Histamine Intolerance: The Current State of the Art

Histamine intolerance, also referred to as enteral histaminosis or sensitivity to dietary histamine, is a disorder associated with an impaired ability to metabolize ingested histamine that was described at the beginning of the 21st century. Although interest in histamine intolerance has considerably grown in recent years, more scientific evidence is still required to help define, diagnose and clinically manage this condition. This article will provide an updated review on histamine intolerance, mainly focusing on its etiology and the existing diagnostic and treatment strategies. In this work, a glance on histamine intoxication will also be provided, as well as the analysis of some uncertainties historically associated to histamine intoxication outbreaks that may be better explained by the existence of interindividual susceptibility to ingested histamine. Keywords: diamine oxidase (DAO); food intolerance; food supplement; histamine; histamine intolerance; histamine intoxication; histaminosis; low-histamine diet

In vitro determination of diamine oxidase activity in food matrices by an enzymatic assay coupled to UHPLC-FL.

Intestinal diamine oxidase (DAO) acts as a protective barrier against exogenous histamine. A deficit of DAO activity can lead to the appearance of histamine intolerance, a clinical condition that may be treated by a low-histamine diet and oral DAO supplementation to enhance intestinal histamine degradation. As sources of DAO, porcine kidneys and certain legume seedlings are suitable components for the formulation of a DAO supplement. The aim of this work was to develop a rapid and reliable methodology for the in vitro determination of DAO activity in food matrices based on an enzymatic assay coupled to UHPLC-FL. The proposed method showed a satisfactory linearity and sensitivity and provided a relative standard deviation lower than 3%, guaranteeing method precision, and a mean recovery greater than 99% both for lyophilized pea sprouts and porcine kidney protein extracts. A high specificity is a key attribute of this method due to the use of histamine as the reaction substrate and the direct quantification of its degradation. Moreover, the lack of interference of catalase and hydrogen peroxide is another advantage in comparison with previously published methods. Lyophilized pea sprouts showed the greatest histamine-degrading activity (0.40 ± 0.01 mU/mg), followed by porcine kidney protein extracts (0.23 ± 0.01 mU/mg) and commercial DAO supplements (0.09 ± 0.06 mU/mg). This technique could be used as a tool to validate the DAO activity of food matrices of potential interest for the treatment of histamine intolerance

Low-Histamine Diets: Is the Exclusion of Foods Justified by Their Histamine Content?

A low-histamine diet is currently the most advised strategy to prevent the symptomatology of histamine intolerance. Conceptually, these diets should be founded on the exclusion of histamine-containing foods, although a certain disparity is found within the list of excluded foods in accordance with the different low-histamine diets available in the literature. This study aimed to critically review low-histamine diets reported in the scientific literature, according to the histamine and other biogenic amine contents of the excluded foods. A total of ten scientific studies that provided specific recommendations on the foods that must be avoided within the framework of a low-histamine diet were found. Overall, the comparative review brought out the great heterogenicity in the type of foods that are advised against for histamine intolerant individuals. Excluded foods were, in most cases, different depending on the considered diet. Only fermented foods were unanimously excluded. The exclusion of 32% of foods could be explained by the occurrence of high contents of histamine. The presence of putrescine, which may interfere with histamine degradation by the DAO enzyme at the intestinal level, could partly explain the reason why certain foods (i.e., citrus fruits and bananas) were also frequently reported in low-histamine diets. Finally, there was a range of excluded foods with an absence or very low levels of biogenic amines. In this case, certain foods have been tagged as histamine-liberators, although the mechanism responsible has not yet been elucidated

Histamine and Other Biogenic Amines in Food. From Scombroid Poisoning to Histamine Intolerance

Histamine is a biogenic amine involved in important physiological activities in the organism, but its ingestion through food is associated with the onset of health disorders. Histamine intoxication, previously known as scombroid fish poisoning, is caused by the intake of foods with high levels of histamine. According to official European Union reports, more than 90% of the outbreaks registered in the last years were caused by the consumption of fish and seafood products. Histamine intolerance, on the other hand, arises when histamine degradation is impaired, mainly by a lower diamine oxidase (DAO) activity. Some of the uncertainties classically associated with histamine intoxication may be explained by this enzymatic deficit in a sensitive population. This chapter reviews the adverse effects of histamine from food within a risk analysis framework, focusing specifically on the components of risk assessment and management

Biogenic Amines in Plant-Origin Foods: Are they Frequently Underestimated in Low-Histamine Diets?

Abstract: Low-histamine diets are currently used to reduce symptoms of histamine intolerance, a disorder in histamine homeostasis that increases plasma levels, mainly due to reduced diamine-oxidase (DAO) activity. These diets exclude foods, many of them of plant origin, which patients associate with the onset of the symptomatology. This study aimed to review the existing data on histamine and other biogenic amine contents in nonfermented plant-origin foods, as well as on their origin and evolution during the storage or culinary process. The only plant-origin products with significant levels of histamine were eggplant, spinach, tomato, and avocado, each showing a great variability in content. Putrescine has been found in practically all plant-origin foods, probably due to its physiological origin. The high contents of putrescine in certain products could also be related to the triggering of the symptomatology by enzymatic competition with histamine. Additionally, high spermidine contents found in some foods should also be taken into account in these diets, because it can also be metabolized by DAO, albeit with a lower affinity. It is recommended to consume plant-origin foods that are boiled or are of maximum freshness to reduce biogenic amine intake

Intestinal dysbiosis in patients with histamine intolerance

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 histaminesecreting 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

Controlled trial of balance training using a video game console in community-dwelling older adults

gamification is a potentially attractive option for improving balance and reducing falls. to assess the effect of balance training using the NintendoTM Wii game console on balance (primary outcome), falls and fear of falling. quasi-randomised, open-label, controlled clinical trial in parallel groups, carried out on community-dwelling patients over 70 years, able to walk independently. Participants were assigned 1:1 to the intervention or control group. Balance training was conducted using the Nintendo WiiFit TM twice a week for 3 months. Balance was assessed using the Tinetti balance test (primary outcome), the unipedal stance and the Wii balance tests at baseline, 3 months and 1 year. Falls were recorded and Fear of falling was assessed by the Falls Efficacy Scale (Short-FES-I). 1,016 subjects were recruited (508 in both the intervention and the control group; of whom 274 and 356 respectively completed the 3-month assessment). There was no between-group difference in the Tinetti balance test score, with a baseline mean of 14.7 (SD 1.8) in both groups, and 15.2 (1.3) at 3 months in the intervention group compared to 15.3 (1.7) in controls; the between-group difference was 0.06 (95% CI 0.30-0.41). No differences were seen in any of the other balance tests, or in incident falls. There was a reduction in the fear of falling at 3 months, but no effect at 1 year. the study found no effect of balance training using the Nintendo TM Wii on balance or falls in older community-dwelling patients. The study protocol is available at clinicaltrials.gov under the code NCT02570178

Resistance to taxanes in triple negative breast cancer associates with the dynamics of a CD49f+ tumor initiating population

Taxanes are a mainstay of treatment for breast cancer, but resistance often develops followed by metastatic disease and mortality. Aiming to reveal the mechanisms underlying taxane resistance, we used breast cancer patient-derived orthoxenografts (PDX). Mimicking clinical behavior, triple-negative breast tumors (TNBCs) from PDX models were more sensitive to docetaxel than luminal tumors, but they progressively acquired resistance upon continuous drug administration. Mechanistically, we found that a CD49f+ chemoresistant population with tumor-initiating ability is present in sensitive tumors and expands during the acquisition of drug resistance. In the absence of the drug, the resistant CD49f+ population shrinks and taxane sensitivity is restored. We describe a transcriptional signature of resistance, predictive of recurrent disease after chemotherapy in TNBC. Together, these findings identify a CD49f+ population enriched in tumor-initiating ability and chemoresistance properties and evidence a drug holiday effect on the acquired resistance to docetaxel in triple-negative breast cancer

A phase 2 trial of neoadjuvant metformin in combination with trastuzumab and chemotherapy in women with early HER2-positive breast cancer: the METTEN study

The METTEN study assessed the efficacy, tolerability, and safety of adding metformin to neoadjuvant chemotherapy plus trastuzumab in early HER2-positive breast cancer (BC). Women with primary, non-metastatic HER2-positive BC were randomized (1:1) to receive metformin (850 mg twice-daily) for 24 weeks concurrently with 12 cycles of weekly paclitaxel plus trastuzumab, followed by four cycles of 3-weekly FE75C plus trastuzumab (arm A), or equivalent regimen without metformin (arm B), followed by surgery. Primary endpoint was the rate of pathological complete response (pCR) in the per-protocol efficacy population. pCR rate was numerically higher in the metformin-containing arm A (19 of 29 patients [65.5%, 95% CI: 47.3-80.1]) than in arm B (17 of 29 patients [58.6%, 95% CI: 40.7-74.5]; OR 1.34 [95% CI: 0.46-3.89], P = 0.589). The rate of breast-conserving surgery was 79.3% and 58.6% in arm A and B (P = 0.089), respectively. Blood metformin concentrations (6.2 μmol/L, 95% CI: 3.6-8.8) were within the therapeutic range. Seventy-six percent of patients completed the metformin-containing regimen; 13% of patients in arm A dropped out because of metformin-related gastrointestinal symptoms. The most common adverse events (AEs) of grade ≥3 were neutropenia in both arms and diarrhea in arm A. None of the serious AEs was deemed to be metformin-related. Addition of anti-diabetic doses of metformin to a complex neoadjuvant regimen was well tolerated and safe. Because the study was underpowered relative to its primary endpoint, the efficacy data should be interpreted with caution

Metformin induces a fasting- and antifolate-mimicking modification of systemic host metabolism in breast cancer patients

Certain dietary interventions might improve the therapeutic index of cancer treatments. An alternative to the "drug plus diet" approach is the pharmacological reproduction of the metabolic traits of such diets. Here we explored the impact of adding metformin to an established therapeutic regimen on the systemic host metabolism of cancer patients. A panel of 11 serum metabolites including markers of mitochondria! function and intermediates/products of folate-dependent one-carbon metabolism were measured in paired baseline and post-treatment sera obtained from HER2-positive breast cancer patients randomized to receive either metformin combined with neoadjuvant chemotherapy and trastuzumab or an equivalent regimen without metformin. Metabolite profiles revealed a significant increase of the ketone body beta-hydroxybutyrate and of the TCA intermediate alpha-ketoglutarate in the metformin-containing arm. A significant relationship was found between the follow-up levels of homocysteine and the ability of treatment arms to achieve a pathological complete response (pCR). In the metformin-containing arm, patients with significant elevations of homocysteine tended to have a higher probability of pCR. The addition of metformin to an established anticancer therapeutic regimen causes a fasting-mimicking modification of systemic host metabolism. Circulating homocysteine could be explored as a clinical pharmacodynamic biomarker linking the antifolate-like activity of metformin and biological tumor response