that contain other biogenic amines that are similar to histamine (tyramine, putrescine, cadaverine)

• Citrus fruits

• Mushrooms

• Soybeans

• Bananas

• Nuts   

So what is okay to eat??

Natural histamine antagonists

• Histamine lowering herbs

  • Oregano, basil, garlic, rosemary, chives, peppermint

• Foods high in vitamin C (inhibits mast cell production)

• Foods high in quercetin (inhibits mast cell degranulation) and other flavonoids

  • Asparagus, apples, onion

• Foods high in zinc and manganese (inhibits the release of histamine from mast cells)

• Legume sprouts (good source of DAO)

  • New seedlings of all legumes produce DAO.  DAO is a protective enzyme, is involved in plant nutrition, and helps the plant to build structural components, such as the stem.  DAO is produced starting at roughly day 3 of development and is at its maximum concentration at 10 days.  Green pea sprouts appear to be the best source of DAO.  If the plant is grown under stress (i.e., in the dark), more DAO is produced.  Consume the seedling as soon as possible after harvest, fresh, and near the time of a histamine-containing meal.  Blending helps to loosen the DAO from the cell walls.  Heating will destroy DAO.  Pea sprouts also contain fiber, calcium, boron, manganese, potassium, copper, and magnesium. 

Low Histamine Foods

• Fresh meat

• Freshly caught fish

• Poultry (skinned and fresh)

• Egg yolk

• Fresh fruits (except strawberries, citrus fruits, pineapple)

• Fresh vegetables (except tomatoes and peppers)

• Grains

• Fresh pasteurized milk

• Milk substitutes

• Most cooking oils

• Most leafy herbs

• Herbal teas (except black, green, and mate tea)

Supplemental DAO

Unfortunately, most commercially available DAO dietary supplements likely do not contain enough DAO enzyme to reduce histamine to a satisfactory level.  Most of these supplements are made from pig kidney and need to be enterically coated.  This results in the accumulation of more chemicals in an already diseased GI tract.  Some products have been found to contain items such as shellac and bentonite clay which can inactivate histamine.  There is plant-sourced DAO from the seedlings of Lathyrus sativus, culinaris, and arietinum.  The histamine activity of this DAO source is thought to be 30 times higher than that of porcine DAO, but the capsule must still be enterically coated.

All diseases begin in the gut.  -Hippocrates

Take care of your gut for your health.