How Histamine Can Cause Way More Problems Than Just Allergies
Histamine is vital for our day-to-day biological rhythms. As a neurotransmitter, it promotes wakefulness, controls satiety, and is crucial to direct goal-oriented behaviors, while the histamine H3 receptor is related to cognitive function and the maintenance of short and long-term memory.
However, the histamine response can become a disruptive force if it is not properly regulated. We are familiar with the ways histamine can produce a runny nose, or draw our attention to a mosquito bite, but histamine can also create hypersensitivity reactions ranging from leaky gut and inflammatory bowel disease to mast cell activation syndrome and anxiety, contributing to neurological dysfunction.
Beyond common allergies, histamine has the ability to destabilize biological balance with significant and deleterious consequences that often go misdiagnosed.
Histamine acts as the body’s defense mechanism when it perceives a threat by a foreign or pathogenic invader. The release of histamine kicks off the body’s “attack mode” making this monoamine the natural opposite of balance and calm. When uncontrolled, histamine is pure fight energy.
Rather than writing off histamine as a bystander in standard allergic reactions, we must consider histamine as a primary agent for various destabilizing effects in the body and a considerable source of systemic stress. Then, we can begin to manage and stabilize histamine for a better sense of everyday balance.
Table of Contents:
- A Deeper Look at Histamine and Sensitivity
- The Link Between Histamine and Sulfur
- A Note on Butyrate and Histamine Balance
- How BodyBio Calm Can Help With Histamine Sensitivity
- Find Relief From Hypersensitivity
A Deeper Look At Histamine and Sensitivity
Histamine is an organic compound involved in the immune response. It acts as an excitatory neurotransmitter in the brain and spinal cord and regulates activity in the gut through GI motility, gastric acid production, and the secretion of H2 (hydrogen) ions in the mucosa. (Patel, 2021; Heidari et al., 2015).
The majority of histamine in the body is generated by mast cells and white blood cells (immune cells), and it is stored inside these cells. When histamine is released, it can instigate a number of chemical reactions:
- Contracting smooth muscle tissues
- Dilating blood vessels
- Lowering blood pressure
- Accelerating the heart rate
- Initiating chemical communication between nerve cells.
Histamine also acts as a hormone regulator and helps keep us awake during the day, and contributes to feelings of satiety when we eat.
This is how histamine works in the body. When an injury, pathogenic threat, or a toxic substance threatens the body, mast cells release histamine, causing the dilation of blood vessels. This dilation permits white blood cells and blood plasma proteins to slip into the bloodstream and travel to the location of the injury or toxin, where immune system cells can begin to fight the invasion (Branco et al., 2018).
Troubles in the body arise when histamine is over-secreted due to what are known as hypersensitivity reactions to various stimuli, some dangerous and others seemingly harmless. Hypersensitivity reactions refer to an immune response resulting in inflammation, tissue damage and even chronic disease states, such as multiple sclerosis, colitis, arthritis, ADHD, anaphylaxis and autoimmunity.
Symptoms of these reactions can include:
- Allergic conditions
- Gastrointestinal disease
- Low gastric acidity
- Sinus congestion
- Gallbladder impairment
- Chronic fatigue.
Significantly, type II hypersensitivities, also known as cytotoxic hypersensitivities, occur when damage happens to our own cells. These reactions are initiated by the antibodies immunoglobulin G (IgG) and immunoglobulin M (IgM). Some common forms of type II hypersensitivities are when the specified immunoglobulins attack our own cells, often causing autoimmune disease (i.e. Grave’s Disease, hemolytic anemia, Myasthenia Gravis).
The most common points of entry for antigens (a substance provoking an immune response) are the skin, respiratory system, and digestive system. Every breath we take and every bite of food we eat offers an opportunity for new, unrecognizable substances, pathogens and toxins to enter the body, where they must be identified, assessed for toxicity, and finally metabolized.
This is not something to be afraid of; our bodies are designed to do this. But in an hypersensitive system, the body looks to seek and destroy foreign materials under the assumption that they may be pathogenic, therefore hypersensitivity may be directly related to excess secretion of histamine.
In cases of histamine intolerance, histamine is over-produced, altering the body’s ability to discern between human cells and antigens.
The Link Between Histamine and Sulfur
Because histamine and gut health are so deeply linked, histamine-producing bacteria are of great concern in cases of mast cell activation syndrome (MCAS). Foods containing the amino acid histidine may be converted via certain types of gut bacteria into histamine.
However, sulfur metabolism impairment can act as a significant contributor to histamine intolerance, and that a unique connection exists between the two.
Because sulfur and histamine intolerance are almost identical in symptomatology, they are easily, and often, confused. However, when we make the connection between impaired sulfur metabolism mechanisms and elevated levels of histamine in the body, it becomes clear that an inability to properly process sulfur is linked to a downstream inability to efficiently regulate histamine.
Sulfur, the fourth most abundant molecule in the body, is a chemical element found in several organic compounds, foods, medications and environmental features, and is essential for turning amino acids into proteins in the body.
The body is able to use sulfur in the body as sulfate. When the conversion of sulfur to sulfate is slowed or compromised, concentrations of sulfate in the body are depleted, while concentrations of sulfur and sulfite may remain elevated.
Among other symptoms, this can result in (Samsel and Seneff, 2013):
- Allergic and inflammatory responses
- Compromised gut integrity
- Impaired cholesterol sulfate metabolism
- Decreased gallbladder function and bile acid activity
- Kidney stones and calcifications.
Another factor that metabolizes sulfur is the CBS gene. A disruption of sulfur metabolism, and any mutations or impairments of the CBS gene may contribute to the depletion of the compound SAM-e, which has been linked to an increase in histamine levels in the body (“The Enzyme CBS”). An additional issue that may arise when the CBS gene is impaired is an excess accumulation of hydrogen sulfide gas (H2S) that may lead to gut dysbiosis.
Normal levels of hydrogen sulfide help regulate gut inflammation and motility, oxidative stress, ulcer healing, apoptosis, vascular tone, and hormone secretion. Imbalances in H2S due to gut dysbiosis may lead to Crohn’s disease, IBS, IBD, ulcerative colitis, obesity, and sepsis.
Too much hydrogen sulfide may also be linked to adrenal insufficiency due to H2S helping to control mitochondrial function in the adrenal tissue (Wang et al., 2014). H2S imbalances could be linked to stress, excessive meat consumption, and high sulfur diets, particularly if an individual has genetic predispositions that impair sulfur metabolism (Teigen et al., 2019).
Histamine, Sulfur, and Gut Dysbiosis
We’ve mentioned a couple of times now that certain gut bacteria are involved in both processing sulfur and producing histamine. When numbers of these bacteria become imbalanced, levels of sulfur and histamine can easily get out of control.
Through clinical observation, our practitioners have identified a common thread between candida and SIBO cases (high histamine levels are a repeat symptom in this group), viral expressions like Lyme Disease and its co-infections, mast cell activation syndrome, and sulfur intolerance. For comparison, here are the common symptoms of sulfur and histamine intolerance:
Sulfur intolerance symptoms:
- Joint pain/Body pain
- Palpitations/Sudden blood pressure changes
- GI pain/Constipation/Diarrhea
- Shortness of breath
- Fatigue/Cognitive impairment
Histamine intolerance symptoms:
- Joint pain/Body pain
- Palpitations/Sudden blood pressure changes
- GI pain/Constipation/Diarrhea
- Shortness of breath
- Fatigue/Cognitive impairment
In cases of candida and SIBO, sulfate-reducing bacteria in the gut produce excess hydrogen sulfide gas when they ferment carbohydrates, further disrupting microbiome health, inducing an immune response, and increasing intestinal permeability and gut inflammation (Figliuolo et al., 2017).
Clients with candida or SIBO often present with an intolerance to sulfur-based medicines and foods, with symptoms that mirror those of histamine intolerance. One red flag for sulfur-sensitive clients is an intolerance to glutathione, a sulfur-based antioxidant. When the body cannot properly break down glutathione, one side effect is an increased production of hydrogen sulfide gas, especially in cases of SIBO. Hydrogen sulfide causes breakdown of the mucus barrier, and reduces concentrations of the mineral molybdenum, which is crucial for the regulation of histamine.
A Note on Butyrate and Histamine Balance
Another consideration with dysbiosis and histamine intolerance is the role of butyric acid.
Butyric acid, also known as butyrate, is a short-chain fatty acid produced in the large intestine when beneficial bacteria break down dietary fiber. As a postbiotic, butyric acid acts as a fertilizer for good bacteria in our gut microbiome, enhances colonic health, modulates gut motility, and regulates gastrointestinal pH (Folkerts et al., 2020). It also modulates systemic inflammation, affects cholesterol and blood sugar levels, and produces a majority of the colon’s energy. (Pituch et al., 2013).
Within the immune system, butyrate assists the immune cells in mounting an immune response, helps to improve food tolerance, supports immune cells that balance inflammation and allergic responses, and enhances macrophage anti-bacterial activity (Tan et al., 2016).
Along with immune system function and gut health, butyrate also regulates mast cell stabilization, managing the degranulation of chemical mediators – including histamine release. It has been found in the laboratory setting to modulate mast cell activation (cells that release histamine) by inhibiting immunoglobulin-E activity (Folkerts et al., 2020).
Much like molybdenum deficiency, low levels of butyrate may result in an increase in histamine or the development of histamine intolerance.
In cases of dysbiosis or impaired sulfur metabolism, the presence of excess sulfites in the GI tract may inhibit the production of butyrate and hinder the balance of the beneficial bacteria in the gut (Cyr, 2020). This imbalance contributes to leaky gut, an increase in oxidation and, ultimately, the malabsorption of fat, sulfur, protein and oxalates. One of the reasons why dietary fiber is so vital to healthy digestion is because it allows the colon to produce adequate levels of butyric acid, which protects the intestinal defense barrier (Canani et al., 2011).
BodyBio Butyrate supplements along with BodyBio Calm are useful for managing the body’s histamine response by regulating mast cell stabilization, supporting healthy immune system function, strengthening gastrointestinal integrity, and balancing a healthy gut microbiome.
How BodyBio Calm Can Help With Histamine Sensitivity
BodyBio Calm is specifically designed to modulate the histamine response, combining potent trace minerals, amino acids and adrenal adaptogens to manage excess levels of histamine and support natural modulators of histamine in the body. These five ingredients include: manganese, taurine, glycine, rhodiola rosea, and phosphatidylserine.
One of the signature innovations of Calm is that it utilizes an underappreciated trace mineral, manganese. Manganese helps to promote a sense of calm by modulating the excitatory neurotransmitter histamine through the following mechanisms.
Manganese (Lee et al., 2016):
- Is a cofactor for the protein that forms superoxide dismutase (SOD), an enzyme that is crucial for the antioxidation of cells
- May support the suppression of mast cell activation
- May rebalance gut dysbiosis.
The amount of manganese in Calm is small enough to ensure sustainable use, and potent enough to provide effective daily care.
Taurine, an amino acid linked to liver and nerve support, may also play a role in modulating (Nam et al., 2017; Zhou et al., 2021):
- Inflammatory cytokines
- Mast cells
- Histamine release in the body.
Modulating histamine and mast cell activity could contribute to a reduction in mast cell activation, and even rebalance the sympathetic nervous system response, regulating dopamine. This is of particular interest since the improper regulation of dopamine can result in a histamine response (Xue et al., 2018). Taurine’s ability to act as a modulator for both dopamine and histamine make it a vital player in this formulation.
Glycine is also an amino acid, and a precursor to betaine that supports healthy levels of serotonin, promotes protein synthesis and regulates cytokines (Bannai et al., 2012; Perez-Torres I et al., 2017). Crucially, glycine may reduce inflammation from digestive autoimmune diseases by lowering inflammation in the epithelial cells of the intestines (Perez-Torres I et al., 2017).
Additionally, a study using mouse models found that oral administration of glycine significantly inhibited allergy development, indicated by a reduction in acute allergic skin response, anaphylaxis, and serum antibodies (Bergenhenegouwen et al., 2018).
Integral to the success of Calm is the inclusion of two adrenal adaptogens: rhodiola rosea and phosphatidylserine. When the adrenal glands are overworked, cortisol levels rise and may depart from normal ranges, depleting the body’s supply of cortisol.
This is noteworthy because, as a natural anti-inflammatory agent, cortisol is key to the modulation of histamine, and strong adrenals are absolutely key to maintaining the healthy production and management of cortisol. By supporting adrenal function with targeted adaptogens, Calm helps to modulate the stress response, which, in turn, modulates the histamine response.
Our first adaptogen, rhodiola rosea, is an herb that helps to manage stress and mental fatigue, and may support the rebalancing of depressive symptoms (Ishaque et al., 2012). Acting as an adrenal adaptogen, rhodiola has the potential to modulate the release of cortisol and reduce inflammatory markers in the body (Anghelescu et al., 2018; Haidari et al., 2019). As a modulator of cortisol, rhodiola indirectly helps to support a balanced histamine response, and may modulate serotonin, contributing to a more balanced mood (Mannucci et al., 2012).
Calm’s final ingredient, phosphatidylserine, is a phospholipid found in the brain that supports healthy myelination, nerve cell structure, memory, and executive functioning (Glade and Smith, 2014). Phosphatidylserine may reduce the release of stress hormones such as ACTH and cortisol, indirectly managing histamine (Hellhammer et al., 2014). Additionally, phosphatidylserine may also positively impact age-related cognitive decline, combat depression, and aid ADHD symptoms (Hashioka et al., 2007; Kato-Kataoka et al., 2010; Hirayama et al., 2013).
Find Relief from Hypersensitivity
Calm provides comprehensive stress relief that goes beyond HPA axis support to target hidden and overlooked sources of stress, including the histamine response. By supporting a more balanced histamine response, Calm introduces a new way to soothe hypersensitive systems, addressing symptomatology that often goes overlooked but can significantly degrade an individual’s quality of life. From seasonal allergies to ADHD and mast cell activation syndrome, Calm is a secret weapon for hard-to-reach symptoms, providing a foundation for systemic balance.
Anghelescu, I.-G., Edwards, D., Seifritz, E., & Kasper, S. (2018, January 11). Stress management and the role of Rhodiola ROSEA: A review. Taylor & Francis. Retrieved September 14, 2021, from https://www.tandfonline.com/doi/full/10.1080/13651501.2017.1417442?scro ll=top&needAccess=true.
Bannai M, Kawai N, Nagao K, Nakano S, Matsuzawa D, Shimizu E. Oral administration of glycine increases extracellular serotonin but not dopamine in the prefrontal cortex of rats. Psychiatry Clin Neurosci. 2011 Mar;65(2):142-9. doi: 10.1111/j.1440-1819.2010.02181.x. PMID: 21414089.
Bergenhenegouwen, J. van, Braber, S., Loonstra, R., Buurman, N., Rutten, L., Knipping, K., Savelkoul, P.J., Harthoorn, L.F., Jahnsen, F.L., Garssen, J., Hartog, A. Oral exposure to the free amino acid glycine inhibits the acute allergic response in a model of cow's milk allergy in mice. Nutr Res. 2018 Oct;58:95-105. doi: 10.1016/j.nutres.2018.07.005. Epub 2018 Jul 10. PMID: 30340819.
Branco, A.C.C.C., Yoshikawa, F.S.Y., Pietrobon, A.J., Sato, M.N. Role of Histamine in Modulating the Immune Response and Inflammation. Mediators Inflamm. 2018 Aug 27;2018:9524075. doi: 10.1155/2018/9524075. PMID: 30224900; PMCID: PMC6129797.
Canani, R. B., Costanzo, M. D., Leone, L., Pedata, M., Meli, R., & Calignano, A. (2011, March 28). Potential beneficial ef ects of butyrate in intestinal and extraintestinal diseases. World journal of gastroenterology. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070119/.
Cyr, J. (2020, April 1). The Role of Sulphur in Ulcerative Colitis. Gastrointestinal Society. https://badgut.org/information-centre/a-z-digestive-topics/the-role-of-sulphu r-in-uc/.
Figliuolo, V. R., Santos, L. M. dos, Abalo, A., Nanini, H., Santos, A., Brittes, N. M., Bernardazzi, C., Souza, H. S. P. de, Vieira, L. Q., Coutinho-Silva, R., & Coutinho, C. M. L. M. (2017, September 12). Sulfate-reducing bacteria stimulate gut immune responses and contribute to inflammation in experimental colitis. Life Sciences. https://www.sciencedirect.com/science/article/abs/pii/S002432051730454X.
Folkerts , J., Maurer, M., Stadhouders, R., Hendricks, R., Galli, S., Tam, S.-Y., Junt , T., van IJcken, W., de Bruijn, M., van den Berg, M., Blokhuis, B., Folkerts, G., & Redegeld, F. (2020, April 24). Butyrate inhibits human mast cell activation via epigenetic regulation of FcεRI-mediated signaling. Allergy. https://pubmed.ncbi.nlm.nih.gov/32112426/.
Glade, M. J., & Smith, K. (2014, November 4). Phosphatidylserine and the human brain. Nutrition. Retrieved September 23, 2021, from https://www.sciencedirect.com/science/article/abs/pii/S0899900714004523.
Haidari, F., Asadi, M., Mohammadi-Asl, J., & Ahmadi-Angali, K. (2019). Evaluation of the effect of oral taurine supplementation on fasting levels of fibroblast growth factors, β-Klotho co-receptor, some biochemical indices and body composition in obese women on a weight-loss diet: a study protocol for a double-blind, randomized controlled trial. Trials, 20(1), 315. https://doi.org/10.1186/s13063-019-3421-5
Hashioka, Sadayuki, Youn-Hee Han, Shunsuke Fujii, Takahiro Kato, Akira Monji, Hideo Utsumi, Makoto Sawada, Hiroshi Nakanishi, and Shigenobu Kanba. “Phosphatidylserine and phosphatidylcholine-containing liposomes inhibit amyloid β and interferon-γ-induced microglial activation.” Free Radical Biology and Medicine 42, no. 7 (2007): 945-954.
Heidari, A., Tongsook, C., Najafipour, R., Musante, L., Vasli, N., Garshasbi, M., Hu, H., Mittal, K., McNaughton, A. J. M., Sritharan, K., Hudson, M., Stehr, H., Talebi, S., Moradi, M., Darvish, H., Arshad Rafiq, M., Mozhdehipanah, H., Rashidinejad, A., Samiei, S., … Vincent, J. B. (2015, October 15). Mutations in the histamine N-methyltransferase gene, HNMT, are associated with nonsyndromic autosomal recessive intellectual disability. Human molecular genetics. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4581600/.
Hellhammer, J., Vogt, D., Franz, N., Freitas, U., & Rutenberg, D. (2014, July 31). A soy-based phosphatidylserine/ phosphatidic acid complex (PAS) normalizes the stress reactivity of hypothalamus-pituitary-adrenal-axis in chronically stressed male subjects: A randomized, placebo-controlled study. Lipids in Health and Disease. Retrieved September 23, 2021, from https://link.springer.com/article/10.1186/1476-511X-13-121.
Hirayama, S., Terasawa, K., Rabeler, R., Hirayama, T., Inoue, T., Tatsumi, Y., Purpura, M., & Jäger, R. (2013, March 17). The ef ect of phosphatidylserine administration on memory and symptoms of attention‐deficit hyperactivity disorder: A randomised, double‐blind, placebo‐controlled clinical trial. Wiley Online Library. Retrieved September 23, 2021, from https://onlinelibrary.wiley.com/doi/full/10.1111/jhn.12090.
Ishaque, S., Shamseer, L., Bukutu, C., & Vohra, S. (2012). Rhodiola rosea for physical and mental fatigue: a systematic review. BMC complementary and alternative medicine, 12, 70. https://doi.org/10.1186/1472-6882-12-70)
Kato-Kataoka, A., Sakai, M., Ebina, R., Nonaka, C., Asano, T., & Miyamori, T. (2010). Soybean-derived phosphatidylserine improves memory function of the elderly Japanese subjects with memory complaints. Journal of clinical biochemistry and nutrition, 47(3), 246–255. https://doi.org/10.3164/jcbn.10-62
Lee, Y. S., Choi, J.-H., Lee, J.-H., Lee, H.-W., Lee, W., Kim, W. T., & Kim, T.-Y. (2016). Extracellular superoxide dismutase ameliorates house dust mite-induced atopic dermatitis-like skin inflammation and inhibits mast cell activation in mice. Experimental Dermatology, 25(8), 630–635. https://doi.org/10.1111/exd.13028
Mannucci C, Navarra M, Calzavara E, Caputi AP, Calapai G. Serotonin involvement in Rhodiola rosea attenuation of nicotine withdrawal signs in rats. Phytomedicine. 2012 Sep 15;19(12):1117-24. doi: 10.1016/j.phymed.2012.07.001. Epub 2012 Aug 24. PMID: 22921986.
Nam, S.-Y., Kim, H.-M., & Jeong, H.-J. (2017, September 1). The potential protective role of taurine against experimental allergic inflammation. Life sciences. Retrieved September 22, 2021, from https://pubmed.ncbi.nlm.nih.gov/28694089/.
Patel, R. H. (2021, May 9). Biochemistry, Histamine. StatPearls [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK557790/.
Pérez-Torres I, Zuniga-Munoz AM, Guarner-Lans V. Beneficial Effects of the Amino Acid Glycine. Mini Rev Med Chem. 2017;17(1):15-32. doi: 10.2174/1389557516666160609081602. PMID: 27292783.
Pituch, A., Walkowiak, J., & Banaszkiewicz, A. (2013, October 28). Butyric acid in functional constipation. Przeglad gastroenterologiczny. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4027827/.
Samsel, A., and Seneff, S. “Glyphosate’s Suppression of Cytochrome P450 Enzymes and Amino Acid Biosynthesis by the Gut Microbiome: Pathways to Modern Diseases.” Entropy, vol. 15, no. 12, 2013, pp. 1416–1463., doi:10.3390/e15041416.
Tan, J., McKenzie, C., Vuillermin, P. J., Goverse, G., Vinuesa, C. G., Mebius, R. E., Macia, L., & Mackay, C. R. (2016, June 21). Dietary fiber and bacterial SCFA enhance oral tolerance and protect against food allergy through diverse cellular pathways. Cell Reports. Retrieved November 29, 2021, from https://www.sciencedirect.com/science/article/pii/S2211124716306301.
Teigen, L. M., Geng, Z., Sadowsky, M. J., Vaughn, B. P., Hamilton, M. J., & Khoruts, A. (2019). Dietary Factors in Sulfur Metabolism and Pathogenesis of Ulcerative Colitis. Nutrients, 11(4), 931. https://doi.org/10.3390/nu11040931
The enzyme CBS: (Cystathione beta synthase): Energy Levels. Activate Your Happy Genes. https://myhappygenes.com/the-enzyme-cbs-cystathione-beta-synthase-energ\ y-levels/. Published July 5, 2020. Accessed November 23, 2021.
Wang, C.-N., Liu, Y.-J., Duan, G.-L., Zhao, W., Li, X.-H., Zhu, X.-Y., & Ni, X. (2014). CBS and CSE are critical for maintenance of mitochondrial function and glucocorticoid production in adrenal cortex. Antioxidants & Redox Signaling, 21(16), 2192–2207. https://doi.org/10.1089/ars.2013.5682
Xue, R., Zhang, H., Pan, J., Du, Z., Zhou, W., Zhang, Z., Tian, Z., Zhou, R., & Bai, L. (2018, October 17). Peripheral dopamine controlled by gut microbes inhibits invariant natural killer t cell-mediated hepatitis. Frontiers. https://www.frontiersin.org/articles/10.3389/fimmu.2018.02398/full.
Zhou, J., Lu, Y., Wu, W., & Feng, Y. (2021, June 19). Taurine promotes the production of cd4+cd25+foxp3+ treg cells through regulating il-35/stat1 pathway in a mouse allergic rhinitis model. Allergy, Asthma & Clinical Immunology. Retrieved September 22, 2021, from https://aacijournal.biomedcentral.com/articles/10.1186/s13223-021-00562-1.