Histamine: Bridging Food and Atopic Dermatitis

Ayaad Bharti¹ and Sanket K. Mishra²

1. Department of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
2. Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA

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PUBLISHED: 30 NOVEMBER 2024

CITATION: BHARTI, Arya; MISHRA, Santosh K.. Histamine: Bridging Food and Atopic Dermatitis. Medical Research Archives, [S.l.], v. 12, n. 11, dec. 2024. Available at: <https://esmed.org/MRA/mra/article/view/6144>

COPYRIGHT: © 2025 European Society of Medicine. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

DOI: https://doi.org/10.18103/mra.v12i11.6144

ISSN 2375-1924

Abstract

Atopic dermatitis (AD) is an inflammatory skin condition, often characterized by intense itching, rashes in humans and animals, and disruption of skin barriers. The prevalence depends on the patient’s age, ethnic background, and geographical origin. In recent years, the average number of cases in industrialized countries has more than doubled, with the disease impacting around 25% of children and 2% of adults worldwide. People with AD have a higher risk of developing other conditions such as arthritis, asthma, depression, anxiety, allergic rhinitis, and sleep problems that negatively impact the patient’s quality of life. Recent data suggest that increased histamine levels are involved in the pathogenesis of AD. However, a review from Bath-Hextall et al. suggested no correlation between histamine levels and the severity of AD. In this article, we focus on the relationship between histamine, food, and AD in humans and animals.

Keywords

Atopic dermatitis, histamine, food, skin barrier, allergies

Introduction

Atopic dermatitis (AD) is an inflammatory skin condition (often named eczema) that causes itchy rashes in humans and animals.¹ The prevalence of disease depends on the patient’s age, ethnic background, and geographical origin.² In recent years, the average number of cases in industrialized countries has more than doubled, with the disease impacting around 25% of children and 2% of adults worldwide.¹ People with AD have a higher risk of developing other conditions such as arthritis, asthma, depression, anxiety, allergic rhinitis, and sleep problems that negatively impact the patient’s quality of life.³ Recent data suggest that neural recruitment is involved early in activating allergic stimulation of AD and helps maintain the inflammatory cascade.⁴ The exact cause/mechanism of AD is not well understood but several comorbidities, including food allergy, asthma, allergic rhinitis, and mental health disorders can impact AD.

The first part of this review will focus on the relationship between AD and histamine, types of food with histamine, and enzymes responsible for regulation of histamine that might be involved in initiation and aggravation of AD and associated itch. Itch is a major symptom associated with AD and the cellular release of histamine and its role in itch is well-established. Therefore, the second part of the review will focus on itch and its mechanisms as well as discussing the role of histamine receptors that have been linked to AD.

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Relationship among histamine or histidine rich food and atopic dermatitis

Foods can significantly trigger AD and food allergies, which have been linked to the disease.⁵ Although food allergies and allergens are not necessarily the direct cause of atopic dermatitis, they can be indirectly involved in the aggravation of the disease. One study in humans shows that ingesting moderate or high amounts of histamine-hydrochloride may aggravate eczema in a subgroup of patients with AD.⁶⁻⁸ Common allergens in AD are mostly high protein foods, cow’s milk, eggs, and fermented foods.⁵⁻⁷⁹ Most of these foods contain the chemical compound histamine that is involved in the aggravation of AD. However, a review from Bath-Hextall et al. suggested no benefit of egg and milk free diet in unselected participants with atopic eczema.¹⁰ The authors also remain open that this may be due to small population size and maybe these individuals are not allergic to these substances in the first place.

Along with an increase of histamine level in plasma, an increase in the level of skin histamine has been reported among patients of acute AD.¹¹ Histamine is a biogenic amine, formed by the action of the enzyme histidine decarboxylase on proteinogenic amino acids, L-histidine. Histamine plays a crucial role in many physiological and pathophysiological processes. Histamine regulates gastric acid secretion in the stomach, acts as a neurotransmitter, and mediates anaphylaxis in allergic conditions.¹² In mammals, histamine is known to be present in all tissues, primarily the skin connective tissue, lung, and most of the gastrointestinal tract.¹³ It is involved in functional execution through primarily four types of histamine receptors that have been identified and characterized; they are H1, H2, H3, and H4 receptors.¹⁴ Excess histamine release in the body either through cellular release or via histamine-rich food¹⁵ can lead to the flare-up of atopic dermatitis.¹⁶¹⁸

Although the link between AD and diet has been unclear for a long time, some connections between AD and food have been proposed based on diet elimination/supplementation that helps to reduce or improve AD conditions in a subgroup of patients.¹⁹ Several reports suggest that histamine and its four receptors are linked to atopic dermatitis and itch.²⁰ Blood plasma histamine levels are higher in AD patients,²¹ and enhanced release has been observed in the skin of AD individuals.²² Their study and others suggest a possible association between high histamine diet and AD.²³²⁴

In an elimination approach, a recent study aimed to investigate the relationship between histamine and atopic dermatitis.²⁵ The study included atopic dermatitis and healthy individuals and was conducted in a hospital setting.

Researchers collected skin biopsies from all participants and analyzed the samples for histamine levels. They used immunohistochemistry methods to determine the amount of histamine in the skin samples. They also recorded the severity of eczema symptoms in each participant, as well as other clinical information such as age, sex, and history of allergies. In addition, in the group of the atopic dermatitis patients, researchers also treated them with an antihistamine (cetirizine) for a period of four weeks, and then re-assessed the histamine levels in the skin and the symptoms of eczema. Participants were given the antihistamine in oral form and at a daily dose of 10 mg.

The results showed that histamine levels were significantly higher in the skin of participants with atopic dermatitis compared to those without the condition. This confirms previous findings that histamine plays a key role in eczema symptoms. Furthermore, the eczema symptoms improved significantly in patients treated with antihistamine. The itching, redness, and inflammation of the skin were all reduced in the group of patients treated with antihistamines.

The study concludes that histamine is involved in the development of the eczema symptoms and that antihistamines may be an effective treatment for atopic dermatitis. The study also highlights the importance of understanding the underlying mechanisms of eczema in order to develop new and more effective treatments. The study is important because it provides more evidence that histamine is involved in the pathology of eczema, and that antihistamines may be effective in reducing symptoms of eczema. The study also provides a rationale for further research in the field, including the development of more specific and targeted antihistamine treatments for eczema.

In another study, a six-year-old boy was admitted to the hospital with severe AD for the evaluation of food as a triggering factor for his skin disease. In a food challenge test, he showed a positive result of exacerbated eczema score for both eczema area and severity index (EASI) score and the visual analog scale (VAS) when he was on 200 g of pork diet compared to eating 60 g of pork. Interestingly, keeping him on a balanced and low-histamine dietary regimen showed improvement in AD symptoms and that lasted for more than seven months. This suggests a low-histamine, balanced diet could be helpful for AD patients, and histamine-rich diet aggravates AD without having any issues of food allergy.

Almost one percent of the human population worldwide is affected by histamine intolerance.²⁷⁻²⁸ Certain lactic acid bacteria with the hdcA (Histidine decarboxylase) gene can convert the amino acid histidine into histamine.²⁹ The main histamine-producing bacterial strains in wine transformation belong to the genera Oenococcus, Lactobacillus, and Pediococcus.²⁹ Analysis of several sample collections from different wineries shows that these bacteria are present in almost all wines at an exceedingly high level. Also, hdcA was detected in most of the unstable plasmids in strains of Oenococcus.³⁰ Therefore, histamine is produced in the body in large amounts due to the food and drinks containing these bacteria that transform histidine into histamine using the enzyme decarboxylase.

Histamine is found in large amounts in many commercial soybean products like tofu, tempeh, tamari, and sufu (fermented soybean), etc. In the case of sufu samples, very high histamine levels (700 mg/kg) were found, which is very unhealthy for a patient. Biogenic amines present in soybean products are not a risk for healthy consumers, but patients who take drugs with monoamine and diamine oxidase inhibitors can suffer adverse health effects by eating such high-histamine foods.³⁰

Several cases of scombroid fish (tuna, mackerel, swordfish, kingfish, etc.) poisoning occur after consuming these fish which are rich in the amino acid histidine.³¹⁻³² Urinary excretion analysis of patients sick with scombroid fish poisoning shows high-level histamine and its metabolite.³²

The primary dietary sources high in histamine are fermented foods, beverages like kefirs, kombucha, yogurt, frozen and smoked fish, and fruits such as strawberries and cherries. Vegetables that are high in histamine are spinach, eggplant, and potato. Chili powder, cinnamon, and cloves are found to be very rich in histamine as well.

Certain foods are not necessarily high in histamine but act as histamine-trigger foods, such as citrus fruits, alcohol, and nuts.²⁷³⁶³⁷ Other common foods such as cheese, blue cheese, and parmesan cheese also have very high histamine. This may not be an issue in healthy individuals with normal histamine-degrading enzyme levels. However, these foods with high histamine can further aggravate symptoms of atopic dermatitis in patients with histamine intolerance (HIT).³⁵³⁸ They are unable to degrade even normal levels of histamine from food, let alone food with higher histamine. This is due to their deficiency in enzymes that help destroy ingested histamine.³⁵

A recent report demonstrated a link between a histamine diet and AD. In this report, 36 patients were placed on a low-histamine diet for one week. Twelve of the 36 patients showed significant improvement in atopic dermatitis after one week of the low-histamine diet intake, which suggests only a small subset of AD patients show a correlation of low-histamine diet and improvement of symptoms in AD patients.³⁹ Briefly, the role of histamine in the maintenance of AD is linked to our daily intake of food, and this might occur in most AD individuals, but the role of types of food described above in the causation of itch is still largely unknown.

In addition to diet, histamine plasma levels did not decrease in AD individuals, suggesting that these large groups react differently and the release of histamine in this group is either due to decreased histamine metabolism or due to continuous release of histamine through IgE-mediated reaction — this is not yet clear.⁴

In mammalian skin, L-histidine is incorporated into filaggrin, which is a skin barrier protein and is linked to AD etiology. To evaluate the therapeutic role of L-histidine in AD patients, the authors conducted a randomized, double-blind, placebo-controlled, crossover, nutritional supplementation pilot study.³⁹ Daily single oral L-histidine administration for 4 weeks significantly reduced AD symptoms by both physician assessment using the SCORing AD tool and patient self-assessment using the Patient Oriented Eczema Measure tool compared to the placebo.

The authors further demonstrated the L-histidine effects on pro-filaggrin processing and skin barrier functions on HaCaT keratinocyte cultures and in organotypic skin-equivalent cultures. On keratinocyte cells, they showed that L-histidine increases filaggrin protein formation, and in the organotypic skin model, they illustrated that L-histidine enhances the barrier function. Both these in vitro observations correlate with evidence from the clinical nutritional pilot study that oral L-histidine may have therapeutic benefits in AD.

In another clinical pilot study by a completely independent group on two different age groups (Adults and Young Children) with AD, the authors showed oral L-histidine is effective for AD management.⁴⁰ A single dose of L-histidine was given to adults (4 g daily) and to young children (0.8 g) supplementation over periods of 4 weeks (adults) or 12 weeks (young children). Compared to the placebo, L-histidine reduced AD in both adult and young children using the SCORing AD tool. The supplementation is well-tolerated and has potential as a safe intervention for long-term use in the management of AD, but some adverse events have been reported, suggesting continuous safety evaluation for long-term usage.

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Involvement of histamine regulating enzymes in atopic dermatitis

Histamine intolerance is a condition that can be further aggravated in HIT patients by histamine-rich foods, which either cause histamine release or block the enzyme diamine oxidase.³⁶⁴¹ It can further lead to many disorders of the gastrointestinal system, skin, lungs, cardiovascular system, and brain. Dermatological problems that can arise include rashes, itch, urticaria, dermatitis, psoriasis, and rosacea.³⁶³⁵⁴²

Diamine oxidase is the main enzyme for the metabolism of dietary histamine and is responsible for the catabolism of extracellular histamine, whereas histamine N-methyltransferase (HNMT) is responsible for catabolizing histamine in intracellular spaces of cells.³⁶ Various single-nucleotide polymorphisms (SNPs) show correlations between inflammatory and neoplastic gastrointestinal diseases like food allergy, Crohn’s, and colitis. However, no significant association is seen by investigating HNMT alleles and patients.

with inflammatory and gastrointestinal diseases.³⁶⁴³⁴⁵ On the contrary, some studies show an association between HNMT polymorphisms and AD in children. A study to evaluate the association between HNMT polymorphisms and AD in children concluded that polymorphisms in HNMT appear to confer susceptibility to AD in Korean children.⁴⁶ A study has shown that Thr105Ile, a functional polymorphism of HNMT, is linked with alcoholism in two ethnically distinct populations.⁴⁷ In another study, association of food additives and HNMT T939C and HNMT Thr105Ile gene polymorphisms was established.⁴⁸

In the CNS, histamine acts as a neurotransmitter and has been shown to be involved in reward function and in the etiology of addiction and stress. In the periphery, it is considered as a mediator, but it will be interesting to explore the role of histamine in the CNS in chronic AD conditions.

Structurally, the diamine oxidase (DAO) enzyme with 700 amino acids is proposed to be a dimer of 92 kDa encoded by the AOCT gene.⁴⁹⁵¹ The association of low DAO and increased plasma histamine was shown in atopic eczema.⁵² In a separate study, high histamine amounts in plasma combined with reduced histamine degradation influenced the clinical score in AD.⁵³ Recently, an experiment with 14 patients with allergic conditions like food hypersensitivity, coeliac disease, etc., was investigated for serum DAO level and clinical response to DAO supplementation.

These patients were placed on histamine-rich food. Their results indicate that 10 out of 14 patients had reduced serum DAO activity (<10 U/ml), which suggests probable histamine intolerance. Moreover, 13 out of 14 patients showed significant relief in disturbances related to food intolerances with the intake of DAO supplementation.⁴¹ Measuring DAO activity in serum is useful in determining histamine intolerance.⁴¹

Furthermore, histamine plays a major part in food and wine intolerance, and lack of DAO in AD patients with intolerance to food or wine causes worsening symptoms in atopy.¹⁵

Based on the influence of active ingredients of certain drugs on the activity of human diamine oxidase, many substances can be designated as DAO inhibitors.⁵⁴ Chloroquine and clavulanic acid are such drugs that showed the greatest inhibition potential of up to 90 percent. Other medications like Verapamil have an inhibition rate of almost 50 percent. Drugs like Diclofenac, metoclopramide, suxamethonium, and thiamine have a very low inhibition rate.⁵⁴

A correlation between atopic eczema and decreased DAO activity was observed in patients with high blood serum histamine levels. Their blood DAO activity and histamine concentration were evaluated with a radio extraction radioimmunoassay. Their results showed the presence of wheals, which were 35 percent larger in diameter in almost 47% of patients. These patients had significantly low DAO activity and high histamine levels compared to the experiment’s healthy people. The authors have cautiously indicated a possible correlation between decreased DAO activity in allergic patients.⁵⁵

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Histamine receptors involved in atopic dermatitis

Histamine receptors belong to the family of GPCRs with seven transmembrane domains and an intracellular second messenger system to transduce extracellular signals through the TRPV1 channel.¹⁶⁵⁶ Since the beginning of the twentieth century, the synthesis of various histamine receptor antagonists has played a therapeutic role in treating a wide variety of diseases like AD, asthma, pruritus, allergic rhinitis, and inflammation.⁵⁷⁶⁰

However, antihistamine drugs’ failure to block histamine’s complete action initiated a research program that started at the laboratory of SmithKline and French in Welwyn Garden City, U.K. (1960), under the direction of James Black. He intended to confirm heterogeneity in histamine receptors (HRs) and discover an antagonist of the histamine receptor. HRs stay in equilibrium in relation to their active and inactive states.⁶¹

Various techniques, including immunohistochemistry, flow cytometry, and western blots, are generally used to analyze HRs.⁶² H1, H2, and H4 receptors are involved in chronic allergic contact dermatitis (CACD) and related inflammatory processes.

atopic dermatitis.⁶³ The study shows that in ovalbumin-induced AD skin lesions, analyzed in H4R knockout mice, the results showed a significant reduction in the severity of skin lesions, reduced inflammatory cells, and lessened hyper-proliferation at the skin lesion site.²⁰ Previously, it was considered that either H1R or H4R is involved in skin inflammation. However, the use of H1R antagonists only shows limited improvement in skin inflammation.

It is now confirmed that co-administration of H1R and H4R antagonists ameliorated chronic allergic inflammation in ovalbumin-induced AD-like skin lesions in a mouse treated with H1R inverse agonist mepyramine or with H4R antagonist JNJ-39758979⁶⁴ and also the itch associated with AD. Conventional treatment with glucocorticoids leads to skin atrophy and has side effects. However, co-administration of H1R and H4R antagonists has an inhibitory effect equal to those of steroids in a chronic allergic dermatitis mouse model.

In summary, HRs play an essential role in alleviating AD but are often inefficient in treating itch associated with AD because of the involvement of histamine-independent pathways. With this finding, next-generation antihistaminic agents using H1R and H4R antagonistic actions can be useful in developing treatments for AD patients.⁶⁵

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Neural Pathways for Itch

One of the common symptoms in AD is itch, and various endogenous mediators have been identified as primary triggers that can cause itch.⁶⁶ Itch has been classified into four main clinical categories based on pathophysiological, anatomical, and psychological components and is further named neurogenic, pruritogenic, neuropathic, and psychogenic.⁶⁷

This section will discuss relevant literature that has been proposed to identify neural mechanisms of itch associated with AD. A labeled-line theory suggests that the itch-specific neuronal fibers are in the continuum from the skin to the dorsal root ganglia (DRG).⁷ Itch is classified into two major subtypes based on histaminergic and non-histaminergic pathways.

The histaminergic pathway is dependent upon the TRPV1-positive (via histamine or endothelin-1) and TRPV1-negative (via histamine) nerve fibers.¹⁶¹⁷⁶⁸⁶⁹

The non-histaminergic pathway usually involves pruritogens other than histamine (protease-activated receptor agonists, cysteine protease, and serotonin), and their effects are mediated through TRPA1 channels.⁷⁰⁷³ Once the sensory neurons are activated or depolarized, they release neurotransmitters/neuropeptides through the central afferents of the DRG into the spinal cord. The message is further propagated through interneurons that express natriuretic polypeptide receptor A (NPRA) in the spinal cord through projection neurons that express gastrin-releasing peptide receptor (GRPR) for the chemical-induced itch to the brain.⁷⁴ The brain finally decodes these messages in the somatosensory cortex.⁷⁵

A pruritogen is a mediator that provokes the sensation of itch in the skin, followed by interaction with molecular detectors. The majority of these molecular detectors are either pruritic receptors (generally G-protein coupled receptors—GPCR) or ion channel receptors (TRPV1, TRPV3, and TRPA1) that act downstream of GPCR to activate sensory neurons involved in the propagation of itch.²⁰⁷⁶⁸⁰

Histamine-mediated itch happens through HR. The four histamine GPCRs include H1, H2, H3, and H4 receptors. The H1 and H4 receptors convey itch neurotransmission directly through DRG sensory neurons via the TRPV1 channel.¹⁶¹⁷

In conclusion, we propose an increase in plasma histamine levels due to a histamine-enriched diet is linked with AD, but antihistamines remain ineffective in alleviating itch in AD individuals, except for a few.⁷⁵ The ineffectiveness of antihistamines is possibly explained by the involvement of other non-histaminergic itch pathways at the periphery or possibly through central mechanisms.

Some of the practical clinical, diagnostic, and therapeutic considerations suggested for individuals with atopic dermatitis include dietary recommendations with low histamine and identifying and avoiding trigger foods high in histamine, including fermented products, citrus fruits, alcohol, nuts, and certain types of fish. Diagnostic recommendations include measuring DAO activity in serum to diagnose histamine intolerance and manage AD symptoms effectively.

Lastly, for therapeutic options, considering L-histidine supplementation for atopic dermatitis management and including DAO supplements may alleviate symptoms in histamine-intolerant individuals.

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Conclusion

Several reports suggest a link between food and atopic dermatitis, but the mechanistic insight into these relationships is still unclear. The role of dietary influence on the accumulation of high histamine in the body has been established and observed by showing that lowering histamine in the diet provides relief to a subgroup of AD patients.

Atopic dermatitis drastically affects a patient’s quality of life and can lead to several other diseases; therefore, it is imperative to understand the complex biological mechanisms in AD. Mechanisms of action behind food and their metabolites involved in AD pathogenesis and associated itch need to be identified, which might help develop better treatment methods.

More research needs to be done to establish a direct role of food in the pathogenesis of AD and itch.

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Table 1. Gene polymorphisms that are linked to food allergy and AD

Gene	SNP	Relationship	References
DAO	C2970G	Food allergy	⁴⁵
HNMT	314C>T, 939A>G	AD, Food additive, alcohol	⁴⁶, ⁸¹, ⁴⁸