Histamine, Mast Cells, and the Immune System: How They Affect Your Health, Hormones, and Healing
Histamine is often only known as the chemical behind allergies — that itchy, sneezy feeling that sends you reaching for an antihistamine. But histamine is far more complex. It’s a powerful immune messenger, a neurotransmitter, and a key regulator of gut, hormonal, and even cardiovascular function.
When histamine signaling becomes dysregulated — as in mast cell activation syndrome (MCAS) or histamine intolerance — symptoms can appear across many systems: flushing, hives, bloating, headaches, rapid heart rate, fatigue, and even anxiety.
In this article, we’ll explore what science tells us about histamine, mast cells, hormones, COVID-19, and the gut, and how they interconnect in ways that are increasingly relevant for modern chronic health issues.
What Is Histamine?
Histamine is a biogenic amine, a small signaling molecule stored primarily in mast cells and basophils, two immune cells that line the skin, gut, airways, and blood vessels. When these cells detect stressors — from allergens and infections to physical or chemical triggers — they release histamine along with other mediators such as tryptase, prostaglandins, and cytokines.
Histamine acts through four main receptors (H1–H4) found on nearly every tissue in the body:
H1 receptors drive allergy-type symptoms (itching, hives, swelling).
H2 receptors regulate stomach acid and vascular tone.
H3 receptors influence neurotransmission in the brain.
H4 receptors guide immune cell movement and inflammation.
Through these pathways, histamine shapes not only allergic responses but also immune tolerance, gut motility, vascular health, and even mood and sleep.
📘 Reference: Branco et al., Front Immunol. 2018; Thangam et al., Front Immunol. 2018.
Mast Cells and MCAS: When the Alarm System Won’t Turn Off
Mast cells are our body’s “first responders.” They sit at interfaces between the external world and our internal systems — in the skin, lungs, and intestinal lining — ready to react.
In mast cell activation syndrome (MCAS), mast cells become overly reactive, releasing mediators too easily or too often. This can lead to chronic, multisystem symptoms that flare unpredictably and mimic allergies, autoimmune disease, or chronic fatigue.
Researchers now recognize MCAS as a heterogeneous spectrum — not one disease, but a cluster of immune dysregulation patterns. Diagnosis requires careful exclusion of other causes, documentation of elevated mediators (like serum tryptase or urinary histamine metabolites), and often clinical improvement with antihistamine or mast-cell–targeted therapies.
📘 Reference: Castells et al., Clin Rev Allergy Immunol. 2024; Valent et al., Allergy. 2022.
Histamine and Hormones: A Two-Way Relationship
If your symptoms seem worse around ovulation or before your period, hormones could be part of the story.
Estrogen amplifies mast cell activity and histamine release, while progesterone and androgens are generally calming to the immune system. Estrogen also downregulates enzymes that break down histamine, such as diamine oxidase (DAO) — meaning higher estrogen can lead to higher histamine levels.
Conversely, histamine can influence hormone production at the hypothalamic and pituitary levels, affecting cycles, PMS, and perimenopausal symptoms. This two-way feedback helps explain why histamine-related issues often fluctuate with hormonal changes or hormone therapy.
📘 Reference: Muñoz-Cruz et al., J Immunol Res. 2015; Wöhrl et al., Front Immunol. 2021.
COVID-19 and Mast Cells: What We’ve Learned
Emerging research suggests SARS-CoV-2, the virus responsible for COVID-19, can directly activate mast cells, releasing histamine and inflammatory cytokines such as IL-1 and IL-6. This may contribute to vascular leak, “cytokine storms,” and persistent inflammation seen in both acute and long-COVID cases.
Interestingly, some small clinical studies have found that antihistamines (H1 and H2 blockers) improve fatigue, palpitations, and brain fog in certain long-COVID patients — hinting that mast cell overactivation could be a piece of the post-viral puzzle.
📘 Reference: Conti et al., J Biol Regul Homeost Agents. 2020; Salvucci et al., J Clin Med. 2023.
The Gut Connection: Histamine, Microbes, and DAO
About 70% of mast cells live in the gut, where they regulate intestinal barrier function and communicate with the nervous system.
When histamine builds up in the digestive tract, people may experience bloating, abdominal pain, diarrhea, or nausea — symptoms often misattributed to irritable bowel syndrome (IBS).
Two major contributors are:
Low DAO enzyme activity, reducing the breakdown of dietary histamine.
Histamine-producing gut bacteria, which can increase the body’s histamine load.
Dietary modification (low-histamine diet), DAO supplementation, and microbiome support can be helpful for some, though testing and interventions should be individualized.
📘 Reference: Comas-Basté et al., Nutrients. 2020; Schnedl et al., Nutrients. 2021.
Supporting Histamine Balance
There’s no one-size-fits-all approach — but several evidence-informed strategies can support histamine regulation:
Reduce triggers: Identify and minimize high-histamine foods, alcohol, and stressors.
Support clearance: Ensure adequate nutrients for DAO activity (vitamin B6, copper, vitamin C).
Modulate immune reactivity: Antihistamines (H1 + H2), quercetin, luteolin, or cromolyn under professional guidance.
Balance hormones: Track symptom patterns and discuss hormone therapy options carefully.
Investigate root causes: Gut infections, dysbiosis, chronic stress, or viral sequelae may all contribute.
The Takeaway
Histamine is far more than an allergy molecule. It’s a key immune regulator, intricately tied to hormones, the gut, and chronic inflammation.
Understanding histamine’s role offers new pathways to address complex conditions — from unexplained digestive distress and cyclical headaches to post-COVID fatigue and brain fog.
If you suspect histamine overload or MCAS, work with a knowledgeable clinician to explore testing and stepwise interventions that are grounded in science and tailored to your unique physiology.
Nutrition for Histamine Balance and Recovery
When it comes to histamine overload or histamine intolerance, nutrition is one of the most direct and effective ways to lower total histamine burden and support the body’s ability to break it down.
However, the goal is not to stay on a restrictive diet forever — rather, it’s to reduce the incoming load, support clearance, and heal the gut and immune system so tolerance improves over time.
Below are the main science-backed nutrition strategies for histamine balance.
1. Lower the Histamine Load: Choosing the Right Foods
Histamine levels in food increase during fermentation, aging, or spoilage. Some foods also trigger histamine release even if they don’t contain much histamine themselves.
Common high-histamine foods:
Fermented foods (sauerkraut, kimchi, kombucha, miso, soy sauce)
Aged cheeses, cured meats, smoked fish
Alcohol (especially wine, beer, champagne)
Vinegar and pickled foods
Leftovers (histamine rises as food ages)
Certain fruits and vegetables (tomatoes, spinach, eggplant, avocado)
Seafood (especially shellfish and canned fish)
Histamine liberators (release histamine from mast cells):
Citrus fruits
Strawberries
Chocolate and cocoa
Nuts (especially walnuts, cashews, peanuts)
Research evidence:
Several clinical and observational studies have shown symptom improvement with short-term low-histamine diets.
In a 2020 review, Comas-Basté et al. concluded that elimination of high-histamine foods led to symptom reduction in up to 80% of histamine-intolerant patients, though more controlled trials are needed.
📘 Reference: Comas-Basté O et al., Nutrients. 2020.
Tip: A low-histamine diet should ideally be used as a diagnostic and therapeutic trial for 2–4 weeks, followed by gradual reintroduction to identify individual thresholds — not as a permanent restriction.
2. Support Histamine Breakdown (DAO Pathway)
The enzyme diamine oxidase (DAO), produced in the intestinal lining, is the primary mechanism for breaking down extracellular histamine (from food and microbes).
Low DAO activity — whether genetic, inflammatory, or due to certain drugs (NSAIDs, antidepressants, antibiotics) — is strongly linked with histamine intolerance symptoms.
Nutrients supporting DAO and histamine metabolism:
Vitamin B6 (pyridoxal-5-phosphate) – a cofactor for DAO synthesis.
Vitamin C – enhances DAO activity and directly degrades histamine in vitro.
Copper – a DAO cofactor; deficiency can impair histamine metabolism.
Magnesium and zinc – help modulate mast cell stability and enzymatic reactions.
Omega-3 fatty acids – reduce inflammatory mediator release from mast cells.
Clinical studies have shown that vitamin C supplementation (500–2000 mg/day) can lower plasma histamine levels and improve allergic symptoms.
📘 Reference: Johnston CS et al., J Am Coll Nutr. 1992; Comas-Basté O et al., Nutrients. 2020.
DAO supplementation:
In a randomized, placebo-controlled trial, oral DAO enzyme supplementation reduced headaches, flushing, and GI distress in individuals with histamine intolerance.
📘 Reference: Izquierdo-Casas J et al., Clin Nutr. 2018.
Tip: For those with low DAO, combining low-histamine intake + DAO support + gut healing offers the best outcomes.
3. Heal the Gut to Improve Tolerance
The gut is both a source and a regulator of histamine. Chronic inflammation, dysbiosis, or increased intestinal permeability can lower DAO production and activate local mast cells.
Evidence-based gut strategies:
Repair the intestinal lining: Nutrients like glutamine, zinc carnosine, and butyrate support epithelial integrity.
Address dysbiosis: Some bacteria (e.g., Morganella morganii, Klebsiella pneumoniae, certain Lactobacillus strains) produce histamine; others help degrade it.
Feed beneficial microbes: A fiber-rich diet with diverse plant foods supports a balanced microbiome and anti-inflammatory metabolites.
A 2021 review found that altering gut microbiota through diet or probiotics may reduce luminal histamine and alleviate histamine intolerance symptoms.
📘 Reference: Schnedl WJ et al., Nutrients. 2021.
Note: Not all probiotics are beneficial for histamine intolerance. Avoid histamine-producing strains (e.g., L. casei, L. bulgaricus, L. reuteri) and consider non-histamine-producing options such as Bifidobacterium infantis, B. longum, and L. plantarum.
4. Anti-Inflammatory and Mast Cell-Stabilizing Nutrients
Certain polyphenols and flavonoids have demonstrated mast-cell–stabilizing and anti-inflammatory properties in experimental and small human studies.
Notable examples:
Quercetin: inhibits histamine release and proinflammatory cytokines (IL-6, TNF-α).
Luteolin: shown to suppress mast cell activation and oxidative stress.
Curcumin: reduces NF-κB signaling and may help regulate immune activation.
📘 References: Chirumbolo S et al., Phytother Res. 2018; Theoharides TC et al., Biofactors. 2020.
5. Rebuild Tolerance Gradually
Long-term healing means restoring immune regulation, gut health, and nutrient balance — not simply avoiding histamine forever. Over time, as the intestinal lining heals and inflammation calms, many individuals can reintroduce moderate-histamine foods without symptoms.
This process is best done slowly and systematically, ideally with practitioner guidance to avoid unnecessary restriction and ensure adequate nutrition.
The Takeaway
Nutritional therapy offers a powerful way to reduce histamine load, support clearance, and heal the gut, helping to restore tolerance and balance.
Through a combination of targeted elimination, nutrient repletion, and microbiome support, many patients can move beyond constant restriction toward long-term resilience.
For ND-approved Low Histamine diet support and Plans click here.
References
Branco ACCC et al. Role of Histamine in Modulating the Immune Response. Front Immunol. 2018.
Thangam EB et al. The Role of Histamine and Histamine Receptors in Mast Cell-Mediated Immunity. Front Immunol. 2018.
Castells M et al. Mast Cell Activation Syndrome: Current Understanding and Management. Clin Rev Allergy Immunol. 2024.
Valent P et al. Mast Cell Activation Syndromes: Collegium Internationale Allergologicum consensus statement. Allergy. 2022.
Muñoz-Cruz S et al. Gender-Related Effects of Sex Steroids on Histamine Release. J Immunol Res. 2015.
Conti P et al. Mast cells activated by SARS-CoV-2 release histamine which increases IL-1 levels causing cytokine storm and inflammatory reaction in COVID-19. J Biol Regul Homeost Agents. 2020.
Salvucci F et al. Antihistamines improve cardiovascular manifestations and other symptoms in long-COVID patients. J Clin Med. 2023.
Comas-Basté O et al. Histamine Intolerance: The Current State of the Art. Nutrients. 2020.
Schnedl WJ et al. Histamine Intolerance Originates in the Gut. Nutrients. 2021.
Izquierdo-Casas J et al. Diamine Oxidase Supplementation Improves Symptoms of Histamine Intolerance. Clin Nutr. 2018.
Johnston CS et al. Vitamin C Depletes Histamine in Human Blood Plasma. J Am Coll Nutr. 1992.
Chirumbolo S et al. Quercetin and Mast Cell Regulation. Phytother Res. 2018.
Theoharides TC et al. Luteolin as a Mast Cell Inhibitor and Neuroprotective Flavonoid. Biofactors. 2020.