Histamine Intolerance, Autoimmunity, and Endometriosis

Histamine-Intolerance

Histamine is a versatile biologic amine. It is involved in fine-tuning the balance between immunity (the ability to fight infection or clear abnormal cells) and tolerance (the ability of the immune system to tolerate “outsider molecules” like foods, dust, environmental chemicals, etc.)

Histamines affect dendritic cells (cells that boost the immune responses by showing antigens on their surfaces to other cells of the immune system), immunoregulatory cells, T-cell polarization (deciding whether T-cells will have the capability to produce T1 or T2 patterns of cytokines), and cytokine production, generally.

*Note: cytokine patterns: 

T1: interleukin (IL)-12 and IFN-γ 

T2: IL-4

Histamine is essential to a variety of physiologic functions. It causes vasodilation or vasoconstriction of blood vessels, it influences heart contractility and heart rate. It is involved in the contraction of smooth muscles in the intestines and the airways. Plus, histamine functions as a neurotransmitter, immunomodulator, and regulator of the production of blood cells and platelets in the bone marrow and the formation of new blood vessels.

Histamine Receptors

There are four distinct histamine receptors (H1R, H2R, H3R, and H4R), which are heptahelical, G-protein-coupled molecules expressed either throughout the body (H1R and H2R) or predominant in particular tissues (H3R in the brain and H4R in the hematopoietic system – the system of blood cell synthesis.) Histamine is synthesized by a unique enzyme, histidine decarboxylase (HDC) (EC.4.1.1.22) that requires pyridoxal-5-phosphate (the active form of vitamin B6) as a cofactor.

 

How does the receptor type influence the action of histamine?

Histamine is both pro- and anti-inflammatory depending on the receptor subtype that it attaches to and to the cell that it stimulates.

The H1-receptor is involved in cellular migration, nociception, vasodilatation, and bronchoconstriction. Histamine attaching to H1R cells is also involved in allergic responses by enhancing the migration of Th2 cells toward the allergen during lung inflammation. Excessive activation of Th2 cells is at the root of overactive allergic responses and some autoimmune diseases.

This is why H1 antagonists from Benadryl to Allegra are so popular.

The H2-receptor modifies gastric acid secretion, airway mucus production, and vascular permeability. This is why H2 antagonists like famotidine are so popular.

The H3-receptor plays an important role in inflammatory diseases of the brain.

Interestingly activation of this receptor inhibits histamine. And, drugs in development for Alzheimer’s disease and cognitive function actually stimulate the production of histamine in the brain by antagonizing this receptor.

The H4-receptor has also been shown to be involved in allergy and inflammation. H4R-mediated mast cell activation can regulate a powerful inflammatory cascade by releasing several inflammatory mediators.

Interestingly, estrogen receptors have been found to be expressed in the cytoplasm of mast cells of endometriotic lesions. With higher levels of estrogen, more mast cells are found along with higher histamine concentrations.

Thus… for optimal immune function, “just right” amounts of histamine are key.

 

What is the Role of Mast Cells?

Basophils and mast cells are the most proficient histamine producers since they can store and release histamine in response to IgE-dependent or independent stimuli. But, other immune cells, dendritic cells, neutrophils, monocytes/ macrophages, and lymphoid cells, can synthesize and release high levels of histamines under certain conditions.

Histamine-Intolerance

Mast Cells and Immune Function in Endometriosis and Other Autoimmune Disorders

Mast Cells are activated via direct interaction with an antigen (IgE-dependent pathway stimulated by T-helper 2 (Th2) cytokines including IL-4, IL-5 and IL-13) and/or via their ability to respond rapidly to innate IgE-independent immune stimuli (IgE-independent pathway) (Binda, Donnez, & Dolmans, 2017). In patients with endometriosis, elevated levels of IL-4 have been found in both the peritoneal fluid and the blood. IL-4 can stimulate mast cell activation, which has been associated with acute and chronic inflammation. It is not yet known whether mast cell activation in endometriosis lesions is IgE-dependent. Once activated, mast cells have also been found to stimulate an inflammatory reaction via the action of several mediators, including histamine proteases, and specific cytokines, such as IL-1, IL6, IL-8, granulocyte macrophage-colony stimulator factor (GM-CSF), TNF-α, and TGF-β32. Inflammatory cytokines including IL-6, IL-8, and TNF-α have been found to be increased in the peritoneal fluid of patients with endometriosis.

Thus, histamine can be seen as a modulator of the immune response. The activation of the immune response itself can upregulate histamine production and secretion, and the impact of the increased availability of histamine is dependent upon the receptor and cell type that it binds to. 

Signs of Histamine Intolerance

First of all, histamine intolerance or sensitivity is not an “allergy” or sensitivity to histamine. It’s distinct from food sensitivity. It’s simply excessive histamine that is trapped in the body due to too much production and release of histamine or an inability to break down the excess histamine appropriately. It can be difficult to identify histamine intolerance because the symptoms can be vague.

Here are some signs to look for:

  • Itchy skin, eyes, ears and nose and/or seasonal allergies

  • Dermatitis

  • Chronic hives

  • Burning in mouth, hands or feet

  • Swelling

  • The feeling of tightness or fullness in the throat

  • Flushing or temperature regulation issues

  • Postural Orthostatic Hypotension Syndrome (POTS) or other forms of dysautonomia

  • Dizziness, Vertigo, or even loss of consciousness

  • Low blood pressure

  • Tachycardia

  • Heart palpitations

  • Sleep disturbance

  • Confusion or Irritability

  • Anxiety or panic attacks

  • Migraines

  • Alcohol intolerance

  • Caffeine intolerance

  • Irregular menstrual cycle

Do you work with patients with endometriosis or other pelvic pain conditions in your practice? Interested in deeper dive training on endometriosis and pelvic pain, click here to learn more…

Genetics and histamine tolerance

Two enzymes are responsible for the breakdown and excretion of histamine when its important work as an immune modulator is done. These enzymes are diamine oxidase (DAO) and histamine methyltransferase (HNMT). DAO enzyme is primarily responsible for breaking down the histamine from foods, while HNMT enzyme is responsible for breaking down the endogenously produced histamine produced by physiologic processes. Many people have single nucleotide polymorphisms (SNPs) in the genes that encode the enzymes. SNPs in these genes make it difficult to break down excess histamine.

For people with DAO SNPs, support with supplemental DAO digestive enzymes can be helpful. Additionally, supplementing with riboflavin (vitamin B2), calcium, and copper supports the functioning of this enzyme. To support HNMT SNPs, supplementing with zinc is helpful, and the ayurvedic herb salacia oblonga can regulate blood sugar and support the efficiency of the HNMT enzyme to better eliminate histamine. Using salacia oblonga to support clients with both histamine enzyme SNPs and blood sugar dysregulation is important because metformin can further inhibit the efficiency of DAO enzyme function. The SNP in rs1050891 of the HNMT gene can increase the risk of Parkinson’s Disease, ADHD, asthma, and migraines. Folate, magnesium, SAMe, vitamins B1, B5, B6, and vitamin C can support the activation of the HNMT enzyme, while turmeric and caffeine, and sodium benzoate can inhibit its activity.

Nourishment to improve histamine balance

It’s important to support the body in six distinct ways if histamine intolerance is an issue for your client struggling with dysregulated immune function – such as an autoimmune disease like endometriosis, or a poor immune response to pathogens (bacteria, viruses, etc.) due to excessive inflammation.

Lower the histamine load

Add foods high in flavonoids (Fisetin, kaempferol, myricetin, quercetin, and rutin) or recommend flavonoid supplements to inhibit the release of histamine from mast cells and reduce the release of proinflammatory cytokines. Foods high in quercetin and other flavonoids include citrus fruits, apples, onions, cabbage, cruciferous vegetables, lettuces, leafy greens, parsley, sage, and other herbs, black or green tea, and red wine. Olive oil, buckwheat, asparagus, figs, grapes, dark cherries, blueberries and blackberries are also high in histamine-reducing flavonoids.

Pycnogenol supplements inhibit the release of histamine from mast cells.

Recommend that your clients eat fewer foods that are high in histamine. (Don’t worry about elimination, focus on reduction and enjoyment!) The highest histamine foods are fermented dairy products, kombucha, and vegetables, pickles, cured meats, aged cheeses, alcoholic beverages, fermented soy and grains (such as sourdough breads), tomatoes, eggplant, spinach, canned fish (such as canned sardines or tuna), and vinegar. It’s important not to completely eliminate these foods as doing so can trigger the nervous system to develop a sensitivity to these foods. It’s better to focus on adding low histamine and high flavonoid foods vs. strictly eliminating high histamine foods. Notice that some of the foods that are highest in flavonoids are also high in histamine. It’s essential not to create fear of any foods in the nervous system, and instead to promote enjoyment of foods high in flavonoids, and even occasional enjoyment of high histamine foods as many of these also have other benefits (such as polyphenols, probiotics, and omega-3 fatty acids) as long as the focus is on a whole foods diet low in packaged and processed foods.

In fact, in the brain, histamine has a positive neurotransmitter function. It promotes motivation, supports the sleep/ wake cycle, and promotes “food anticipatory activity.” In other words, among the benefits of histamine activity in the brain are enhancement of nourishing sleep, daytime motivation, and the pleasure of eating.  

Eat foods high in histamine receptor antagonists

Nettles and foods high in bromelain block the histamine receptors in allergic response symptoms. Drinking nettle tea, and eating pineapples and papayas, kiwi, ginger, asparagus, sauerkraut, kimchi, yogurt, and kefir support modulation of the histamine response at the receptor level. 

Add DAO enzyme supplements

Taking 1-2 capsules of DAO enzyme supplements at the beginning of each meal that contains higher histamine foods will help promote their digestion and breakdown.

Support the function of DAO and HNMT enzymes with supplemental nutrients

Depending on your client’s specific DAO and HNMT enzyme SNPs, supplemental nutrients such as riboflavin (vitamin B2), calcium, copper, zinc, folate, magnesium, other B vitamins, and vitamin C can improve the efficiency of the enzymes that break down histamine. And, be mindful of excess turmeric, caffeine, or sodium benzoate in the diet depending on your client’s unique genetic risk factors.

Be mindful of probiotic supplements that contain bacteria that produce histamine

In patients with histamine intolerance, reduced gut microbiome diversity is found. Additionally, patients with histamine intolerance were found to have higher levels of Proteobacteria and Bifidobacteriaceae compared with controls. Certain gut bacterial species have been found to secrete histamine, including Escherichia coli, Lactobacillus vaginalis, and Morganella morganii strains. Conversely, some species, such as Bifidobacterium longum and Lactobacillus rhamnosus have been found to reduce allergic symptoms by suppressing allergic response chemokines and downregulating mast cells.

Plus, patients with histamine intolerance were more likely to have increased intestinal permeability (demonstrated by elevated levels of zonulin in the stool.) 

Lower the load of gut irritants that can trigger a histamine response, such as yeast, dysbiotic gut bacteria, chronic infections, or parasites, and optimize digestive function.

And, just like most health challenges, histamine intolerance can begin in the gut. When clients are challenged by chronic yeast overgrowth, dysbiosis, or other chronic toxicant exposure, the immune system is chronically responsive to the irritant. Identifying chronic and eliminating yeast overgrowth, dysbiosis, chronic infections or other irritants, supporting detoxification pathways, and optimizing digestive function – including restoring small intestinal barrier function and healthy gut motility aer key to eliminating chronic immune activation from the source.

Summary

In summary, histamine intolerance can trigger significant symptoms. Fortunately, by reducing the histamine load, strategically antagonizing histamine receptors, and supporting optimal digestive function and a healthy, diverse gut microbiome the immune challenge of histamine intolerance that many of our clients with autoimmune diseases struggle with can be overcome. Your clients can restore function of the immune system and better histamine balance.

References:

Binda, M. M., Donnez, J., & Dolmans, M. M. (2017). Targeting mast cells: a new way to treat endometriosis. Expert opinion on therapeutic targets, 21(1), 67–75. https://doi.org/10.1080/14728222.2017.1260548

Iwabuchi, N., Takahashi, N., Xiao, J.-Z., Yonezawa, S., Yaeshima, T., Iwatsuki, K. and Hachimura, S. (2009), Suppressive effects of Bifidobacterium longum on the production of Th2-attracting chemokines induced with T cell–antigen-presenting cell interactions. FEMS Immunology & Medical Microbiology, 55: 324-334. https://doi.org/10.1111/j.1574-695X.2008.00510.x

Jing, H., Wang, Z., & Chen, Y. (2012). Effect of oestradiol on mast cell number and histamine level in the mammary glands of rat. Anatomia, histologia, embryologia, 41(3), 170–176. https://doi.org/10.1111/j.1439-0264.2011.01120.x

​​Mlcek, J., Jurikova, T., Skrovankova, S., & Sochor, J. (2016). Quercetin and Its Anti-Allergic Immune Response. Molecules (Basel, Switzerland), 21(5), 623. https://doi.org/10.3390/molecules21050623

Oksaharju, A., Kankainen, M., Kekkonen, R. A., Lindstedt, K. A., Kovanen, P. T., Korpela, R., & Miettinen, M. (2011). Probiotic Lactobacillus rhamnosus downregulates FCER1 and HRH4 expression in human mast cells. World journal of gastroenterology, 17(6), 750–759. https://doi.org/10.3748/wjg.v17.i6.750

Park, H. H., Lee, S., Son, H. Y., Park, S. B., Kim, M. S., Choi, E. J., Singh, T. S., Ha, J. H., Lee, M. G., Kim, J. E., Hyun, M. C., Kwon, T. K., Kim, Y. H., & Kim, S. H. (2008). Flavonoids inhibit histamine release and expression of proinflammatory cytokines in mast cells. Archives of pharmacal research, 31(10), 1303–1311. https://doi.org/10.1007/s12272-001-2110-5

Roschek, B., Jr, Fink, R. C., McMichael, M., & Alberte, R. S. (2009). Nettle extract (Urtica dioica) affects key receptors and enzymes associated with allergic rhinitis. Phytotherapy research : PTR, 23(7), 920–926. https://doi.org/10.1002/ptr.2763

Schink, M., Konturek, P. C., Tietz, E., Dieterich, W., Pinzer, T. C., Wirtz, S., Neurath, M. F., & Zopf, Y. (2018). Microbial patterns in patients with histamine intolerance. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society, 69(4), 10.26402/jpp.2018.4.09. https://doi.org/10.26402/jpp.2018.4.09

Schneider, E., Leite-de-moraes, M., & Dy, M. (2010). Histamine, immune cells and autoimmunity. Advances in experimental medicine and biology, 709, 81–94. https://doi.org/10.1007/978-1-4419-8056-4_9

Secor, E. R., Jr, Szczepanek, S. M., Castater, C. A., Adami, A. J., Matson, A. P., Rafti, E. T., Guernsey, L., Natarajan, P., McNamara, J. T., Schramm, C. M., Thrall, R. S., & Silbart, L. K. (2013). Bromelain Inhibits Allergic Sensitization and Murine Asthma via Modulation of Dendritic Cells. Evidence-based complementary and alternative medicine : eCAM, 2013, 702196. https://doi.org/10.1155/2013/702196

Sharma, S. C., Sharma, S., & Gulati, O. P. (2003). Pycnogenol inhibits the release of histamine from mast cells. Phytotherapy research : PTR, 17(1), 66–69. https://doi.org/10.1002/ptr.1240

Thangam, E. B., Jemima, E. A., Singh, H., Baig, M. S., Khan, M., Mathias, C. B., Church, M. K., & Saluja, R. (2018). The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Allergy and Inflammation: The Hunt for New Therapeutic Targets. Frontiers in immunology, 9, 1873. https://doi.org/10.3389/fimmu.2018.01873

https://www.thermofisher.com/us/en/home/life-science/cell-analysis/cell-analysis-learning-center/immunology-at-work/t-helper-2-cell-overview.html

Torrealba, F., Riveros, M. E., Contreras, M., & Valdes, J. L. (2012). Histamine and motivation. Frontiers in systems neuroscience, 6, 51. https://doi.org/10.3389/fnsys.2012.00051

http://www.turkupetcentre.net/petanalysis/target_histamine.html

One thought on “Histamine Intolerance, Autoimmunity, and Endometriosis

  1. Jessica,

    Well done! Your best blog yet, this will be shared to those in need, and help you to expand your clients and coaching students!

    Salutations,

    Maureen

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