Genetic DAO Deficiency

 

One of the primary mechanisms contributing to HIT is a genetic reduction in DAO enzyme activity, the key enzyme responsible for the degradation of extracellular histamine, particularly in the intestinal mucosa [2][3].

 

DAO, encoded by the AOC1 gene on chromosomes and several single nucleotide polymorphisms (SNPs) have been identified that reduce DAO activity or stability. Individuals with these polymorphisms may have lower baseline DAO levels, rendering them more susceptible to symptoms after consuming histamine-rich foods. Studies show that up to 79% of patients with HIT carry one or more of these genetic variants [4].  

 

Dysbiosis

 

The intestinal microbiota plays a crucial role in histamine metabolism. Certain bacteria produce histamine as part of their metabolism [8]. Dysbiosis, which is a state of microbial imbalance in the gut, can shift the microbial population toward histamine-producing strains, thereby increasing luminal histamine levels and aggravating symptoms [8]. 

 

Additionally, dysbiosis is often linked with impaired gut barrier function, leading to leaky gut syndrome, further compounding histamine absorption [3][8].

 

Gastrointestinal Damage

 

DAO is produced by the epithelial cells of the small intestine, and its expression is highly dependent on the integrity of the mucosal barrier. Thus, gastrointestinal diseases that cause inflammation or mucosal erosion can significantly reduce DAO production [2][8]. 

 

Conditions such as inflammatory bowel disease (IBD), irritable bowel syndrome (IBS), celiac disease, and non-celiac gluten sensitivity (NCGS) are all associated with reduced DAO activity [3][8]. Furthermore, bowel surgeries, chronic infections and dysbiosis can further diminish enzyme expression, leading to increased histamine absorption from the gut and exacerbation of symptoms [3][5].

 

Medication-Induced DAO Inhibition

 

Numerous medications reduce DAO activity either by competing with histamine for enzymatic breakdown or by altering the gut epithelium, making patients more vulnerable to histamine overload [2][3][4][8][11]. Common DAO diminishing drugs include:

 

• Antibiotics: clavulanic acid, cefuroxime

• NSAIDs: aspirin, diclofenac, ibuprofen

• Antidepressants: amitriptyline

• Antihypertensives: verapamil,  inhibits DAO by ~60–80% [11]

• Muscle relaxants: thiopental, pancuronium

• Antacids: Metoclopramide, Cimetidine, inhibits DAO by ~70% [11]

• Autoimmune Management: Chloroquine, inhibits DAO by ~80% [11]

 

HNMT Dysfunction

 

Although DAO plays the dominant role in degrading dietary histamine, the HNMT enzyme is also crucial for histamine inactivation, particularly intracellularly in the liver, kidneys, lungs, and CNS [2]. 

Genetic variations (SNPs) in the HNMT gene have been linked with Impaired HNMT activity, and when combined with low DAO levels, can dramatically elevate total histamine burden in the body [2].

 

Excessive Histamine Intake and Biogenic Amines

 

Dietary histamine itself is a key contributing factor. Fermented, aged, and poorly stored foods often contain high levels of histamine and other biogenic amines such as putrescine, tyramine, and cadaverine, which not only burden the detoxification pathways but also compete with histamine for DAO [2][8]. 

 

Even in individuals with normal DAO levels, frequent intake of these foods can lead to a histamine build-up, especially when combined with other cofactors like alcohol or stress [2][5][8].

 

Nutrient Deficiencies

 

DAO is a copper dependent enzyme that also requires vitamin B6 and vitamin C for optimal activity. Deficiencies in these nutrients impair histamine degradation [5][6]. 

 

Vitamin C serves a dual function by acting as an antioxidant and by directly reducing circulating histamine levels, while vitamin B6 supports the production of DAO as well as neurotransmitters affected in HIT [6]. Nutrient depletion may also result from poor diet, chronic inflammation, alcohol consumption, or malabsorption syndromes [6].

 

High Estrogen / Estrogenism 

 

Estrogen has been shown to increase histamine levels by downregulating DAO expression. As a result, women, especially those of reproductive age, report cyclic exacerbations of HIT symptoms, including menstrual migraines, flushing, and fatigue, particularly in the follicular phase of their menstrual cycle, approximately 10 days after beginning the menstrual bleed [4][5]. 

 

Conditions such as endometriosis and PCOS, which are characterized by estrogen dominance, may further aggravate histamine-related complaints [5].

 

Alcohol Consumption

 

Alcohol is a well-established histamine liberator and DAO inhibitor. Red wine and beer contain substantial amounts of histamine and sulfites, both of which can trigger or exacerbate HIT symptoms. Alcohol also damages the gut lining, further reducing DAO production and promoting histamine absorption [3][5].