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Mast Cells Getting Active

Speaking of Mast Cells...

They are getting lots of news these days especially with the protocols we are seeing for Long Covid.

What the heck are mast cells?

Mast cells are immune cells that are throughout different regions of the body including the gut, lungs, bladder, and the brain . They are involved with releasing histamine, leukotrienes, tryptase, and heparin amongst other mediators (including VEGF, bFGF, TGF-beta, TNF-alpha, and IL-8.)

In a purest sense they function normally to help the body respond to inflammatory triggers .

The problem lies when they are overabundant and/or over stimulated.

The mast cell lies sentient but then through an allergen or other inflammatory trigger it can become activated and start to degranulate.

When they degranulate they release mediators of inflammation such as those mentioned above.

This system can works perfectly fine in one-off situation; such as an acute allergy exposure.

But what about if the insult is chronic like with gut inflammation or viral infection? Or stress?

In these scenarios, mast cell activation can be highly problematic. There are many degrees of mast cell activation including a serious disease called mastocytosis and also mast cell activation disorder. More about that in this podcast .

It has been shown in IBS patients have increased numbers of of mast cells in the digestive tract . When these mast cells are activated they release histamine to nearby nerve tissue. This can cause abdominal pain.

Most recently, there is current thinking that long Covid symptoms are partially to blame on mast cell activation.

There are many triggers of mast cell activation. As you can see the list featured below is exhaustive but not complete.

source: Wouters, M. M., Vicario, M., & Santos, J. (n.d.). The role of mast cells in functional GI disorders.

In the Irritable Bowel Syndrome (IBS) world we think of lipopolysaccharide (LPS), Stress Hormones, Estrogen, hypoxia, histaminic foods, IgE reactions, and stress being amongst the major triggers.

Let's talk about stress for a second:

Most people "eye-roll " when their Dr. tells them to reduce stress. ⁠

They say " It's part of life, right?:⁠

As the late Bruce McEwen taught..too little and too much stress is not so great, but some is good. ⁠ (allostatic load model)

When the body is under a lot of stress (emotionally and physiologically); it releases hormones Corticotropin Releasing Hormone (CRH) , Neurotensin (NT), and Substance (P), as well as the anti-inflammatory hormone called cortisol.⁠

It is literally " Fired-up".⁠

Downstream in the periphery of the body (ie. gut, brain, lungs, bladder) mast cells can bind CRH and secrete inflammatory molecules including, IL-1B, IL-6, TNF-alpha, CCL2, VEGF, and CXL8⁠.

If that wasn't enough; it is known that Mast Cells also release CRH when activated. The problem begets the problem. Stress response begets more stress respons

This inflammation can override cortisol's protective effects.⁠

Now you know why Naturopathic Physicians are so focused on the adrenal glands ; which is the source of cortisol production. Too much cortisol can be a problem but then again too little can be a problem.

It's all about balance. ⁠

One of the impacts of this inflammation (especially IL-6 and VEGF) is increasing increasing vascular permeability in the brain (and gut for that matter)⁠

The brain becomes more open for toxins, viral/bacterial particles , and inflammatory cytokines. This scenario especially doubles down when you combine the stress with infection or allergy or gut problems.⁠

This brain leakiness may result in....⁠

  • Brain Fog

  • Confusion⁠

  • Difficulty multitasking⁠

  • Dizziness⁠

  • Dysautonomia⁠

  • Brain fatigue⁠

  • Headache⁠

  • Insomnia⁠

  • Irritability⁠

  • Lightheadedness⁠

  • Inability to find the right words⁠

  • Memory loss⁠

This is a scenario called brain inflammation (neuroinflammation)

And mast cell activation outside of the brain can cause

  • Body fatigue

  • Sinus congestion

  • Cough/wheezing

  • Skin rashes and itching

  • Edema

  • Palpitations

  • Paresthesia's

  • Temperature dysregulation

  • Flushing

  • Low blood pressure

  • Bloating

  • Reflux

  • Diarrhea

  • Abdominal pain and discomfort

  • and more....

Some things that can be discussed or explored to see if one has a histamine or mast cell problem.

1. Are your symptoms worse when you eat leftovers ( a big source of histamine)?

2. Are your symptoms worse during peak estrogen time of the month? (mid-follicular phase and mid luteal phase)?

3. Do you have excessive microbes in your gut driving up histamine?

The later of these might be found on a stool test (such as the gut zoomer) or possibly found on a lactulose hydrogen breath test (such as trio smart):

The categories of concern as contributors for mast cell activation can be:

Hydrogen Sulfide Producers such as:

  1. Desulfovibrio spp.

  2. Salmonella spp.

  3. Campylobacter jejuni

  4. Citrobacter freundii

  5. Aeromonas spp.

  6. Morganella spp.

  7. Proteus spp.

  8. Pseudomonas aeruginosa

  9. Yersinia enterocolitica


Hydrogen Producers such as:

  1. Streptococcus spp

  2. Escherichia coli

  3. Staphylococcus species:

  4. Micrococcus: primary colonizers of the oral cavities, mucous membranes, and skin

  5. Bacteroides spp

  6. Clostridium spp

  7. Peptostreptococcus spp

  8. Enterococcus species spp

Gut Dysbiosis (overgrowth or imbalance of gut microbes) can be a source of bacterial lipopolysaccharides (LPS) . This is an cell wall component found on the outer surface membrane components in almost all Gram-negative bacteria .

LPS; when exposed to the immune system through the gut can be a major stimulator of the immune system as well as an activator of histamine release.

Let me pause for a second....before saying...."this is me!!!" It's wise to take a little bit of a stoic approach to your health journey and say' "Just because it makes sense, doesn't mean it's true ". Instead say to yourself "Maybe, lets see". Finding your health answers involve implementing a hypothesis and observing a response.

How do you explore whether or not your mast cells are a culprit?

Serum Tryptase (baseline and again at a flare)

Chilled plasma for prostaglandin D2 (PGD2) (and/or 11-β-PGF2)

Chilled plasma histamine

Chilled random and 24-hr urine collections for PGD2 (and/or 11-β-PGF2α)

Chilled 24 hour Urine N-methylhistamine

Serum Chromogranin A (CgA)

However, unless in an active flare these tests often come back negative. Also it is important to note that persistent elevated serum tryptase that is > 20 ng/mL in two or more specimens should be referred for a discussion related to potential biopsy to screen for systemic mastocytosis ; the most serious mast cell disorder. The biopsy is done in the bone marrow , and possibly also skin, upper and lower gastrointestinal (GI) tract mucosa, and potentially other tissues, especially those at the environmental interfaces.

And also checking for genetic predisposition of histamine/mast cell concerns may be helpful; including but not limited to these single nucleotide polymorphisms (snps).

  • HNMT (Histamine N-methyltransferase)

  • AOC1 (Amine Oxidase Copper Containing 1....regulates diamine oxidase enzyme activity)

  • ALDH (aldehyde dehydrogenase)

  • MAO-A (monoamine oxidase enzyme involved with intracellular break down of histamine)

  • KIT (proto-oncogene receptor tyrosine kinase). Gene associated with systemic mastocytosis

Genetic testing is available through many direct to consumer companies and specialty companies such as Intellxxdna.

Certain deffficiencies can sometimes be measured

  • Serum diamine oxidase test . (DAO) . Diamine Oxidase is one of the most important enzymes in the breakdown of histamine. For an eye opening article of what effects foods block Diamine Oxidase Activity see this link.

  • Nutrient levels can be measured that are involved in histamine metabolism such as Riboflavin (B2), and Copper (plasma). I recommend a test for intracellular levels of these nutrients such as with the Spectracell test or Vibrant America micronutrient assay.

Finally, we sometime screen for histamine intolerances coming from the diet by serum testing using the LEAP/MRT test . Food that are found reactive on this test can be correlated with food mediated mast cell activation. This test measures changes in white blood cell volume from the subjects blood when being exposed to over 100 different foods. White blood cell volume correlates with the release of histamine mediators such as, leukotrienes, histamine, cytokines, and heparin.

Testing is certainly nice but not always practical for everyone; sometime a therapeutic challenge using a low histamine diet and nutritional supplementation is a fine way to assess whether mast cell activation is playing a role in your health. A low histamine diet involves reducing known histamine producing foods, leftovers, and also reduction of known histamine liberating foods.

Mast cells are a normal part of our immune system; without their ability to acutely activate we would be in trouble. But the myriad of things that chronically activate them lead a number of chronic maladies that lead to lower quality of life. The degree of symptoms range when mast cells problems have turned against us; and there are many areas to explore for what is driving the imbalance. While testing exists to look for a root cause; we can also find many information with changes in the diet and nutritional supplementation.

If found that you have histamine related issues (either MCAS or Histamine Intolerance) ; there are many treatment options to consider . Here is a list of some of my favorite natural support for histamine issues.

PS: Like my posts? Please subscribe to our quarterly newsletter Soundbites by clicking here. If you like the research I do for my articles and want to support me further please click here and see the myriad of ways you can continue to support me.

Also here is a Q&A I recently gave on Mast Cell Activation Syndromes.


Afrin LB, Molderings GJ. A concise, practical guide to diagnostic assessment for mast cell activation disease. World J Hematol 2014; 3(1): 1-17 [DOI: 10.5315/wjh.v3.i1.1]

Theoharides, TC, Cholevas, C, Polyzoidis, K, Politis, A. Long-COVID syndrome-associated brain fog and chemofog: Luteolin to the rescue. BioFactors. 2021; 47: 232– 241.⁠

Theoharides, T. C. (2020). The impact of psychological stress on mast cells. Annals of Allergy, Asthma & Immunology, 125(4), 388–392.


Wouters, M. M., Vicario, M., & Santos, J. (n.d.). The role of mast cells in functional GI disorders.


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