Search Results (52)

Background/Objectives: Diamine oxidase (DAO) enzyme metabolizes dietary histamine in the gastrointestinal tract. DAO deficiency can lead to histamine intolerance (HIT), manifesting as migraines, gastrointestinal disturbances, and allergic reactions. DAO supplementation has been shown to enhance histamine breakdown, alleviating these symptoms. This randomized, double-blind, single ascending dose (SAD) Phase I clinical trial aimed to evaluate the safety and tolerability of escalating doses of DAO supplementation in healthy volunteers. Methods: Thirty participants were randomly assigned to receive single doses of 42 mg, 84 mg, or 210 mg of DAO extract (adiDAO^® Veg) or placebo under fasting conditions. Vital signs, laboratory parameters, and adverse events (AEs) were monitored. Results: No serious adverse events or clinically significant changes in vital signs, ECGs, or laboratory parameters were observed. Conclusions: This trial confirms the safety and tolerability of high-dose DAO supplementation. Future studies are recommended to explore the effects of chronic high-dose administration and alternative dosage forms to improve convenience. Full article

Self-reported food intolerances are estimated to affect between 15–20% of the population. Among them, histamine intolerance (HIT) has emerged as a focus of particular interest. It is defined as a disequilibrium between dietary histamine and the capacity of the organism to degrade intestinal histamine, leading to the appearance of intestinal and extra-intestinal symptoms. HIT 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. Limited clinical evidence reflects the difficulty of dietary management and suggests a beneficial role of DAO supplementation on the clinical manifestations associated with HIT. Full article

Exogenous histamine obtained from the intake of histamine-rich food is mainly metabolized by the diamine oxidase enzyme (DAO). Histamine intolerance (HIT) is an alteration mainly caused by DAO deficiency, which is commonly associated with gastrointestinal, respiratory, cardiovascular, central nervous system, muscular, skeletal, and skin symptoms. Despite four single-nucleotide polymorphisms (SNPs) being mainly associated with DAO deficiency, the probability of inheriting these variants and their relationship with HIT in the Mexican population remain unknown. Objective: The aim of this study was to evaluate the prevalence of these SNPs and their relationships with HIT in the Mexican population, including both individual volunteers and family groups. Methods: Four SNPs related to DAO deficiency were detected in 112 volunteers; medical questionnaires were answered. Results: The prevalence of genetic DAO deficiency attributed to at least one risk allele was 78.57% (rs1049793 was the main SNP). Fifteen DAO SNP combinations were detected (the main rs2052129, rs10156191, rs1049742 (wild-type homozygotes), and rs1049793 (heterozygote), 31.25%). A total of 41.07% of the volunteers presented at least three symptoms in different systems related to HIT, of whom 84.78% presented at least one SNP. The DAO deficiency genetic risk score varied among individual volunteers and families. The highest probability of having a mutated homozygote was 11.8% (rs1049793). HIT symptoms varied among relatives sharing identical genotypes. Conclusions: The prevalence of SNPs related to DAO deficiency in the Mexican population correlates with globally reported data; however, further analysis with volunteers distributed throughout the country would be desirable. Although genetic predisposition was common, the presence of SNPs alone did not predict specific HIT symptoms. Multiple SNPs may increase the presence of HIT symptoms, regardless of the type of allele. These findings highlight the multifactorial nature of HIT and underscore the need for standardized diagnostic criteria. Full article

A novel diamine oxidase (DAO) was discovered in the bacterium Glutamicibacter halophytocola (DAO-GH). The gene of DAO-GH was integrated into the genome of the yeast Komagataella phaffii and recombinantly produced under control of the methanol-inducible AOX1 promoter in a bioreactor cultivation. A high DAO activity of 70.2 ± 5.2 µkat/L_culture (5.25 ± 0.22 µkat/g_protein) was yielded after 90 h of cultivation. The DAO-GH was partially purified by the polyethyleneimine precipitation of nucleic acids, fractionated ammonium sulfate precipitation and hydrophobic interaction chromatography, resulting in a specific DAO activity of 19.7 µkat/g_Protein. The DAO-GH was then biochemically investigated regarding its potential for histamine and tyramine degradation in fermented foods and the human small intestine. Interestingly, the DAO-GH showed activity even at a low pH of 5 and low temperature of 6 °C. Both histamine and tyramine were effectively degraded and DAO-GH showed especially very high affinity towards tyramine (K_m of 0.009 mM). The DAO-GH was shown to be capable of degrading around 20% of the initially applied histamine in tuna paste (pH 5.6) at 5 °C within 24 h and completely degraded the histamine in a simulated intestinal fluid within 1.5 h in bioconversion experiments. The DAO-GH was spray-dried for the production of a storable enzyme preparation. Only around 17% of activity were lost in this process and the DAO-GH remained stable at room temperature for at least 3 months. The discovery of this DAO with its very advantageous biochemical properties allows the preparation of histamine-reduced or -free fermented foods by a simple enzymatic treatment or the treatment of histamine intolerance symptoms as a dietary supplement or medicine. Full article

Background: Self-reported food allergy is a common concern among adults and often prompts the use of diagnostic allergy testing. However, serum diamine oxidase (DAO) measurement is rarely performed, despite the fact that symptoms of histamine intolerance can closely mimic those of IgE-mediated food allergy. This study aimed to analyze and compare the results of commonly used food allergy tests in relation to serum DAO levels in this patient population. Methods: A total of 61 adult patients with self-reported food-related symptoms were enrolled. All participants underwent skin prick testing and serum DAO measurement using an enzyme-linked immunosorbent assay (ELISA). In addition, serum-specific IgE (sIgE) testing was performed in 29 of the 61 patients. DAO levels were compared across groups based on skin prick testing and sIgE results. Results: Fewer than half of the patients had positive test results, 36% for skin prick testing and 38% for sIgE, and 38% showed reduced serum DAO levels. DAO levels did not differ significantly between patients with positive and negative skin prick or sIgE results; however, a slight decrease in DAO was observed in patients with negative sIgE. Patients with negative skin prick tests were significantly older than those with positive results. Conclusions: The majority of adults with self-reported food allergies had negative allergy test results and normal DAO levels. Nevertheless, a considerable proportion showed either positive allergy tests or reduced DAO levels, suggesting the potential role of histamine intolerance. These findings underscore the importance of a detailed pre-test clinical assessment that considers both IgE- and non-IgE-mediated mechanisms in patients with suspected food-related hypersensitivity. Full article

Patients with Inflammatory Bowel Disease (IBD) exhibit a dysregulated immune response that may be further exacerbated by bioactive compounds, such as histamine. Current dietary guidelines for IBD primarily focus on symptom management and flare-up prevention, yet targeted nutritional strategies addressing histamine metabolism remain largely unexplored. This narrative review aims to summarize the existing literature on the complex interplay between IBD and histamine metabolism and propose a novel dietary framework for managing IBD progression in patients with histamine intolerance (HIT). Relevant studies were identified through a comprehensive literature search of PubMed/MEDLINE, Google Scholar, ScienceDirect, Scopus, and Web of Science. The proposed low-histamine diet (LHD) aims to reduce the overall histamine burden in the body through two primary strategies: (1) minimizing exogenous intake by limiting high-histamine and histamine-releasing foods and (2) reducing endogenous histamine production by modulating gut microbiota composition, specifically targeting histamine-producing bacteria. In parallel, identifying individuals who are histamine-intolerant and understanding the role of histamine-degrading enzymes, such as diamine oxidase (DAO) and histamine-N-methyltransferase (HNMT), are emerging as important areas of focus. Despite growing interest in the role of histamine and mast cell activation in gut inflammation, no clinical trials have investigated the effects of a low-histamine diet in IBD populations. Therefore, future research should prioritize the implementation of LHD interventions in IBD patients to evaluate their generalizability and clinical applicability. Full article

Background/Objectives: Diamine oxidase (DAO) deficiency can lead to excessive histamine absorption at the intestinal level, triggering symptoms that affect the gastrointestinal, neurological, dermatological, respiratory, circulatory, and musculoskeletal systems. This condition, known as histamine intolerance, is more prevalent in women. While serum DAO levels have been observed to increase during pregnancy in healthy women, there is a lack of in-depth studies evaluating the relationship between pregnancy, DAO activity, and histamine intolerance symptoms. This is the first study to assess serum DAO activity before, during, and after pregnancy, as well as the evolution of histamine intolerance symptoms in women diagnosed with this condition. Due to low histamine, diets are quite restrictive, no dietary intervention was considered for pregnant women. Methods: This prospective observational study used an assessment questionnaire to evaluate the presence or absence of histamine-related symptoms in 30 adult women with histamine intolerance before, during, and after pregnancy. Serum DAO activity was also measured at the three time points. Results: Nearly all women (27 out of 30) experienced symptom improvement during pregnancy (p < 0.001). Specifically, at least 77% of women reported a marked reduction in flatulence, bloating, headache, rhinorrhea, flushing, pruritus, hypotonia, or muscle pain. Concurrently, the DAO activity significantly increased 11-fold from the baseline, coinciding with symptom relief. At two months postpartum, symptoms tended to reappear, accompanied by a significant decrease in DAO activity in all participants. Conclusions: This first-of-its-kind observational study demonstrates an improvement in histamine intolerance symptoms and an increase in serum DAO activity during pregnancy. The pronounced symptom relief suggests that restrictive diets, such as low-histamine diets, may not be necessary during pregnancy. Further research is required to confirm these novel findings. Full article

Histamine intolerance is a condition that occurs when there is an imbalance between the accumulation and degradation of histamine within the body. Excess histamine is metabolized and then degraded by two enzymes, of which the most abundant is the vesicular diamine oxidase (DAO). An imbalance or a state of dysbiosis of the intestinal microbiota has been observed in patients with histamine intolerance compared to healthy individuals. Studies indicate that the administration of bifidobacteria or lactobacilli alone or in mixtures can alter colonic microbiota populations and metabolic activities. The present study has evaluated the ability of a probiotic bacterial strain to stimulate the release of cellular DAO from an in vitro model of the human intestinal epithelial barrier. The results indicate that, under the experimental conditions used, probiotic strain Lactiplantibacillus plantarum LP115 has a significant stimulatory effect on DAO secretion in adenocarcinoma cell line HT-29. Full article

Background: Histamine intolerance, a disorder due to impaired degradation of dietary histamine, is frequently associated with headaches, but the underlying pathophysiology is largely unknown; the sensitization of meningeal afferents appears likely. We approached this issue by examining histamine concentrations in different tissues and meningeal histamine release in a new mouse model of high-histamine diets. Methods: C57BL/6 mice of both sexes were fed with diets containing 3 or 9 g/kg histamine and compared to control groups. After 10–30 days, the histamine concentration was determined in plasma, samples of homogenized ileum, trigeminal ganglia, spinal medulla, and cerebellum using an ELISA. The histamine release from mast cells in the dura mater stimulated with compound 48/80 was also examined. Results: Animals supplied with high dietary histamine showed normal behavior and no signs of suffering. Compared with the controls, the histamine concentration was significantly higher in plasma and ileum of mice fed with 3 g/kg, highest in animals fed with 9 g/kg histamine. In addition, this group of animals showed also higher histamine concentrations in the trigeminal ganglion. The histamine release from the dura mater in mice supplied with 3 g/kg histamine was not significantly different to control animals, but the relative increase in stimulated release was lower in male animals of the high histamine group. Conclusions: High dietary histamine increases histamine levels in blood plasma and the gut, whereas the histamine content of neural tissues is not significantly influenced. The lowered stimulated release in animals subjected to high dietary histamine may indicate compensatory mechanisms. Full article

Background/Objectives: Elimination diets targeting amines and salicylates have been used since the 1980s to diagnose pharmacological food intolerance in individuals with atopic dermatitis (eczema), yet supporting evidence regarding relevance is limited. To our knowledge, this systematic review with meta-analysis is the first to examine the prevalence and association between atopic dermatitis flares and amine intolerance (including histamine intolerance) and salicylate intolerance in individuals with atopic dermatitis. Methods: Following the PRISMA guidelines, searches of PubMed, Embase, CINAHL, and Cochrane were conducted. Included studies involved children and adults with atopic dermatitis who underwent dietary elimination and double-blind placebo-controlled challenges involving histamine, other amines, or salicylates. Risk of bias was assessed using the Joanna Briggs Institute Checklist for Prevalence Studies. Meta-analysis of the prevalence of atopic dermatitis flare by food chemical type was performed using a random effects model in Stata/MP, version 16.1 for Windows. Heterogeneity was assessed using the I² statistic and Cochrane’s Q test. Results: A total of 2323 titles and abstracts were screened, with 46 full-text articles evaluated independently by two reviewers, resulting in the inclusion of four prevalence studies involving 188 participants. Meta-analysis of two trials showed histamine intolerance prevalence at 31% [95% CI, 20–41%] with no heterogeneity (I² = 0.01%). Two trials showed amine intolerance prevalence at 32% [95% CI, 16–48%] with moderate heterogeneity (I² = 34.91%). Two trials showed salicylate intolerance prevalence at 53% [95% CI, 44–62%] with no heterogeneity (I² = 0.00%). Conclusions: This review suggests there may be low-certainty evidence linking intolerance to histamine, amines, and salicylates to atopic dermatitis flare in a substantial proportion of individuals with atopic dermatitis. Further, well-designed studies are needed to confirm these findings and clarify the role of pharmacological food intolerance in atopic dermatitis. Full article

Background/Objectives: Despite its long-standing recognition, the etiopathogenesis of idiopathic granulomatous mastitis (IGM) remains poorly understood. This study aims to investigate the relationship between IGM and food intolerance, allergies, and immunological factors to shed light on its etiology. Materials and Methods: This case–control study included 32 patients with IGM and 32 healthy women. In order to examine their potential relevance to allergy and immunology, serum interleukin (IL)-4, IL-4 receptor, histamine, and histamine-releasing factor (HRF) were measured by ELISA. Furthermore, serum IgG antibodies against specific food allergens were measured to evaluate food intolerance. Results: The patient group exhibited significantly higher intolerance values for lentils and curry compared to the control group (p = 0.023 and p = 0.012, respectively). Histamine (p < 0.001) and IL-4 (p = 0.003) levels were elevated in IGM patients compared to the control group, while HRF and IL-4R outcomes did not show any significant differences (p > 0.05). Conclusions: Elevated histamine and IL-4 levels may suggest the involvement of allergy and immunological factors in IGM’s etiopathogenesis. The integration of anti-histamine medications for IGM patients with elevated histamine levels could provide an alternative therapeutic strategy. Full article

Background/Objectives: Limited research has explored histamine intolerance from the perspective of primary caregivers. Our objective was to develop a practical symptom profile from the standpoint of general practice. We also aimed to gather data on the frequency and timing of disease progression and to establish a staging system. Methods: This study utilized a nonrandomized, quasi-experimental design. An in-depth interview was conducted with 217 patients involving 120 questions. To evaluate associations between food intake and symptoms, we recommended either an exclusion diet or a low-histamine diet. A follow-up questionnaire was subsequently administered. We also analyzed 3831 doctor–patient meetings involving upper respiratory symptoms. Results: Symptoms in 77 patients were associated with histamine-rich meals. The most characteristic symptoms included respiratory symptoms (95%), bloating (94%), headache (91%), fatigue (83%), postprandial drowsiness (81%), skin symptoms (81%), diarrhea/loose stool (77%), psychological symptoms (77%), dyspepsia (69%), and muscle/eyelid twitching (61%). Patients with suspected histamine intolerance visited primary care three times more often with upper respiratory symptoms than those without suspected histamine intolerance. The symptom spectrum of histamine intolerance involves multiple organ systems and occurs in distinct, repeating patterns. Symptoms can be described by their duration, sequence, and severity level, which is the key focus of this research, including visual representations. In its most severe stages, histamine intolerance may potentially involve mast cell activation. A personalized diet is associated with a gradual reduction in both the intensity and frequency of symptoms. Conclusions: The spectrum of histamine intolerance can be characterized by specific symptom patterns with defined frequencies, timelines, and symptom stages. Full article

Background/Objectives: Histamine intolerance is becoming a critical medical problem across numerous clinical specialties, due to the absence of a standardized diagnostic and therapeutic strategy to manage patients with a suspicion of or diagnosis of this condition. Histamine intolerance is a type of non-immune food hypersensitivity, characterized by heterogenous etiologies and a very broad range of symptoms. The condition is the result of an imbalance between the amount of histamine accumulated within the body and the body’s systemic ability to degrade it. In regard to the diagnostics of histamine intolerance, the need to preliminarily exclude other potential conditions associated with increased histamine levels in the blood has been highlighted. The co-occurrence of allergies and histamine intolerance is not uncommon, and the similarity of the clinical manifestations can lead to diagnostic, as well as therapeutic, difficulties. This paper details the diagnostic and clinical workflow for a patient with histamine intolerance and polyvalent allergy comorbidity, with the aim being to help outline a protocol that may be helpful to clinicians managing patients with histamine intolerance. Case Presentation: This article presents the case of a 30-year-old patient with a polyvalent allergy and multimorbidity (allergic rhinitis, asthma, a food allergy, and eosinophilic esophagitis), with comorbid histamine intolerance. Due to the violent and severe symptoms, including facial erythema, urticaria, pruritus, abdominal pain, and tachycardia, experienced after meals, the patient received intramuscular epinephrine injections three times a week. The diagnostic protocol and the course of therapeutic management are presented. Conclusions: The diagnosis of histamine intolerance is difficult due to the high variability and heterogeneity of clinical symptoms in individual patients. Many studies on the issue recommend ruling out an allergic background in terms of the complaint. However, the possibility of the symptoms of an IgE-dependent allergy overlapping with those of histamine intolerance should be taken into account in every case. This is particularly important in patients presenting with an atypical and severe course of allergic diseases. The clinical case presented herein may be helpful for the daily practice of allergologists and physicians with other specialties, as an example of multimorbidity with both allergic and non-allergic backgrounds. Full article

Background/Objectives: Histamine intolerance is primarily caused by a deficiency in the diamine oxidase (DAO) enzyme at the intestinal level. The reduced histamine degradation in the gut leads to its accumulation in plasma, thereby causing multiple clinical manifestations, such as urticaria, diarrhea, headache, dyspnea, or tachycardia, among others. The dietary management of this food intolerance consists of the follow-up of a low-histamine diet, often combined with DAO supplementation. To date, around twenty studies have investigated the effectiveness of these dietary strategies in reducing the frequency and/or intensity of symptoms, with promising results. However, the limitations of these studies (small patient cohort, lack of control group, and short dietary intervention periods) highlight the need for more ambitiously designed research. Therefore, the main objective of this prospective, unicentric, double-blind, randomized, and placebo-controlled trial is to evaluate the efficacy of a low-histamine diet and/or DAO supplementation over a three-month period in improving symptoms of histamine intolerance. Additionally, the impacts of these dietary strategies on the intestinal microbiota composition, urinary profile of histamine metabolites, serum DAO activity, and plasma histamine levels will be assessed throughout the intervention. Methods: The trial will enroll 400 patients who will be randomly assigned to one of two groups: the intervention group, which will follow a low-histamine diet, or the control group, which will maintain their habitual dietary habits. Within each of these groups, participants will be further divided into four subgroups to receive either exogenous DAO enzyme supplementation (from porcine or plant sources, with the latter administered at two different dosages) or a placebo. Therefore, a total of eight distinct intervention groups will be considered. The comparison of these groups will allow the evaluation of the individual effects of the low-histamine diet or DAO enzyme supplementation, as well as their possible synergistic effect. Results: The results of this study should help to improve dietary recommendations for histamine-intolerant patients and ultimately enhance their quality of life. Full article

Edible legume sprouts have been proposed as a promising plant-based source of the enzyme diamine oxidase (DAO), which plays a key role in degrading histamine at an intestinal level and preventing the development of histamine intolerance symptoms. However, the temperature and humidity conditions required for seed germination can also favor the rapid growth of yeast and mold, potentially compromising sprout yield and quality. The aim of this study was to evaluate the influence of different seed disinfection treatments on both the germination rate and DAO enzymatic activity in sprouts of four Leguminosae species. Seed disinfection with 70% ethanol for either 5 or 15 min slightly increased the germination rates of chickpea and soybean sprouts without affecting DAO activity, regardless of treatment duration. However, in lentil and green pea sprouts, ethanol disinfection caused a statistically significant reduction in histamine-degrading capacity. In contrast, treating seeds with sodium hypochlorite for 15 min increased germination rates by up to 14% and preserved DAO activity in all legume sprouts tested. These results indicate that incorporating a seed disinfection step during legume sprouting may affect both the DAO enzymatic activity and germination rate. Full article