DAO… histamine… diet… and migraine: these four words have an intimate relationship. To know how the deficit of the digestive enzyme Diamine Oxidase (DAO) gives rise to symptoms such as migraine or gastrointestinal disorders, we must first understand the role played by histamine acquired by diet in our body.
The relevance of this relationship lies in the fact that 15% of the world population that suffers from migraines, 90% is associated with a deficiency of DAO.
If studies show that the deficiency in this biomarker causes migraines and the rest of associated disorders, we are talking about a population of one thousand million people who could benefit from new therapies, which would trigger a multi-million dollar business around this disease so misunderstood.
Discover the role of histamine in this process …
Histamine: essential for the body but instigator of migraines and other disorders
Histamine is a biogenic amine known to be involved in inflammation and allergic reactions, although it also plays a role in the secretion of gastric acids, tissue healing or regulation of immune function. It also acts as a neuromodulator of the central nervous system, modulating or regulating the responses to other neurotransmitters such as acetylcholine, opiates and GABA.
For this reason, histamine is a vital molecule for the body.
Histamine can be differentiated into two types, that of endogenous and exogenous origin.
The endogenous, produced by our organism, is located in connective tissue cells, mast cells and basophils and other tissues such as skin, lungs and intestines. On the other hand we find exogenous histamine, present in all foods in greater or lesser extent and that we incorporate by diet.
This is where the DAO enzyme comes into play, which is produced in the digestive tract. When the ingested histamine coming from the food reaches the intestine it undergoes an oxidative deamination of the primary amino group, catalyzed by the DAO enzyme, and results in imidazolacetaldehyde. Later this molecule is eliminated by the urine.
If we take into account, on the other hand, that the endogenous histamine is inactivated by the histamine-N-methyltransferase (NMT) after fulfilling its function, giving as product N-methylhistamine, we obtain a balanced system.
What happens when there is a deficiency of DAO?
It is known as histamine intolerance to the imbalance between the accumulation of histamine and the ability to degrade it due to a reduction in DAO activity.
When the activity of DAO is low, due to the presence of genetic mutations (discussed at the end of the article), intestinal pathological processes, alcohol intake or inhibition by commonly used drugs (among them: analgesics such as diazepam, antihistamines, antidepressants, antihypertensives, diuretics or antibiotics), ingested histamine accumulates in the intestinal mucosa.
When it can not be eliminated, the histamine enters the bloodstream and is distributed at different points in the body. Histamine is recognized by different receptors on the cell surface of tissues and organs, and when captured by its cells it triggers symptoms such as migraine, gastrointestinal and skin disorders and chronic fatigue. In addition, DAO deficit has been related to attention and hyperactivity disorder (ADHD) in childhood and adolescence.
However, the appearance of the symptoms is not immediate after having ingested foods rich in histamine or after its punctual consumption, but they appear later, from the sustained accumulation of that molecule in the blood.
On the other hand, for the detection of the lack of DAO, within the Spanish health system the analysis is already offered in many centers and hospitals to measure its functional activity, according to the amount of histamine that it can degrade in the sample. In this way, levels of DAO below 80 HDU / ml (Histamine Degrading Units), represent a reduced activity of the same, so it would be necessary to propose a change of eating habits or a therapeutic contribution of the enzyme.
How is the DAO deficit treated?
Although there are currently no drugs to treat the deficit of DAO, there are dietetic foods with medical uses, such as Migrasin from the biotechnological DR Healthcare, which supply the deficiency of the enzyme.
DR Healthcare is a Spanish biomedical company, based in Barcelona, specializing in biofunctionalism: a discipline in which enzymatic supplements and natural adjuvants are studied and developed, both of a non-pharmacological nature, to mitigate the effects of many pathologies.
The biomedical company dedicates its activity to research, development and innovation of new products aimed at preventing chronic pathologies, to alleviate pain and correct physiological and / or metabolic dysfunctions, mainly associated with the deficit of the enzyme DiAminoOxidasa (DAO).
Crystal Structure of Human Diamine Oxidase (DAO) from the AOC1 gene, rendered by James Lee in Pymol. Public Domain.In particular, the DAO enzyme used in the migrasin capsules comes from the extract of Pig Kidney Protein, which contains 7% Diaminooxidase (DAO). As adjuvants of the treatment against migraine include caffeine, vitamin B2, vitamin B6 and vitamin B12.
Taking a capsule 20 minutes before food intake increases the amount of DAO enzyme in the small intestine and, therefore, the ability to degrade histamine.
It is also advisable to follow a balanced diet and avoid eating foods with a high amount of histamine. In this group we find fermented foods or those that have been in contact with bacteria. This list is headed by alcoholic drinks (many wines have histamine and alcohol contributes to further decrease the activity of the DAO enzyme) and fermented products: such as sausages and dairy products. We can also find high-level vegetables such as spinach, eggplant, pumpkin, zucchini and tomato. Fruits are safe with the exception of bananas, strawberries, papaya and citrus fruits.
The food with more significant amounts of histamines is the flesh of the fish. Their histamine levels are a product of the bacterial decomposition that occurs after being captured. This is because the bacterial activity causes the degradation of the amino acid histidine present in the meat, which leads to the occurrence of high concentrations of histamine in this type of food.
A high intake in these conditions can cause a food poisoning called Scombroidosis.
Functional foods that contain the enzyme: an effective solution
DR Healthcare proposes another solution to the deficit of DAO: the incorporation of the enzyme into daily foods such as yoghurts, milk preparations or soy milk.
The DAO enzyme can be obtained biotechnologically or extracted from animals or plants. This is added to the preparations in free form, powder, lyophilized powder, microcapsules, nanocapsules or liposomes.
Among the research groups that have developed clinical studies on the relationship between DAO and migraines is the one led by Dr. Ramón Tormo, head of the Gastroenterology and Nutrition Unit of the Hospital Quirón of Barcelona, specifically about the digestive origin of the migraine -presented at the congress of the European Society of Pediatric Gastroenterology in Jerusalem, Israel, and the congress of the European Society for Paranteral and Enteral Nutrition, in Leipzig, Germany-, which reaffirms what neurologist Dr. Joan Izquierdo has already concluded from the General Hospital of Catalonia in a pioneering study whose results presented at the World Congress of Neurology held in Vienna in 2013, causing some stir by the novelty of this link in the etiology of migraines.
In a study conducted by the company DR Healthcare, the effects of functional food were compared in two groups of patients with DAO deficiency: a control group of 30 subjects, who were not given any dietary supplement containing DAO, and a group of 40 subjects supplied daily with functional food, which had a percentage of DAO comprised between 0.01 and 5% with respect to the total weight of the food. Both were subjected to a diet rich in histamine for 4 weeks.
Based on the results, it was observed that while the control group had a blood histamine concentration higher than 20 μg / 0.1L of blood, the concentration of histamine in the group supplied with functional food was between 2 and 20 μg / 0.1L of blood, a concentration considered normal.
In this way, both functional foods and tablets are presented as two options to improve the symptoms associated with DAO deficiency. And what about the use of probiotics?
The good results that probiotics have shown against multiple functional disorders of the digestive system – colics, diarrhea and gas, among others – may be due to intestinal bacteria being able to metabolize histamine, which would convert them into another catabolic pathway. histamine, another point that is also investigating our team.
Dr. Ramón Tormo, head of the Gastroenterology and Nutrition Unit of the Quirón Hospital of Barcelona, in an interview with La Vanguardia.
The genetics behind DAO Deficiency
The DAO enzyme is encoded by the human amiloride binding protein 1 gene (also known as ABP1, ABP or directly DAO1 or DAO), located on chromosome 7q36.1.
In this last decade, a high number of possible genetic and epigenetic backgrounds associated with DAO deficiency and migraine have been identified. Through studies that associate diseases with genetic variations (GWAS) polymorphisms were associated in two genes: in MTDH and PGCP, with the risk of suffering migraines, although later studies could not confirm it. In a similar example are the investigations of the Dutch-Icelandic migraine genetics consortium (DICE) and Dr. Lannie Ligthart, of the EMGO health and care research institute, which through the first GWAS meta-analysis focused on population migraine identified an SNP (rs9908234) in the NGFR gene. Unfortunately, they could not replicate this finding, as they point out in the same study. The reason behind replication failure is believed to be based on the use of different programs (MACH and IMPUTE) and the heterogeneity of samples used, which included simple headaches.
On the other hand we have the Spanish team headed by Dr. Elena García Martín, professor and researcher of the Department of Bioengineering at the Carlos III University of Madrid, CIEMAT-CIBER. Through the study of 197 patients diagnosed with migraine and 245 healthy controls, they first identified 4 SNPs associated with this disease: Thr16Met (rs10156191), Ser332Phe (rs1049742), and His645Asp (rs1049793), which are located in the DAO gene and in the promoter. of the rs2052129 gene (G4586T).
The team of Dr. Elena García observed that the SNPs rs10156191 and rs2052129 alter the activity of the DAO enzyme in vivo, reducing its ability to degrade histamine in circulation. It was also seen that SNP rs10156191 was more frequent in women than in men. Although the results seem promising, the authors themselves acknowledge that they are unaware of the clinical impact of these SNPs and that further studies are necessary.
This study was carried out in 2015 so we hope that soon updates shed some light on the subject.
We leave you with the talk of INFARMA (European pharmacy congress) in which Adriana Duelo, dietitian-nutritionist and migraine specialist produced by DAO deficiency, together with Dr. Ismael San Mauro, director of Grupo CINUSA, company dedicated to nutrition and research in this area, deepen the topic this time emphasizing the dietary approach.
Adriana herself told us that “although there is still a long way to go, both on a scientific and clinical level we are on the right track.”
We will continue to report new developments in this intricate relationship that combines the fields of biotechnology, nutrigenomics, enzymology, metabolomics and even epigenetics.
Women have a predisposition 3 times higher than men to suffer from DAO deficit, but pregnant women present the opposite case: they have levels of DAO in blood between 500 and 1000 times higher than normal since the DAO is produced additionally in the placenta . This increase in DAO levels suggests an additional defense mechanism for the fetus against the adverse effects of histamine.