Histamine intolerance: why a low-histamine diet is not enough and how to truly solve it?

Are you troubled by unexplained bloating, migraines, or hives that appear seemingly without a cause? A hidden culprit may be histamine intolerance (HIT) – a condition that often has roots in impaired gut health, hormones, or genetics.
In this article, we will offer you a comprehensive insight into the world of histamine – we will look beneath the surface of common recommendations, explore the functioning of key enzymes, the influence of estrogen, and offer a path to effective diagnosis and long-term improvement of the condition.

What you will learn in this article?

1. How Does Histamine Intolerance Manifest?
2. Main Symptoms of Histamine Intolerance
3. What is Histamine Actually?
4. Diagnosis of Histamine Intolerance
5. Diet in Histamine Intolerance
6. Gut Health as a Key Factor in the Development of HIT
7. Genetics and HIT
8. Hormonal Interactions: Estrogens, Progesterone, and Histamine
9. The Effect of Stress on Histamine Load
10. Treatment of Histamine Intolerance
11. Key Takeaways

How Does Histamine Intolerance Manifest?

Histamine intolerance (HIT) has in the last decade come to the forefront of interest of gastroenterologists, immunologists, and nutrition experts. Histamine intolerance is defined as an imbalance between the accumulation of histamine in the body and the body’s ability to break it down. Given that histamine receptors are found in a wide spectrum of tissues in the body – from the gastrointestinal tract through the cardiovascular system to the central nervous system, the clinical symptoms of HIT are very diverse.

Most commonly, gastrointestinal issues appear, such as bloating, abdominal pain, diarrhea, or nausea. Skin manifestations are also typical, for example redness, hives, itching, or swelling. Respiratory symptoms are also common, such as a runny nose, blocked nose, or shortness of breath, and cardiovascular manifestations including heart palpitations, a drop in blood pressure, or dizziness. In some patients, neurological difficulties may also occur, for example headaches, migraines, fatigue, or sleep disorders.

Main Symptoms of Histamine Intolerance

What is Histamine Actually?

Histamine is a biologically active substance (a biogenic amine) formed from the amino acid L-histidine, which in the body functions as a signaling molecule. In the organism, it is formed mainly in mast cells (i.e., mastocytes = a type of immune cells), cells of the intestinal mucosa (enterocytes), and also in some neurons.

The following infographic shows what histamine affects in the human body [1]:

In order for the organism to prevent the toxic effects of excessive histamine, it has two main enzymes for its breakdown.

1. DAO: The enzyme diamine oxidase (DAO) is found mainly extracellularly (outside cells) in the intestine and is important for breaking down histamine ingested from food.
DAO requires for its proper function a sufficient amount of copper (key for the activity of the DAO enzyme itself), vitamin B6 (supports enzymatic reactions and amine metabolism), and vitamin C (helps stabilize histamine and supports its breakdown).

2. The enzyme histamine-N-methyltransferase (HNMT) ensures histamine homeostasis inside cells and is found mainly in the liver and central nervous system. HNMT uses methylation for histamine deactivation (= a biochemical process necessary, for example, for regulation of gene expression, detoxification, neurotransmitter production, or cardiovascular health), where with the help of a methyl group donor SAMe (S-adenosyl-L-methionine) it converts histamine into N-methylhistamine. This means that HNMT activity is directly dependent on functional methylation, which requires a sufficient amount of certain nutrients, such as vitamins B12, B9, B6, or magnesium.

Since HNMT is the dominant enzyme in the brain, imbalance in its metabolism manifests rather in systemic and neurological symptoms, such as migraines, sleep disorders, and anxiety states.

Diagnosis of Histamine Intolerance

In practice, to confirm histamine intolerance, patients and doctors often rely on determining the activity or concentration of the DAO enzyme in the blood. However, scientific evidence suggests that this test is a useful indicator, but on its own is not sufficient for diagnosing HIT. [2]

Why is serum DAO activity not enough?

There are several reasons why diagnosis based only on blood is problematic. First of all, DAO activity in blood serum does not necessarily reflect the activity of this enzyme directly in the mucosa of the small intestine. [3] A patient may show normal systemic DAO levels, but still suffer from a local deficiency in the intestine as a result of inflammation or dysbiosis, which leads to uncontrolled passage of histamine into the bloodstream. Conversely, some asymptomatic individuals may naturally have lower DAO levels without any clinical difficulties.

Another factor is high intraindividual variability. DAO levels in the blood fluctuate in response to a number of stimuli. In premenopausal women, DAO activity is influenced by phases of the menstrual cycle – it is significantly higher in the luteal phase (the phase from ovulation to menstruation) compared to the follicular phase. [2] Measuring DAO activity at the wrong time of the cycle can thus lead to a false diagnosis.

Consumption of alcohol, use of certain medications (e.g., some antibiotics, analgesics, or non-steroidal anti-inflammatory drugs such as Ibuprofen), or even acute stress can also reduce DAO levels.

Measurement of DAO activity can therefore serve rather as a supportive marker. In the Czech Republic, values below 3 U/ml are considered risky, 3–10 U/ml borderline.

Diet in Histamine Intolerance

In the diagnosis of histamine intolerance, adjustment of diet is usually recommended primarily with the aim of reducing the total intake of histamine. This is a so-called low-histamine diet, which limits the consumption of foods rich in histamine or foods supporting its release, such as fermented products, aged cheeses, alcohol, or some types of fish. It is also recommended to monitor tolerance of individual foods, because histamine tolerance is highly individual.

In some cases, dietary supplements supporting histamine breakdown may also be part of the recommendations, for example the DAO enzyme. However, these steps usually do not address the cause of the condition.

Gut Health as a Key Factor in the Development of HIT

Current research increasingly emphasizes that histamine intolerance is very closely related to impaired gut health. [3] The intestine is not only a place of nutrient absorption but represents a complex immunological barrier, whose integrity is critical for histamine metabolism.

Damage to enterocytes and the mucosal barrier

Since DAO is produced by enterocytes (intestinal cells) located at the tips of the villi of the small intestine, any disease disrupting the intestinal mucosal barrier leads to a subsequent deficiency of this enzyme. [3] These diseases include, for example, celiac disease, ulcerative colitis, Crohn’s disease, irritable bowel syndrome (IBS), SIBO (small intestinal bacterial overgrowth), but also food allergies or intolerances.

The phenomenon of SIBO (small intestinal bacterial overgrowth)

SIBO represents one of the most significant contributors to the development of HIT. In a healthy intestine, most bacteria are located in the large intestine, while the small intestine is relatively sparsely populated. In SIBO, bacteria overgrow in the small intestine, which can have negative consequences for histamine metabolism. Bacterial metabolites and inflammatory mediators produced in SIBO can damage enterocytes and thus reduce DAO secretion. Overgrown bacteria in the small intestine also disrupt the mucosal barrier and cause the release of tight junctions between cells of the intestinal wall (so-called “leaky gut”), which leads to the passage of histamine into systemic circulation.

Gut dysbiosis

A study from 2022 published in the journal Nutrients shows that patients with histamine intolerance exhibit altered composition of the gut microbiome (dysbiosis), characterized by increased representation of histamine-producing bacteria (e.g., Staphylococcus, Proteus, Clostridium perfringens) and reduced occurrence of bacteria associated with gut health, such as Faecalibacterium prausnitzii or representatives of the Prevotellaceae family. [4]

Genetics and HIT

Genetics may also play a role in the development of HIT. In some individuals, genetic polymorphisms occur that affect the activity of the diamine oxidase (DAO) enzyme. These genetic deviations may lead to a reduced ability to break down histamine, which increases its level in the body.

Hormonal Interactions: Estrogens, Progesterone, and Histamine

According to available studies, histamine intolerance occurs more often in women than in men. Some sources state that women make up as much as around 70–80% of patients with HIT. This difference is influenced by the close connection between sex hormones and histamine metabolism. [5]

How does estrogen increase histamine?

1. Activation of mast cells: Estrogens activate mast cells (mastocytes), which leads to the release of histamine and other inflammatory mediators.

2. Reduction of DAO activity: Estrogens also reduce the activity of the DAO enzyme in tissues

3. Increase in expression of the enzyme histidine decarboxylase – an enzyme that converts histidine into histamine, which ultimately leads to higher histamine production.

Histamine as a stimulator of estrogen production

At the same time, histamine itself supports the ovaries in producing more estrogen. A vicious cycle then occurs, where more estrogen releases more histamine, which subsequently stimulates further estrogen production. This mechanism is responsible for the worsening of HIT symptoms during ovulation and in the premenstrual phase, when estrogen levels peak.

Progesterone as a stabilizer

Progesterone, on the other hand, suppresses histamine release and increases DAO activity. A relative deficiency of progesterone (e.g., in perimenopause or during anovulatory cycles) thus contributes to increased histamine levels in the body and worsening of histamine intolerance symptoms.

The Effect of Stress on Histamine Load

Chronic stress is considered a significant factor influencing histamine release and its metabolism in the body. The stress response is associated with activation of the immune system and increased reactivity of mast cells, which are the main source of histamine. Stress can contribute to dysregulation of mastocytes and thus to increased release of histamine and worsening of histamine intolerance symptoms [6].

At the same time, stress is associated with disruption of the intestinal barrier and gut homeostasis, which can further worsen histamine metabolism and support its systemic accumulation. [7] Moreover, stress directly affects the gut microbiome, which may support the development of SIBO and disruption of DAO production in enterocytes. Stress can thus trigger reactions even to foods that patients with HIT otherwise tolerate.

Treatment of Histamine Intolerance

Histamine intolerance is not an isolated diagnosis, but rather an indicator of disturbed physiological balance. Its increase in the modern population is probably related to a combination of a disrupted gut microbiome (due to industrially processed diet and overuse of antibiotics), chronic stress, and environmental burden.

Successful treatment of HIT therefore requires a multifactorial approach that goes beyond simple dietary adjustment within a low-histamine diet. With the correct approach, HIT is a reversible condition in a large proportion of patients. The key to successful therapy is:

1. Identification of the primary cause: Is DAO deficiency genetic, or caused by gut damage (SIBO, celiac disease, IBD)?

2. Treatment of the intestinal mucosa: Regeneration and restoration of the intestinal mucosa is essential for restoring DAO production.

3. Optimization of cofactors: The efficiency of DAO and HNMT enzymes is directly dependent on sufficient supply of micronutrients, such as copper, vitamin B6, vitamin C, and also nutrients necessary for proper methylation.

4. Targeted microbiome support: In HIT, the selection of probiotics is crucial. Many commercial probiotics contain strains that may worsen the condition by producing histamine (e.g., L. casei, L. reuteri, L. bulgaricus). [8] Ideal are strains that degrade histamine or stimulate natural DAO secretion. These strains include, for example, Lactobacillus rhamnosus GG, Bifidobacterium infantis and B. longum, or Lactiplantibacillus plantarum LP115. [9]

5. Holistic approach: Monitoring interactions with medications and the hormonal cycle in women may also help.

Key Takeaways?

Sources:

[1] Smolinska S, Winiarska E, Globinska A, Jutel M. Histamine: A Mediator of Intestinal Disorders-A Review. Metabolites. 2022 Sep 23;12(10):895. doi: 10.3390/metabo12100895. PMID: 36295796; PMCID: PMC9610630.https://pmc.ncbi.nlm.nih.gov/articles/PMC9610630/

[2] Jackson K, Busse W, Gálvez-Martín P, Terradillos A, Martínez-Puig D. Evidence for Dietary Management of Histamine Intolerance. Int J Mol Sci. 2025 Sep 20;26(18):9198. doi: 10.3390/ijms26189198. PMID: 41009760; PMCID: PMC12470264. https://pmc.ncbi.nlm.nih.gov/articles/PMC12470264/

[3] Schnedl WJ, Enko D. Histamine Intolerance Originates in the Gut. Nutrients. 2021 Apr 12;13(4):1262. doi: 10.3390/nu13041262. PMID: 33921522; PMCID: PMC8069563. https://pmc.ncbi.nlm.nih.gov/articles/PMC8069563/

[4] Sánchez-Pérez S, Comas-Basté O, Duelo A, Veciana-Nogués MT, Berlanga M, Latorre-Moratalla ML, Vidal-Carou MC. Intestinal Dysbiosis in Patients with Histamine Intolerance. Nutrients. 2022; 14(9):1774. https://doi.org/10.3390/nu14091774

[5] https://www.larabriden.com/high-histamine-can-make-for-a-tougher-perimenopause/

[6] Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr. 2007 May;85(5):1185-96. doi: 10.1093/ajcn/85.5.1185. PMID: 17490952.

[7] Comas-Basté O, Sánchez-Pérez S, Veciana-Nogués MT, Latorre-Moratalla M, Vidal-Carou MDC. Histamine Intolerance: The Current State of the Art. Biomolecules. 2020 Aug 14;10(8):1181. doi: 10.3390/biom10081181. PMID: 32824107; PMCID: PMC7463562. https://pmc.ncbi.nlm.nih.gov/articles/PMC7463562/

[8] Wadu Mesthri Deepika Priyadarshani, Sudip K Rakshit, Screening selected strains of probiotic lactic acid bacteria for their ability to produce biogenic amines (histamine and tyramine), International Journal of Food Science and Technology, Volume 46, Issue 10, October 2011, Pages 2062–2069, https://doi.org/10.1111/j.1365-2621.2011.02717

[9] Cavaliere G, Costanzi E, Cenci-Goga B, Misuraca M, Traina G. Potential Role of Probiotic Strain Lactiplantibacillus plantarum in Control of Histamine Metabolism. Biology (Basel). 2025 Jun 19;14(6):734. doi: 10.3390/biology14060734. PMID: 40563983; PMCID: PMC12189723. https://pmc.ncbi.nlm.nih.gov/articles/PMC12189723/