Research studies on histamine intolerance and mast cells

Inflammation, allergies, and histamine issues affect so many people today, irritating us with a variety of seemingly unrelated symptoms.  The term ‘histamine intolerance’ applies to the symptoms that occur due to eating too many histamine-containing foods.

Symptoms of histamine intolerance include the allergy-type symptoms (sinus drainage, itching, watery eyes, hives), gastrointestinal symptoms (diarrhea, stomach pain, heartburn, nausea), and brain-related symptoms (anxiety, insomnia, headaches).

Getting to the bottom of my own histamine related problems prompted me to search for the ‘root causes’ for histamine intolerance. By breaking down this problem, I looked at how our body produces histamine, the ways histamine is used, triggers for producing too much, and solutions for blocking the release of histamine.

This is a departure from my usual articles on genetic variants.  If you are interested in some of the genes involved in histamine intolerance, please read my article on the genetic variants involved in histamine intolerance.  While those genetic variants do play a role in histamine-related issues, they exacerbate the problem rather than being a single cause.

Hopefully, something in the studies below will help you to figure out the root cause of your own histamine related issues.

Histamine production in the body:

Histamine plays several important roles in the body, and the body produces it in a couple of different ways.

Sources of histamine production include:

Mast cells, a type of white blood cell, release histamine in the following circumstances:

  • When presented with an allergen (IgE ) – this is the typical allergic mechanism.
  • If activated by protozoa, helminth (worms)[ref], and lipopolysaccharides (toxins from certain bacteria)[ref]
  • Activated by platelet-activating factor (a mediator of platelet aggregation and anaphylaxis)[ref][ref]
  • Mast cells have 50 – 200 granules in the cytoplasm that store histamine, heparin, and cytokines[ref]

Basophils, another type of white blood cell and a part of our immune system, can also release histamine.

  • “Mast cells and basophils represent the most relevant source of histamine in the immune system. Histamine, along with other amines (e.g., serotonin, proteases, proteoglycans, cytokines/chemokines, and angiogenic factors), are stored in cytoplasmic granules and rapidly release upon triggering with a variety of stimuli. Moreover, mast cell and basophil histamine release are regulated by several activating and inhibitory receptors.”[ref]

Neutrophils store and release histamine.[ref]

Histamine decarboxylase enzyme (HDC gene) converts histidine, an amino acid, to histamine.

  • “Histamine is released from subcutaneous mast cells during the anaphylaxis phase via an IgE-mediated mechanism, whereas in the post-anaphylaxis phase, histamine is produced because of an increased HDC activity “.[ref]

Stomach cells called enterochromaffin-like cells also produce histamine, which signals the release of stomach acid through the H2 receptors.

Gut bacteria produce histamine:

  • Lactobacillus species (in the presence of histidine)[ref][ref].
  • Alternatively, h. pylori infection may actually inhibit histamine release in the stomach.[ref]

Histamine Receptors:

We have four different histamine receptors in the body, giving rise to the huge variety in symptoms of histamine related problems.

H1 receptors:

  • itching and allergy type response,
  • also in wakefulness in the brain,
  • motion sickness
  • Zyrtec, Benadryl and other antihistamines block this receptor

H2 receptors:

  • initiate acid production in the stomach
  • H2 Blockers like Tagamet and Pepcid attach to these receptors, blocking histamine from binding (list of H2 antagonist)

H3 receptors:

  • located in the brain, central nervous system
  • act in the opposite direction to H1 (wakefulness) in the brain[ref]

H4 receptors:

  • involved in an immune response.[ref][ref]

Ways & Reasons Histamine Is Released:

IgE / IgG / IgA activation:

  • IgE (typical allergy) normally activates mast cells. The antigen links to a receptor on the cell surface causing degranulation. There is a lot of information and studies on IgE/allergic reactions and histamine.
  • IgA deficiency has recently been linked to chronic urticaria (itching/hives). A 2016 study (small study) linked IgA deficiency, autoimmunity, and chronic urticaria.  Other studies have found a similar link.[ref][ref]
  • IgG can also bind to mast cells and cause anaphylaxis.[ref]

Substances & toxins that cause the release of histamine:

  • “Calcium triggers the secretion of histamine from mast cells after previous exposure to sodium fluoride.”[refThe addition of sodium fluoride to drinking water is common in most US municipalities.
  • PFOA’s (Perfluorooctanoic acid) have found to release histamine and cause mast cell degranulation. “… PFOA exacerbated allergic symptoms via hypothermia, and an increase of serum histamine, TNF-α, IgE, and IgG1 in the ovalbumin-induced systemic anaphylaxis. The present data indicate that PFOA aggravated FcɛRI-mediated mast cell degranulation and allergic symptoms.”[ref] You will find PFOA’s in Teflon, stain-resistant carpeting, microwave popcorn bags, and other food wrappers, etc.
  • Off-gassing from carpeting may cause mast cell release in the case of sick building syndrome.[ref]
  • Sodium benzoate, a common preservative, causes histamine release in people with allergies and asthma.[ref]
  • For some people, aspirin and other salicylates can cause histamine problems – possibly through basophil activation.[ref]
  • The food additive Polysorbate 80 causes histamine release.[ref]

Virus and bacteria that activated mast cells:

  • Lyme disease (Borrelia burgdorferi) causes mast cells to release histamine.[ref]
  • Influenza A virus increases histamine released by e. Coli, salmonella, and staph.[ref] And other studies show the virus (as well as other viruses) can trigger mast cell degranulation.[ref]
  • Cimetidine (Tagamet), an H2 blocker used for heartburn, had been studied in conjunction with other treatments for Lyme disease.[ref]
  • h. Pylori can activate mast cells and cause chronic urticaria (hives).[ref][ref]
  • Lipopolysaccharide, aka endotoxin, from bacteria, exacerbates mast cell activation.[ref]
  • An antihistamine (chlorcyclizine ) inhibits hepatitis C.[ref]

Fungi/mold activating mast cells and/or causing histamine release:

  • Inhaled mold spores (Trichoderma viride) cause histamine release.[ref]
  • Another role that mast cells play in the immune response is to react to fungi, specifically, this 2016 study used Malassezia sympodialis which binds to the Decklin-1 (aka CLEC7A) receptor on the mast cell and causes degranulation.  Curdlan was also used in the study and shown to bind to the Decklin-1 receptor on mast cells.[ref]  So what is curdlan? It is a beta-glucan produced by certain bacteria used as a food additive (gum) allowed in the US but not in the EU.
  • Sweat allergy and atopic dermatitis can be due to Malassezia globosa, a fungus commonly found on the skin.[ref]

Physical stimulation:

  • Histamine released from mast cells at an acupoint plays a role in how acupuncture works.[ref]
  • Histamine is released in response to exercise[ref][ref] especially aerobic exercise.[ref]
  • Taking OTC histamine blockers (Allegra + Zantac) decreased muscle pain and strength loss but increase muscle damage through creatine release after exercise.[ref]
  • Vibratory urticaria (hives due to vibrations) can be caused by a mutation in the ADGRE2 gene (rs199718602 T-allele; not covered in 23andMe or AncestryDNA).[ref]

Sleep:

  • Histamine regulates sleep phases.[ref]
  • Ambien, a prescription sleep medicine, works by increasing the action of GABA on histaminergic neurons in the brain.[ref]

Regulation of Body Temperature:

  • In a study using histamine knockout mice, it found histamine lowered body temperature only in mice with a functioning HDC (histamine decarboxylase) gene.[ref]
  • Another study from the 1950s looked at the effect of histamine on body temperature in several mammals and found that adding histamine lowered body temperature.[ref]  Another 2016 study found histamine involvement in low body temperature setpoints using the H1 receptor.[ref]

Other conditions tied to Mast Cells and histamine deregulation:

  • Histamine plays a role ADHD – antihistamines help[ref][ref] H3 receptors.[ref][ref]
  • Oral Lichen Planus has links to histamine derangement and H4 receptors.[ref]
  • Rheumatoid arthritis, an autoimmune arthritis, is linked to mast cells releasing histamine through stimulation by IL-33.[ref][ref][ref]
  • Cardiovascular disease “Mast cells have also been detected in the arterial wall and are implicated in the onset and progression of numerous cardiovascular diseases.”[ref]
  • Atherosclerosis – “The results of this work indicate that the co-activation of macrophages and mast cells by oxLDL is an important mechanism for endothelial dysfunction and atherogenesis. The observed synergistic effect suggests both macrophages and mast cells play a significant role in the early stages of atherosclerosis. Allergic patients with a lipid-rich diet may be at high risk for cardiovascular events due to high concentrations of low-density lipoprotein and histamine in arterial vessel walls.”[ref][ref] interaction with nicotine.[ref]
  • IBS and intestinal permeability[ref][ref]
  • Interstitial cystitis (bladder) is caused by mast cell dysfunction.[ref][ref]
  • Benign prostate problems can include mast cell degranulation/inflammation.[ref][ref][ref]
  • Role of mast cells in diabetes[ref]
  • Mast cell involvement in endometriosis[ref]
  • Histamine and mast cell degranulation both have a role in migraines.[ref] The role in migraines may also be influenced by estrogen levels including BPA (xenoestrogen).[ref]
  • Mast cells and histamine are involved in post-surgery mental confusion and inflammation. Cromolyn (mast cell stabilizer) decreases mental confusion.[ref]
  • Interesting links to autism spectrum disorders with mast cell degranulation and brain inflammation.[ref][ref][ref][ref]
  • “histamine plays a pivotal role in the pathogenesis of atherosclerosis” and “although its etiology is complicated and multifactorial, histamine/HRs signaling has a close relationship with the development of metabolic syndrome”[ref]
  • BMI and skin reactivity in people with nasal allergies are all linked.[ref]

Foods, herbs, and probiotics to reduce histamine:

Switching gears here to focus on some of the things we can do to reduce histamine related problems. The first line of defense includes lowering histamine levels from food through eating a low histamine diet. You can use this list of histamine-containing foods as a starting point for customizing your low-histamine diet.

  • A low FODMAP diet reduces histamine[ref] 8x reduction in histamine.[ref]
  • Brain “fog,” inflammation and obesity: key aspects of neuropsychiatric disorders improved by luteolin.[ref] Luteolin is used as a natural antihistamine. Another study looked at the synergistic effect of PEA and luteolin.[ref]
  • Rosae multiflora fructus extract stops mast cell release of histamine (rat study)[ref] This is used in Korean medicine as a tea – same plant as the wild rose and an invasive species in my backyard. https://en.wikipedia.org/wiki/Rosa_multiflora
  • Quercetin blocks histamine release due to chemotherapy drugs [ref] and generally works for allergies.[ref]
  • Cannabinoid receptor agonists suppress mast cell release of histamine.[ref]
  • Chicoric acid (from chicory and Echinacea) inhibits mast cell degranulation.[ref]
  • Curcumin also acts as an antihistamine.[ref][ref]
  • Manuka honey, when used topically for atopic dermatitis, was found to inhibit mast cell degranulation.[ref]
  • Nigella sativa (black cumin seed) blocks mast cell degranulation.[ref]
  • Probiotics that help:
    • Clostridium butyricum C/GMC/C0313-1 inhibits mast cell degranulation.[ref]
    • Lactobacillus G/G[ref]
  • The way food is processed can change how much of an IgE reaction a person has to it. Here is a study discussing the different effects of processing on hazelnuts[ref]. I’m throwing this in here to explain (at least to myself) as one reason why food that is fine sometimes will cause a histamine reaction other times.
  • Luteolin protects against histamine release from mast cells.[ref]
  • Citrus peels contain flavonoids that inhibit mast cell release.[ref]
  • Arsenic inhibits mast cell degranulation[ref] Still not a good reason to eat arsenic in rice.
  • Geranium essential oil was found to inhibit mast cell degranulation.[ref]
  • Omega 3 fats may suppress allergy activation of mast cells.[ref][ref]
  • Omega-6 fats may promote inflammatory activation of mast cells.[ref]

Vitamins:

  • An interesting study on retinoic acid (vitamin A) and mast cells inhibit the proliferation of mast cells but not histamine release.[ref]
  • Vitamin E, in some studies, has found to decrease mast cell degranulation.[ref]

Stopping histamine production with OTC drugs:

  • Antihistamines blocking the H1 receptor can downregulate the production of histamine by histamine decarboxylase (HDC gene). Specifically, diphenhydramine (Benadryl) suppressed the production the most with effects continuing for 9 hours or more.  Other antihistamines suppressed histamine production at least somewhat, with the exception of chlorphenamine (Allarest, Tylenol Cold).[ref]

Mast cells are important in our health!

While this article focused on mast cells misbehaving, they do play an important role in immune function and the goal shouldn’t be to suppress mast cell activation too much.

For example, a study of diabetic wound healing found reduced mast cell function was what caused the extended wound healing time.[ref] This increased wound healing from mast cells may also play a role in how low-level laser therapy works in wound healing.[ref]


Related Genes and Topics:

Mast cells: MCAS, genetics, and solutions
Mast Cell Activation Syndrome, or MCAS, is a recently recognized disease involving mast cells that are misbehaving in various ways.  Symptoms of MCAS can include abdominal pain, nausea, itching, flushing, hives, headaches, heart palpitations, anxiety, brain fog, and anaphylaxis.

HLA-B27: Genetic Variant That Increases Susceptibility to Autoimmune Diseases
Our immune system does an awesome job (most of the time) of fighting off pathogenic bacteria and viruses. But to fight off these pathogens, the body needs to know that they are the bad guys. This is where the HLA system comes in.



Author Information:   Debbie Moon
Debbie Moon is the founder of Genetic Lifehacks. She holds a Master of Science in Biological Sciences from Clemson University and an undergraduate degree in engineering. Debbie is a science communicator who is passionate about explaining evidence-based health information. Her goal with Genetic Lifehacks is to bridge the gap between the research hidden in scientific journals and everyone's ability to use that information. To contact Debbie, visit the contact page.