Mast Cell Activation

Mast Cell Activation Syndrome (MCAS): A Nutrition and Natural-Health Reference

1. Definition and Overview

Mast cell activation syndrome is a heterogeneous disorder, defined by a combination of (1) recurrent symptoms typical of mast cell activation, (2) an increase of validated mast cell-derived mediators, and (3) response to treatment with mast cell-stabilizing or mast cell mediator-targeted therapies. Disordered mast cell activation occurs when mast cells are pathologically overproduced or if their activation is out of proportion to the perceived threat to homeostasis.

Mast cells are a subtype of white blood cells involved in the immune system. These cells contain many chemical substances called mediators, which are involved in the allergic response. Mast cells have normal physiologic functions such as homeostasis, tissue repair, angiogenesis, and their role in the innate/acquired immune system. Mast cell activation and liberation of mediators are needed for the maintenance of normal physiological processes. However, there are also abnormal conditions, in which this process is not regulated and, like mast cell activation syndrome, causes manifestations in different organ systems in the body.

Onset of mast cell activation syndrome ostensibly reflects the loss of tolerance in the mast cell compartment to nonthreatening entities and nonhazardous environmental conditions. The etiology of chronic mast cell dysregulation and associated intolerance to self-antigens or harmless entities is not well understood, but a growing number of studies point to exposure of the epithelial borders, which leads to inappropriate or excessive mast cell activation or impaired resolution of acute inflammation following neutralization of the identified pathogen.

Over the past 50 years, an increasing number of patients have been experiencing episodes of aberrant mast cell activation not associated with allergen-specific mast cell disease or systemic mastocytosis, which led to proposed diagnostic criteria of mast cell activation syndrome.

2. Classification

Based on the etiology of mast cell activation, patients can further be classified as having (i) primary MCAS where KIT-mutated, clonal mast cells are detected; (ii) secondary MCAS where an underlying IgE-dependent allergy or other reactive MCA-triggering pathology is found; or (iii) idiopathic MCAS, where neither a triggering reactive state nor KIT-mutated mast cells are identified.

In primary MCAS, researchers theorize that the threshold for chemical mediator release, also called degranulation, is lower, meaning it takes less outside stimulation to cause a reaction. Other research has demonstrated that some patients, specifically those with Monoclonal Mast Cell Activation Disorder and those with mastocytosis, have something of an "overpopulation" of mast cells in the bone marrow, which leads to a stronger response when triggered.

Secondary MCAS is far more common, and involves an unclear etiology, though not directly related to monoclonal cells. In these cases, reactions occur as a result of IgE-mediated (an environmental allergen, such as food or medication) and non-IgE-mediated (such as exercise) mechanisms.

In addition to immunoglobulin E (IgE) receptor-triggered mast cell activation, commonly referred to as allergic or atopic disorders, non-IgE mediated mast cell activation follows engagement of toll-like receptors (TLRs), immunoglobulin G (IgG) receptors, and complement receptors.

3. Diagnostic Criteria

Mast cell activation syndromes are characterized by recurrent episodes of systemic symptoms associated with the release of mast cell-derived mediators. The consensus diagnostic criteria of MCAS, updated in 2022, require all three criteria to be fulfilled, including recurrent severe systemic symptoms in at least two organ systems consistent with mast cell mediator-related symptoms.

The second criterion requires significant transient increases in serum tryptase level (20% over baseline plus 2 ng/mL) or other mast cell-derived mediators, such as urinary histamine/N-methyl histamine, leukotriene E4, or prostaglandin D2/2,3-dinor-11β–prostaglandin F2 alpha (PGF2α) metabolite over baseline during a period of increased symptoms.

The third criterion requires a significant response of clinical symptoms to medications that counteract mast cell mediator effects (e.g., histamine H1 and H2 receptor blockers, leukotriene, and prostaglandin blockers), and/or suppress mast cell activation (e.g., sodium cromolyn, ketotifen, and anti-IgE).

The standard laboratory diagnostic marker for MCAS is serum tryptase, with a normal serum level defined as between 0 and 11.4 ng/mL in adults. Studies have shown that blood samples should be taken within 1 to 4 hours of the beginning of symptoms, and that basal levels should be evaluated in advance during a symptom-free period of at least 24–48 hours after complete recovery.

Some mediators, such as histamine metabolites or prostaglandin D2 metabolites, may be helpful in the evaluation and ultimate diagnosis of mast cell activation and should therefore be considered, especially when the serum tryptase assay is not available or when results are equivocal.

4. Clinical Presentation: Symptoms and Body Systems Involved

The first criterion encompasses the episodic occurrence of typical mast cell-related clinical symptoms, such as urticaria, angioedema, flushing, pruritus, nausea, hoarseness, vomiting, diarrhea, abdominal cramping, hypotensive syncope, tachycardia, wheezing, conjunctival injection, nasal congestion, and headache.

MCAS is a disorder that should be considered with specific signs and symptoms of mast cell activation in individuals with skin, gastrointestinal, cardiovascular, respiratory, and neurological system involvement.

MCAS is often difficult to identify due to the heterogeneity of symptoms and the "lack of flagrant acute presentation." Many of the numerous symptoms are non-specific in nature.

4.1 Mediators Responsible for Symptoms

Mast cells contain many cytoplasmic granules containing prestored mediators, including histamine and tryptase, that are massively released into the bloodstream after mast cells are activated, leading to clinical manifestations. These cells produce not only pro-inflammatory mediators and cytokines, including histamine, cysteinyl leukotrienes, and prostaglandins, but also certain proteoglycans such as heparin and various proteases.

Preformed mediators include histamine, serotonin (5-HT), proteases, heparin, and growth factors including TNF-α, proteoglycans, initiating early recruitment of immune cells at the infection site. Newly synthesized mediators consist of lipid-derived mediators, such as prostaglandins and leukotrienes, and cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-16, and IL-18) that affect the physiology of neighboring cells.

Vascular instability may not only be triggered by histamine but also by prostaglandins and/or leukotrienes derived from activated mast cells in the same patient. Other potentially relevant mediators associated with activation of mast cells are platelet activating factor (PAF), tryptases, and various cytokines.

4.2 Neuropsychiatric Involvement

MCAS is associated with various neurologic and psychiatric disorders, including headache, dysautonomia, depression, generalized anxiety disorder, and many others. Mast cell activation disease, which includes MCAS and mastocytosis, is associated with neuropsychiatric disorders, including various types of dysautonomia, neuropathy (including small fiber neuropathy), myalgia, migraine, headache, cognitive dysfunction, restless legs syndrome, sleep disturbance, non-pulsatile tinnitus, depression, generalized anxiety, and panic attacks.

Mast cells discharge hundreds of various mediators such as histamine, tryptase, and leukotrienes, and degranulation of meningeal mast cells contributes to the activation of the trigeminal vascular afferent pathway.

4.3 Gastrointestinal Involvement

The ability of mast cells to rapidly sense and respond to specific triggers, including neuropeptides, underlies their activated status in various human gastrointestinal disorders, such as celiac disease, irritable bowel syndrome, and inflammatory bowel disease. IBS patients have higher numbers of colonic mast cells, often co-localized with enteric nerves, which was shown to correlate with abdominal pain severity. Furthermore, increased mast cell degranulation was reported in colonic biopsies from IBS patients, suggestive of increased mast cell activation, that could modulate visceral sensitivity and epithelial barrier function through the release of neuroactive mediators.

5. Contributing and Associated Factors

5.1 Genetic Factors

Mast cell activation is seen in a variety of clinical contexts and pathologies, including IgE-dependent allergic inflammation, other immunologic and inflammatory reactions, primary mast cell disorders, and hereditary alpha tryptasemia (HαT).

Researchers have identified that a duplication of the α-tryptase–encoding sequence in the TPSAB1 gene causes Hereditary Alpha-Tryptasemia (HαT). This genetic mutation leads to elevated basal serum tryptase and hyper-reactive mast cells, providing a clear biological link for the highly common clinical triad of MCAS, POTS, and Ehlers-Danlos Syndrome (EDS).

The severity of mast cell activation-related symptoms depends on a number of factors, including genetic predisposition, the number and releasability of mast cells, organs affected, and the type and consequences of comorbid conditions.

5.2 Comorbid Conditions: The MCAS–POTS–EDS Triad

Common comorbidities include postural orthostatic tachycardia syndrome, Ehlers-Danlos syndrome, Long COVID, and myalgic encephalomyelitis/chronic fatigue syndrome.

Autonomic dysfunction, such as postural tachycardia syndrome and gastrointestinal motility disorders, are also associated with MCAS.

5.3 Gut Microbiome

Gut microbiota is essential to promote the maturation of the intestinal mast cell progenitors and to ensure normal physiological function. The gut microbiota activates Toll-like receptor (TLR) signaling in intestinal epithelial cells, leading to MyD88-dependent activation of downstream kinases and transcription factors, resulting in the production of cytokines and chemokines.

Novel insights into the mechanisms behind the attraction and activation of mast cells are mediated by TLR4 and H4 receptor-mediated pathways, including the possibility that gut bacteria engage in direct contact with intestinal mast cells, contributing to gut dysfunction and visceral hypersensitivity.

5.4 Stress and the HPA Axis

Mast cells are able to respond to activation of the principal stress system, the HPA axis, and in turn, pro-inflammatory cytokines are potent stimulators of the HPA axis. Their aberrant activity may also give rise to neurodegenerative and mood disorders.

5.5 Epithelial Barrier Dysfunction

As mucosal mast cell activation increases intestinal permeability, mast cells can also contribute to the initiation of food allergic inflammation through a greater influx of allergens and microbes to the lamina propria. In addition, mediators released by mast cells may affect epithelial integrity and viability.

5.6 Estrogen and Hormonal Factors

Hormones, particularly estrogen, influence mast cell behavior. Fluctuations in estrogen levels, such as those occurring during menstrual cycles, can exacerbate MCAS symptoms.

5.7 Autoimmune and Chronic Inflammatory Conditions

Autoimmune diseases like lupus or Sjögren's syndrome create chronic inflammation that can activate mast cells. In many patients with MCAS, several different factors act together to lead to severe or even life-threatening anaphylaxis.

6. Nutrients, Herbs, and Natural Ingredients

Research into dietary components and their relationship to mast cell activity spans in vitro cell studies, animal models, and, more rarely, controlled human trials. The following sections strictly differentiate traditional use (where documented) from the available scientific evidence, and characterize the strength of that evidence honestly.

6.1 Quercetin

Traditional Use

Quercetin is a flavonoid polyphenol found abundantly in onions, apples, capers, and leafy greens. Its food sources have been consumed across virtually all traditional cuisines globally for millennia, though quercetin was not isolated or identified as a distinct compound until the 20th century. No specific traditional medicinal system employed isolated quercetin; its effects were embedded within the broader use of flavonoid-rich plants in folk herbalism.

Scientific Evidence

A key in vitro study compared the flavonoid quercetin and cromolyn on cultured human mast cells. Both quercetin and cromolyn at 100 µM can effectively inhibit secretion of histamine and PGD2. Flavonoids are potent anti-oxidant and anti-inflammatory compounds with mast cell inhibitory actions.

Quercetin inhibits mast cell degranulation, reduces the production of histamine and pro-inflammatory cytokines, and restores homeostasis of the immune system by modulating the Th1/Th2 and Treg/Th17 balances. Additionally, its antioxidant properties help to dampen oxidative stress, a critical factor in the pathophysiology of allergic diseases.

Quercetin can selectively bind to CLM-1 on mast cells, leading to SHP-1 phosphorylation and subsequent inhibition of downstream MyD88/IKK/NF-κB signaling. Furthermore, activation of CLM-1 modulated the surface expression of MRGPRX2 by inhibiting F-actin, leading to internalization of the MRGPRX2 receptor via the PI3K/AKT/Rac1/Cdc42 pathway. These findings suggest quercetin is a promising treatment for allergic diseases by acting as a CLM-1 agonist that inhibits MRGPRX2-mediated mast cell degranulation.

Evidence strength: In vitro studies have consistently demonstrated quercetin's ability to suppress allergic reactions. In vivo studies, particularly in murine models of allergic rhinitis, have confirmed its efficacy in relieving symptoms and dampening type 2 mucosal inflammation. Preclinical evidence also supports its therapeutic potential in asthma, conjunctivitis, atopic dermatitis, and food allergies. However, human studies are still scarce, as only two clinical trials investigated quercetin as a monotherapy. Both studies reported promising results, including symptom reduction and improved quality of life, though larger, randomized trials are needed to validate these findings. Overall, the evidence base is predominantly preclinical (in vitro and animal), with limited and preliminary human trial data.

6.2 Luteolin

Traditional Use

Luteolin is a flavone found naturally in celery, parsley, thyme, chamomile, and artichoke. Traditional use has historically taken the form of herbal teas and culinary consumption of luteolin-containing plants, particularly chamomile (Matricaria chamomilla), which has a long history in European and Middle Eastern herbal traditions for digestive and anti-inflammatory applications. Isolated luteolin supplementation is a modern development with no established traditional pharmacopoeial monograph.

Scientific Evidence

Luteolin, a flavone analogue of quercetin, inhibits IgE-mediated release of histamine, leukotrienes, prostaglandin D2, and granulocyte-macrophage colony-stimulating factor from human cord blood-derived mast cells.

Luteolin effectively inhibited myelin basic protein-induced mast cell mediator release at 10 and 100 µM, exhibiting dose-dependent inhibition of mast cell-induced IL-2 release.

Luteolin belongs to a flavone group of compounds called flavonoids; it has anti-oxidant properties, inhibits some cancer cell proliferation, and exerts a regulatory effect on mast cell-mediated inflammatory diseases and allergy.

Evidence strength: Luteolin was among the most effective dietary components in suppressing the release of preformed and de novo synthesized mediators from mast cells or in animal models. In addition to in vitro and in vivo studies, the effects of dietary components on allergic diseases have also been reported in randomized controlled trials. However, direct clinical trials in MCAS patients specifically are lacking; the current human evidence pertains to allergic diseases more broadly. Evidence remains largely preclinical.

6.3 Vitamin C (Ascorbic Acid)

Traditional Use

Vitamin C-rich foods — including rosehips, citrus fruits, and berries — have been used across traditional herbal and folk medicine globally for centuries to treat inflammatory conditions, support wound healing, and maintain general health. The specific anti-histamine properties of vitamin C were not recognized in traditional systems, which employed the whole food rather than isolated ascorbic acid.

Scientific Evidence

In one study, 7.5 g of vitamin C administered intravenously in 89 patients with allergies or upper respiratory infections caused a significant reduction in serum histamine. Several mechanisms may be responsible for the inhibitory effect of vitamin C on histamine: vitamin C may inhibit mast cell activation, increase histamine degradation by diamine oxidase, or alternatively decrease histamine production by inhibiting histidine decarboxylase.

Evidence strength: The human clinical evidence is limited in size and scope; the study cited used intravenous dosing in allergy and respiratory infection patients rather than MCAS-specific populations. The mechanistic rationale — particularly around diamine oxidase co-factor activity and direct histamine degradation — is supported by biochemical and observational data, but confirmatory randomized controlled trials specifically in MCAS are lacking.

6.4 Resveratrol

Traditional Use

Resveratrol is a stilbenoid polyphenol found in grape skins, red wine, and some berries. The consumption of red wine and grape products has a long traditional history across Mediterranean and Asian cultures. However, resveratrol as an isolated compound has no traditional pharmacopoeial status; its use as a supplement is entirely a modern, evidence-driven development.

Scientific Evidence

Analysis of resveratrol in both an ovalbumin-induced allergic enteritis and experimental colitis model in mice showed that treatment with resveratrol prevented the increase in mast cells in both allergic enteritis and chronic colitis. Further, it delayed the onset of disease symptoms and ameliorated disease parameters such as tissue damage. In addition, resveratrol inhibited IgE-dependent degranulation and expression of pro-inflammatory cytokines such as TNF-α in activated bone marrow-derived mast cells.

In randomized controlled trials, vitamin D, quercetin, O-methylated epigallocatechin gallate (EGCG), resveratrol, curcumin, and cinnamon extract improved symptoms of allergic rhinitis and reduced the number of inflammatory cells in patients.

Evidence strength: Animal studies are supportive; on average, the inhibitory effect of the dietary components on mast cells was lower in vivo than in vitro. Resveratrol's poor oral bioavailability is a recognized limitation of current formulations, and direct MCAS human trials are absent.

6.5 Curcumin

Traditional Use

Curcumin is the primary active polyphenol in turmeric (Curcuma longa), which has been used for thousands of years in Ayurvedic medicine in India and traditional Chinese medicine. Traditionally it was consumed as a dietary spice, used in preparations for digestive disorders, inflammatory conditions, and skin diseases. The German Commission E has reviewed turmeric rhizome for dyspeptic complaints, and the European Medicines Agency (EMA) recognizes its traditional use as a herbal medicine for digestive discomfort.

Scientific Evidence

Curcumin directly inhibited Syk kinase activity in vitro, and also inhibited the phosphorylation of additional downstream signaling molecules including Akt, p38, and JNK, all of which are relevant to mast cell activation pathways.

Curcumin was among the dietary components most effective in suppressing the release of preformed and de novo synthesized mediators from mast cells or in animal models.

Evidence strength: Curcumin improved symptoms of allergic rhinitis and reduced inflammatory cells in some randomized controlled trials. However, these trials are conducted in allergic disease, not MCAS specifically, and curcumin's notoriously low bioavailability continues to limit clinical translation. Evidence for direct anti-mast cell effects in humans with MCAS is preliminary.

6.6 Kaempferol

Traditional Use

Kaempferol is a flavonol present in capers, broccoli, kale, leeks, and many medicinal herbs including Ginkgo biloba and Moringa oleifera. Traditional use of kaempferol-containing plants spans multiple systems of medicine, including Traditional Chinese Medicine and Ayurveda, primarily in the context of anti-inflammatory and anti-allergic applications, though not specifically for isolated kaempferol.

Scientific Evidence

Kaempferol exhibited potent inhibitory effects on mast cell degranulation, arachidonic acid metabolites, and cytokine release, as observed in both in vitro and in vivo studies, highlighting the potential of this substance to modulate mast cell activity and associated inflammatory responses.

Evidence strength: Primarily preclinical. Human data on kaempferol in the context of MCAS specifically are not yet available in peer-reviewed literature.

6.7 Diamine Oxidase (DAO) and Histamine Metabolism Support

Traditional Use

No traditional use exists for isolated diamine oxidase (DAO) supplementation; this is a contemporary nutritional intervention.

Scientific Evidence

Histamine intolerance is thought to be associated with low activity or blockade of diamine oxidase (DAO), the main enzyme for histamine degradation. The diagnosis is hampered by the lack of a validated biomarker and is mainly based on clinical assessment and response to a low histamine diet and reintroduction.

The therapeutic approach is centered on dietary management, restricting foods that may increase circulating histamine levels. DAO supplementation has been shown to potentially contribute to histamine degradation in the intestinal lumen, but its activity varies depending on the presence of cofactors and the enzyme's origin.

Diamine oxidase (DAO) is also under preclinical or clinical evaluation as a potential mast cell activation biomarker. Vitamin B6 is a critical cofactor for DAO; deficiency in B6 impairs the production of DAO.

Evidence strength: DAO supplementation has clinical trial data in histamine intolerance (a related but distinct condition), showing some benefit in reducing histamine-related symptoms. The specific application to MCAS remains indirect; overlap between histamine intolerance and MCAS symptoms is widely discussed but mechanistically distinct.

6.8 Omega-3 Fatty Acids (EPA and DHA)

Traditional Use

Oily fish and fish liver oils have been used in coastal and Nordic folk traditions for centuries. While the anti-inflammatory properties of fish consumption were part of traditional dietary practice, isolation of specific omega-3 fatty acids EPA and DHA and their targeted use for mast cell conditions is a modern, evidence-driven application.

Scientific Evidence

Components of the daily diet, including certain fatty acids, amino acids, and vitamins, as well as secondary plant components, may have effects on mast cells and thus may be of interest as nutraceuticals for the prevention and treatment of allergies.

Dietary components such as fatty acids, amino acids, vitamins, carotenoids, flavonoids, and spices are able to attenuate proinflammatory, particularly IgE-dependent mast cell-mediated responses in vitro and in vivo.

Evidence strength: Evidence for omega-3 fatty acids modulating mast cell activity is largely mechanistic and indirect. RCTs demonstrating benefit specifically in MCAS patients are absent; evidence in related allergic and inflammatory diseases is supportive but not definitive for this application.

6.9 Vitamin D (Calcitriol)

Traditional Use

Vitamin D has no traditional herbal use per se; historically, sun exposure and cod liver oil consumption served as vitamin D sources. Supplemental vitamin D in the context of immune modulation is a modern application.

Scientific Evidence

Calcitriol (the active form of vitamin D) was among the dietary components most effective in suppressing the release of preformed and de novo synthesized mediators from mast cells in vitro and animal models. In randomized controlled trials, vitamin D improved symptoms of allergic rhinitis and reduced the number of inflammatory cells in patients.

Evidence strength: Vitamin D's role in immune modulation — including mast cell regulation — has support from both mechanistic studies and some RCTs in allergic disease. Direct MCAS-specific human trials are lacking; the evidence for this specific application remains preliminary.

6.10 Short-Chain Fatty Acids (SCFAs): Butyrate

Traditional Use

Butyrate is produced endogenously through the fermentation of dietary fiber by gut bacteria. Fermented foods and high-fiber diets have been staples across traditional dietary patterns globally. Isolated butyrate supplementation for mast cell conditions is a recent, research-driven development.

Scientific Evidence

Butyrate was among the most effective dietary components in suppressing the release of preformed and de novo synthesized mediators from mast cells or in animal models. Dietary components such as butyrate showed a potent suppressive effect on the release of histamine, cytokines/chemokines, or eicosanoids due to their influence on signaling molecules of mast cells.

Evidence strength: Evidence for butyrate's effects on mast cells is primarily from in vitro and animal studies. The indirect connection via gut microbiome modulation (dietary fiber supporting butyrate-producing bacteria) has a rationale grounded in gut-immune biology, but human clinical trials specifically in MCAS are absent.

7. Dietary and Lifestyle Factors

7.1 Low-Histamine Diet

There are individuals who theorize that some people with MCAS symptoms have a histamine intolerance. Histamine intolerance refers to when the body has difficulty breaking down histamine, so a buildup of this compound can lead to worsening MCAS-like symptoms since histamine is one of the many compounds released by mast cells that can lead to swelling, hives, diarrhea, and other issues. Determining if an individual has difficulty with breaking down histamine properly is challenging, and research in this area is still lacking.

A low-histamine diet can help reduce symptoms for many with MCAS. This involves avoiding foods high in histamine such as aged cheeses, fermented foods, alcohol, and processed meats.

Everyone is different, so some with MCAS may be able to tolerate some higher-histamine foods, and what is considered by providers to be "higher-histamine" or "histamine liberators" can vary.

7.2 Elimination and Reintroduction Approaches

An elimination diet can help identify specific food triggers. This involves removing potential trigger foods from the diet and slowly reintroducing them one at a time to observe reactions. A registered dietitian may recommend 2–6 weeks of following a low-histamine diet, then recommend reintroducing high-histamine foods. If there is a significant difference in symptoms when foods are eliminated or reintroduced, histamine intolerance may be a contributing factor. If there is no symptom relief when high-histamine foods are removed, histamine intolerance may not be the driver.

7.3 Trigger Identification and Environmental Factors

Common triggers for mast cell activation include certain foods, environmental factors, medications, stress, and temperature changes. Keeping a symptom diary can help identify specific triggers. Reducing exposure to common environmental triggers such as strong scents, chemicals, and allergens by choosing fragrance-free products and using air purifiers is also recommended.

Food intoxication resulting from high histamine content (e.g., scombroid fish poisoning) can mimic MCAS unless pre-event and post-event tryptase levels were measured.

7.4 Gut Microbiome and Dietary Fiber

Through the mediators they release, intestinal mast cells perform diverse functions that contribute to the maintenance of epithelial barrier integrity and overall mucosal homeostasis. The involvement of neuro-immune interactions has been reported in allergic disease, demonstrating that neurons communicate with and regulate mast cell activation during allergic inflammation, and in turn, mast cells reciprocally stimulate nerve endings.

Some bacterial strains (e.g., Lactobacillus rhamnosus GG and Bifidobacterium infantis) can degrade histamine, whereas others produce it. Choosing specific strains shown to lower histamine is advisable, while avoiding broad-spectrum probiotic blends without guidance. This area of research is evolving and lacks robust MCAS-specific clinical trial evidence.

7.5 Sleep and Stress

Mast cells are able to respond to activation of the principal stress system, the HPA axis, and pro-inflammatory cytokines are potent stimulators of the HPA axis. Their aberrant activity may also give rise to neurodegenerative and mood disorders. Various preclinical evidence suggests that the intestinal microbiota contributes substantially to mood and behavioral disorders. In humans, conditions of the microbiota have been linked to stress, anxiety, depression, and pain.

8. Evidence Summary and Research Gaps

Mast cell activation syndrome is a term applied to several clinical entities that have gained increased attention from patients and medical providers. Although several descriptive publications about MCAS exist, there are many gaps in knowledge, resulting in confusion about this clinical syndrome.

Conventional therapies for allergies have limitations, prompting exploration into alternative approaches such as small-molecule natural compounds derived from botanical sources. Existing literature on the effects of these compounds on pathologic mast cells and basophils highlights their potential in allergy management.

Short-chain fatty acid butyrate, vitamin D, polyphenols such as kaempferol, quercetin, luteolin, and resveratrol, and spices such as curcumin and cinnamon exhibited the most potent inhibitory effects on mast cell degranulation, arachidonic acid metabolites, and cytokine release. These effects were observed in both in vitro and in vivo studies, highlighting the potential of these substances to modulate mast cell activity and associated inflammatory responses. On average, the inhibitory effect of the dietary components on mast cells was lower in vivo than in vitro.

Strategies to overcome the poor bioavailability of many of these nutrients are an important part of current research. Large-scale, well-powered randomized controlled trials in clinically verified MCAS populations remain an unmet need across the entire natural-compound research landscape in this condition.

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