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Genetic variants that seriously impact digestion and the gut by creating histamine and zonulin.

In my March, 2014 article on Methylation Pathways, we learned about the Methylation cycles, and how genetic variants can reduce methyl groups, folate and the methylation cycle. We explored how the DNA makes enzymes, and how genetic variants can impact the enzyme production, and consequently, the levels of folate, oxidants and antioxidants in the body.

In the September 2014 issue, we explored how low BH4 (tetrahydrobiopterin), NOS (Nitric Oxide Synthase) variants, variants in SOD (Superoxide Dismutase, a master anti-oxidant) and Glutathione can increase the dangerous oxidizing agent, Peroxynitrite, that we referred to as the, "Gorilla in the Room", that we were often overlooking.

As a continuation of this series, we are now going to learn how low methyl donors and variants in the DAO (diamine oxidase) enzymes can cause high histamine, and then, as a result, create the gut destroying molecule, zonulin. After you read and understand this article, you will have new tools to support your patients' gut issues, which are often the root causes of many health concerns.

I have been quite surprised at how many of my clients experience high histamine and zonulin, and the detrimental effect it has. Finally, we will explore natural remedies to reduce the histamine and zonulin and support the healing of the gut.

Histamine (The Other Gorilla In The Room)

Histamine is a bio-active chemical that acts as a signaling molecule for a variety of functions throughout the body. With the help of vitamin B6, the enzyme histidine decarboxylase (HDC) catalyzes the reaction that produces the biogenic amine histamine from the amino acid histidine. HDC is biosynthesized only when a cell needs to produce histamine, and then quickly degrades (Schwelberger).

Histamine wears a number of hats within the human body. It helps to regulate a variety of functions such as: immune response, digestion, inflammation, sexual function, blood pressure/vasodilation, muscle contraction, wakefulness, and neuromodulation. Each of these functions relies on which type of cell and which type of receptor it binds to. Found in highest concentrations in our skin, lungs, and GI tract, histamine is also found in smaller amounts in the brain and heart. In addition to being produced by our bodies, histamine is also found in the plants and animals that we eat, both naturally occurring and in dyes and preservatives found in processed products.

Best known for its role in allergic response, histamine acts to protect the body from potential disease-causing agents like bacteria: viruses and allergens. Most histamine in the body is produced and stored in mast cell granules in tissue or basophils that circulate in blood. When the immune system senses an antigen or "foreign invader," histamine is released, signaling inflammation, in an attempt to fight it off.

After its release, histamine is naturally degraded by certain enzymes. Histamine intolerance (HIT) occurs when there is more circulating histamine in the body than can be effectively broken down by these enzymes (either because of enzyme deficiency or inhibition), creating symptoms throughout the body. It is difficult to distinguish between low enzyme levels and histamine excess, as they are two sides of the same coin.

The primary enzyme for the metabolism of histamine is di-amine oxidase (DAO) (Maintz & Novak, 2001), which degrades extracellular histamine through oxidative deamination (NCBI). DAO is formerly called histaminase. In addition to catabolizing endogenously released histamine, DAO in the gut also breaks down dietary histamine to prevent its uptake into the blood (Schwelberger). DAO is located in greatest amounts in the intestinal mucosa, thymus, and seminal vesicles. It also is produced in abundance during pregnancy in the placenta (Rangachari, 1992).

Another enzyme, histamine-N-methyltransferase (HNMT, aka HMT) inactivates histamine only in the intracellular space of cells, through methylation. After histamine is methylated by HNMT, it is further metabolized by diamine oxidase or monoamine oxidase-B (MAO-B) (Maintz & Novak, 2001). HNMT is widely expressed in human tissues, with the highest amounts in the: jejunum, stomach, liver, lung, kidney, spleen, and brain (Joneja, 2004). The International Society of DAO Deficiency states that "high histamine concentrations in the blood are related to DAO deficiencies, not HNMT" (International Society of DAO Deficiency, 2012).

Recent research indicates that in tissues where both enzymes occur together, DAO tends to exhibit a histamine-degrading capacity ten times higher than that of HNMT (Huertz, 2003).

Symptoms of High Histamine and Histamine Intolerance Because histamine is released in various sites throughout the body, imbalances can manifest in a plethora of ways. Histamine intolerance is cumulative, unlike food sensitivities or allergies. The amount of histamine in the blood fluctuates depending on types of food consumed (rich in histamine and/or histamine liberating) and environmental factors that trigger histamine or block DAO activity. Symptoms occur when the level of histamine in the body exceeds what the body can clear, often indistinguishable from allergy (Joneja, 2004). A common comparison of histamine intolerance likens it to a bucket. Adding water (histamine) to a bucket (the body) will not create an overflow (presentation of symptoms) unless water levels have already accumulated to being nearly full.

Disease, various phases of the female cycle, various medications and physiological conditions are all factors that may affect tolerance threshold (Joneja, 2004). It has been speculated that tolerance levels may be of genetic origin (Joneja, 2004).

Symptoms of histamine intolerance include: diarrhea, hypotension, heart arrhythmia, headache, pruritus (WOhrl, 2004), hives, eczema, contact dermatitis, tissue swelling (especially of the oral and facial tissues), hypotension, anxiety, depression, irritability, inflammation, arthritis, asthma, nasal congestion/runny nose, heartburn, bloating, flatulence, fatigue and joint and muscle pain (Vickerstaff, 2001). Interestingly, histamine creates an excessive amount of saliva. Lack of dental decay may be an indicator of histamine excess (Venza, 2006).

Depending on dosage, a common reaction triggered by histamine-rich food is a vascular headache caused mainly by nitric oxide (Thomsen, 2001). In addition to headache, gastrointestinal diseases like: Crohn's disease, ulcerative colitis, food allergies, and colorectal neoplasmas are symptoms of elevated histamine/diminished DAO activities (Maintz & Novak, 2001).

Estrogen is pro-histamine, and there is a positive correlation between estrogen dominance and histamine status.

Some less-obvious histamine reactions have a latency period, such as sleep disturbance and anxiety. This is because high histamine levels cause the body to produce adrenaline (epinephrine) to increase blood pressure. This rise in adrenalin can produce anxiety and disturbances in sleep, which is the flipside of why anti-histamines can cause drowsiness by lowering histamine levels.

Histamine Levels That aAre Too High Can Stem From Different Causes And Can Elicit A Myriad Of Health Challenges.

Genetic variants in the genes that create DAO and FINMT can create decreased activity that hinders histamine metabolism. The gene responsible for synthesizing DAO is amiloride binding protein 1 (ABP1), also known as amine oxidase, copper containing 1 (A0C1). The HNMT gene codes for the HNMT enzyme. Diamine oxidase polymorphisms have been associated with inflammatory intestinal diseases, including food allergies, whereas low enzyme activity caused by HNMT polymorphisms has been associated with asthma (Maintz L. e., 2006).

Food and drink can cause histamine levels to elevate. There are foods that are naturally rich in histamine, like: meat, pickled foods, alcohol and aged cheeses, since histamine levels increase as food ages.

There are also foods that signal the release of histamine, even if they don't contain large amounts of histamine themselves. These are foods like citrus, chocolate, avocado, strawberries and tomatoes.

Other factors that can cause elevated histamine levels are substances that inhibit the DAO enzyme. Alcohol, tea, and cocoa, along with various medications are known to block the effectiveness of DAO.

Histamine-Rich Foods

Meat (especially smoked)

Pickled foods


Aged cheeses

Nuts (walnuts, cashews)

DAO Inhibitors


Tea (black, green, Mate)


Various medications

Histamine-Liberating Foods






Another cause for high histamine/diminished DAO activity is poor gut function, because it is primarily made in the microvilli of the GI tract. Low levels of DAO correlate with poor mucosal integrity, which is associated with inflammatory conditions like: Crohn's disease, ulcerative colitis and celiac disease. Also, bacteria in the gut are able to degrade histamine, but there are also strains that are histamine-producing. A healthy, balanced gut-biome will ensure proper histamine degradation (Iannitti, 2010) (Thomas, 2012).

Histamine As A Neurotransmitter

Within the central nervous system, histamine performs as a neurotransmitter (Bowen, 2008). It is produced by neurons, mast and microglia cells in the adult brain (Rocha, 2014). The neuronal histaminergic system is involved in many physiological functions (Rocha, 2014) and modulates a number of important processes in the brain, including: the sleep-wake cycle, cognitive ability, consumption of food, pain perception, release of tears, sexual libido, and pituitary hormone secretion (Nuutinen, 2011). It also promotes hypothalamus release of serotonin, epinephrine and norepinephrine (Batmanghelidj, 1990). Histamine triggers melatonin production, which is necessary for fat metabolism (Super, 2003). The histaminergic system is severely affected in age-related neurodegenerative diseases (Rocha, 2014). Postmortem studies suggest alterations in this system in psychiatric and neurological diseases.

Although levels of histamine tolerance depend on numerous factors, a measurement of more than 70mcg/ dl indicates high serum histamine. High histamine levels have been linked to obsessive compulsive tendencies, depression, and headaches.

Low histamine levels can contribute to paranoia, low libido, fatigue, seizures, and medication sensitivities (Batmanghelidj, 1990). Histamine is a stress regulator. Histamine deficiency can lead to higher levels of stress, increasing the body's need for more histamine (Ghi, 1992).

Growing evidence indicates that changes in the histaminergic system may be associated with the pathogenesis and progression of several neurogenerative diseases (Rocha, 2014). High levels are found in the brains of Parkinson's disease patients, while levels were decreased in Alzheimer's disease patients (Nuutinen, 2011). Furthermore, Gilles de la Tourette syndrome, addictive behaviors, and multiple sclerosis are also associated with changes in histamine signaling (Panula, 2013).

Brain injury, degeneration or infection, can alter the release of histamine (Nuutinen, 2011) indicating that histamine may play an important role in modulating neuronal survival (Rocha, 2014). Additionally, histamine is always present when inflammation occurs, and symptoms of inflammation are caused by excess histamine; this fact is true for the entire body, not just the brain. Rocha's study demonstrated that histamine promotes the release of toxic inflammatory factors, including cytokines and nitric oxide, by microglial cells, which can be capable of damaging dopaminergic neurons.

Studies have established that histamine, its synthesizing enzyme 1-histidine decarboxylase (HDC) and histamine receptor are involved in disease states or experimental models of brain disease (Panula, 2013).

The Methylation/Histamine Relationship

There is an interesting inverse relationship between adequate methyl groups and histamine.

Because methylation deactivates histamine (Van Kon-ynenburg) by donating a methyl group, histamine is negatively correlated with methylation capability (Walsh, 2012). SAMe, the universal methyl donor, is derived from methionine through methylation. When it receives a methyl group from SAMe, histamine is deactivated. Proper methylation ability is one factor that provides adequate levels of SAMe to keep histamine in check.

Adding to this, methylation cycle expert Dr. Amy Yasko states in chapter 2 of her book, Autism: Pathways to Recovery (Yasko, 2009), that histamines cause allergic reactions when they are released in response to antigens. Impaired methylation leads to abnormally high levels of histamine and increased allergic sensitivity, a correlation she frequently sees in children with autism.

Additionally, the late, renowned speaker and expert on methylation, Dr. Rich Van Konyenburg, states in a forum (PhoenixRising), "High histamine occurs in people who are getting folic acid as their main source of folate, but are not able to convert it readily to the active, chemically reduced forms of folate."

He attributes this inability to having inherited a variant in the DHFR (dihydrofolate reductase) gene that lowers the ability of DHFR to reduce dihydrofolate into tetrahydrofolate (BH4), which is essential for breaking down histidine, from which histamine is synthesized. The reason for this is because with a DHFR polymorphism, folic acid (the synthetic form of folate) is unable to be efficiently broken down for use by the body. Inactive folate competes with active forms of folate for absorption. So the problem of excess histamine is not caused by too much folate, but not enough of the proper forms. Other polymorphisms that involve the folate cycle, such as MTHFR and FOLR, can affect histamine as well. Van Konyenburg further states that folic acid should be avoided by people that have elevated histamine.

If you suspect histamine intolerance, you may want to ask your patients if they experience any difficulties with histamine foods.

It Gets Worse!!!! Zonulin

What makes high histamine so insidious is that it often also creates a very damaging molecule called zonulin. When secreted by epithelial cells in the gut in response to a stimulus, zonulin triggers the tight junctions between the intestinal cells to open. These junctions are critical in protecting the body from foreign substances, ideally only opening to let nutrients pass through the intestinal wall. Zonulin causes these tight junctions to open and remain open longer than necessary, or indefinitely. This condition is referred to as gut permeability, or "leaky gut."

High plasma zonulin is associated with intestinal permeability (Klaus, 2013). Elevated zonulin levels have been shown to precede the onset of diabetes, autoimmune conditions and allergies, and therefore may be an early marker of disease processes (Sapone, 2006).

A positive-feedback loop exists with leaky gut and high serum levels of histamine (histadelia). This is because the body excretes watery mucous as a result of a histamine response, and the watery mucous causes the gut lining to become more weak and permeable to things like gluten. Leaky gut conditions deplete DAO, allowing a feed-forward cycle of systemic inflammation. The opening of tight junctions can allow undigested proteins and perceived invaders into the blood, triggering an immune response as the body reacts each time the proteins appear. This may ultimately lead to autoimmune diseases, where the immune system is on such high alert that it is attacking anything that resembles these invaders, even the body's own tissues. These toxins also overwhelm the liver's ability to clear these substances, creating additional problems.

To make matters worse, these invaders may cross the blood-brain barrier and wreak havoc on the nervous system. Histamine alone enhances BBB permeability (Daryl W. Hochman, 2012), and recent studies have reported that zonulin may affect the tight junction permeability of the blood-brain barrier (1..TIVIM, 2000). There has been a correlation between an increase in zonulin expression and gliomas (Skardelly M, 2009).

The release of zonulin is activated by several mechanisms, most commonly from overgrowth of harmful organisms (bacteria, yeast, parasites) or food sensitivities, especially gluten (more specifically, a protein in gluten called gliadin) (Fasano, 2011). Gliadin causes zonulin levels to increase in people regardless of whether they have celiac disease or not (Fasano, 2011). Since certain types of "bad" bacteria in the gut make histamine from undigested food, a close relationship exists between histamine intolerance, SIBO and dysbiosis. Optimal levels of beneficial gut bacteria effectively clear histamine. When there is an overgrowth of harmful organisms, the intestinal microvilli that make diamine oxidase are compromised, affecting histamine degradation and causing us to be more sensitive to histamine. Antigens in the gut, and the resulting immune activation, creates more damage to the intestinal cells (enterocytes), compounding the inflammation and permeability. Additionally, damage to the microvilli affects absorption of nutrients, leading to deficiencies.

The key to downregulating the zonulin pathway is to reestablish intestinal barrier function (Fasano, 2011). This can be done by increasing bacteria that promote gut health and by eliminating food derived triggers and things that feed the bad bacteria. DAO comes from microvilli. Things that cause villi atrophy cause decreased DAO activity. Rebuilding microvilli will help restore DAO production.

Some of the bacteria known to assist in histamine degradation are many of the bifidobacteria species, Bifidobacterium infantis (found in breast milk), Bifidobacterium longum, as well as Lactobacillus rhamnosus, which may actually enhance the activity of anti-inflammatory agents.

Some strains ofprobiotics actually produce histamine, like Lactobacillus reuteri (Thomas C. M., 2012), Lactobacillus casei and Lactobacillus bulgaricus (Priyadarshani, 2011). These strains are commonly found in most yogurts and fermented foods.

When histamine levels are lowered, whether by increasing methyl groups by supporting methylation and SAMe production, eliminating histamine-rich and histamine-liberating foods, or by increasing DAO, the inflammation of the gut lining is lowered as well.

Autoimmune Diseases

Celiac disease

Type 1 diabetes

Rheumatoid arthritis

Inflammatory bowel disease

Systemic lupus


Brain gliomas

Breast Cancer

Lung adenocarcinoma

Ovarian cancer

Pancreatic cancer

Diseases of the Nervous System

Multiple Sclerosis


Chronic inflammatory demyelinating polyneuropathy

Pulling It All Together

As you now know, low folate caused by MTHFR and other methylation cycle variants is made worse when combined with DAO genetic variants. This will create elevated histamine and can cause any of the issues mentioned above.

Adding to the problem, histamine triggers the release of zonulin, which damages the gut, inhibiting DAO production. This creates the vicious cycle of histamine intolerance.

In addition to creating and being the result of severe gastrointestinal issues, zonulin also has the potential to be a cause or contributing factor to autoimmune disease.

Being able to look at genetic tests will allow you to determine if there are variants that: reduce folate, decrease DAO enzyme activity, create imbalances in beneficial gut bacteria and increase the likelihood of gluten sensitivity. These tests give insight to those troublesome gut issues like never before.

So What To Do!

Understanding that low methylation ability, and its association with low SAMe and methyl folate, can cause elevated histamine and the potential for high zonulin, gives the health practitioner powerful new methods to support their patients.

I suggest that whenever the patient discusses chronic digestive difficulties, allergies, or the other issues described in this article, you may want to investigate if high histamine and high zonulin are factors that need to be evaluated.

Dunwoody Labs,, offers a blood test for histamine and DAO.

In addition, Doctors Data, offers a methylation plasma test that shows you methionine, SAMe, SAH, Homocysteine, Cysteine and Cystathionine. The SAMe levels will help you understand if they have adequate methyl groups, since SAMe is the major methyl donor.

I have found the inexpensive and accurate DNA tests from 23andme,, to be extremely helpful in finding out if there are genetic variants that decrease methyl donors (FOLR, DHFR, MTHFR, MTRR and others), and genetic variants that may decrease DAO essential for breaking down histamine.

I am in the process of developing an online site that will allow you to upload the genetic data from 23andme and other DNA sources and get a detailed print out of the relevant variants. This online program will estimate if methyl groups are low or high, and provide details about what you can do to create balance. For more information, e-mail me at

If histamine, zonulin and low folate levels have damaged the gut, this must be the first priority. This may include soothing and healing nutrients for the gastrointestinal lining, removing inflammatory foods (especially gluten), and reducing inflammation in the gastrointestinal tract.

Some suggestions are:

Coconut oil - antimicrobial and antifungal

Omega 3's for inflammation

Colostrum contains immunoglobulins and other compounds that can promote tissue repair and improve immunity. Products containing immunoglobulins close tight junctions and quickly begin to heal leaky gut, which can counteract the effects of zonulin.

Beneficial bacteria are critical for immune function and gastrointestinal health. Probiotics promote a healthy microbiome and strengthen the epithelial cells.

Traditional herbal remedies such as aloe, degly-cyrrhizinated licorice (DGL), slippery elm, or marshmallow, are known to help heal the gastrointestinal lining. Aloe vera provides mast cell stabilization and antioxidant effects. DGL, slippery elm bark and marshmallow root provide soothing relief, improve the quality of mucus, and heal the digestive tract.

When there are methyl folate issues, supplementation with methyl folate may be helpful, as well as methylcobalamin for B12. TMG can also be helpful if the individual has the BHMT genetic variant and has a difficult time converting homocysteine into methionine.

Nettle Leaf and Vitamin C may be very helpful in reducing histamine, while the combination of bromelain and quercetin may help with the associated inflammation. Diamine Oxidase enzyme supplement--For individuals with the DAG variant (or anyone with excess histamine), taking the DAO enzyme with meals and especially with foods containing histamine may be quite helpful.

Taken orally, it may help degrade histamine from food and balance histamine/DAO ratio. By lowering histamine, and consequently inflammation, the GI tract can heal, which allows for endogenous production of DAO.

To learn more about the genetic variants, please visit In coming months, there will be video lessons on each of the genetic variants, including the DAG and other variants related to histamine.

In future articles, we will explore in more detail, the FUT2 gene that impacts B12 Assimilation and the friendly bacteria, and the HLA gene that may predispose you to gluten intolerance. When these exist together, it can create serious gut issues, but with this new knowledge, you may have the tools to help even the most difficult cases.

by: Robert Miller, CTN

Symptoms of histamine intolerance

Abdominal Cramps            Anaphylaxis               Anxiety

Bronchoconstriction    Chest Pain                   Constipation

Difficulty             Dysmenorrhea/Abnormal Cycle  Fatigue

Heartburn/Acid Reflux  Hypertension                 Irritable Bowel

Inflammation           Arthritis                    Depression

Low Muscle Tone        Changes in Body Temp         Changes in Memory
                                                    and Learning

Mast Cell Secretion    Nasal                        Nausea

Rhinitis               Skin Flushing/Itching        Sleep Problems

Throat Tightening      Tissue Swelling              Urticarial
                       (especially around
                       the face)

Abdominal Cramps       Arrhythmia/Accellerated
                             Heart Rate

Bronchoconstriction    Diarrhea

Difficulty             Headache/Migraine

Heartburn/Acid Reflux  Itchy/Watery Eyes

Inflammation           Estrogen Dominance

Low Muscle Tone        Changes in Food Intake/Satiety

Mast Cell Secretion    Prurtis

Rhinitis               Sneezing

Throat Tightening      Vertigo/Dizziness
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Author:Miller, Robert
Publication:Original Internist
Article Type:Report
Date:Dec 1, 2014
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