An underlying cause of histamine intolerance is diamine oxidase (DAO) deficiency, which leads to defective homeostasis and a higher systemic absorption of histamine. Impaired DAO activity may have a genetic, pharmacological or pathological origin. A recent proposal also suggests it can arise from an alteration in the gut microbiota, although only one study has explored this hypothesis to date. A greater abundance of histamine-secreting bacteria in the gut could lead to the development of histamine intolerance. Thus, the aim of this study was to characterize the composition of the intestinal microbiota of patients with histamine intolerance symptoms and compare it with that of healthy individuals. The study was performed by sequencing bacterial 16S rRNA genes (V3-V4 region) and analyzing the data using the EzBioCloud Database. Dysbiosis of the gut microbiota was observed in the histamine intolerance group who, in comparison with the healthy individuals, had a significantly lower proportion of Prevotellaceae, Ruminococcus, Faecalibacterium and Faecablibacterium prausnitzii, which are bacteria related to gut health. They also had a significantly higher abundance of histamine-secreting bacteria, including the genera Staphylococcus and Proteus, several unidentified genera belonging to the family Enterobacteriaceae and the species Clostridium perfringens and Enterococcus faecalis. A greater abundance of histaminogenic bacteria would favor the accumulation of high levels of histamine in the gut, its subsequent absorption in plasma and the appearance of adverse effects, even in individuals without DAO deficiency.

A retrospective pilot study was carried out to investigate the prevalence of four variants of the diamine oxidase (DAO) encoding gene (AOC1) in Caucasian adults with symptoms of histamine intolerance. In a cohort of 100 patients and 100 healthy individuals, DAO-encoding gene non-synonymous Single Nucleotide Variations (SNVs) were genotyped by multiplex single-nucleotide primer extension (SNPE) and capillary electrophoresis, and serum DAO activity was analyzed with a radio-extraction assay. The study found that 79% of individuals with symptoms of histamine intolerance harbored one or more of the four SNVs associated with reduced DAO activity. No significant differences were found in the prevalence of any variant between the group of patients and healthy controls. However, when considering the status of the alleles associated with DAO deficiency, more homozygous alleles were observed in histamine-intolerant patients. Moreover, a slightly but statistically higher percentage of patients had a high genetic risk score, reflecting the cumulative effect of carrying multiple DAO deficiency-associated gene variants and a high load of risk alleles (homozygous). A relationship between serum DAO activity and the genetic load of one specific SNV was observed, with DAO activity being significantly lower in patients homozygous for rs2052129. These results potentially support that carrying multiple DAO deficiency-associated gene variants and a high load of risk alleles (homozygous) is more relevant than the mere presence of one or more SNVs. Further studies are needed to determine the predictive value of these DAO-encoding gene variants.

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.

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.