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Histamine, Stool

The detection of an elevated histamine concentration in the stool of a patient is used as a diagnostic aid about the necessity to prescribe appropriate dietetic interventions, such as the intake of probiotics or the recommendation of a low-histamine diet.

Stool histamine plays an important role in conditions such as food allergies, irritable bowel syndrome, and Crohn's disease, among others.

Histamine is a biological amine, transmitter, and tissue hormone important for essential physiological functions such as cell proliferation and differentiation, hematopoiesis, and regeneration. It influences a number of immune responses associated with allergies and inflammation. In irritable bowel syndrome (IBS) high histamine levels lead to Increased gastrointestinal motility, increased mucosal permeability, and more gastrointestinal hypersensitivity, which may be associated with the pathogenesis of IBS. Diets, that reduce histamine levels, decrease histamine synthesis, or increase histamine degradation have been shown to improve symptoms in IBS patients. Histamine is synthesized endogenously, e.g., by mast cells and basophils. In addition, resident gut microbial species have been identified as histamine-producing sources, that are unfavorable to IBS. On the other hand, probiotics that do not produce histamine are beneficial for the treatment of IBS.

Histamine which is produced endogenously and by the microbiota is an important player in gut health and affects gastrointestinal motility, mucosal permeability, and gastrointestinal hypersensitivity.

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Histamine [2-(4-imidazolyl)-ethylamine] is a short-acting endogenous amine, which is widely distributed throughout the body. Histamine is synthesized by the enzyme histidine decarboxylase (HDC), which decarboxylates the semi-essential amino acid l-histidine. Histamine was isolated from many different tissues, and thus, its name was based on the Greek word ‘histos’, which means tissue. Studies have revealed the multiple effects of histamine on allergic, peptic, and neurologic functions, while more recent studies demonstrate the influence of histamine on wound healing, circulatory disease, immunology, oncology, and infectious disease.

Histamine can be produced by a wide variety of different cell types. Mast cells, basophils, gastric enterochromaffin-like cells, and histaminergic neurons are the best described cellular sources of histamine, but other cell types, for example, platelets, dendritic cells (DCs), and T cells can also express HDC following stimulation. In addition, certain microbes can express HDC. HDC expression and histamine release are influenced by cytokines including IL-1, IL-3, IL-12, IL-18, GM-CSF, M-CSF, and TNF-α. Mast cells and basophils store large quantities of histamine, which is released upon degranulation in response to immunological and nonimmunological stimuli. However, other cell types such as DCs and lymphocytes do not store histamine intracellularly but secrete it following synthesis.

An important aspect of histamine biology is the enzymes that degrade histamine. Histamine can be metabolized by oxidative deamination (diamine oxidase – DAO) or by ring methylation (histamine-N-methyltransferase – HNMT). Diamine oxidase is stored in plasma membrane-associated vesicular structures in epithelial cells and is secreted into the circulation following stimulation. Histamine-N-methyltransferase is a cytosolic enzyme, which can convert histamine only in the intracellular space of cells. In mammals, DAO expression is restricted to specific tissues; the highest activities are in the small bowel, colon, placenta, and kidney. Histamine-N-methyltransferase is widely expressed in human tissues.

The role of histamine in inflammatory disorders of the gut

Histamine intolerance

Histamine intolerance is thought to result from an incorrect balance between accumulated histamine and the capacity for histamine degradation. The increased availability of histamine may be caused by endogenous histamine overproduction (e.g., allergies or mastocytosis) or increased exogenous ingestion of histidine or histamine (in food, alcohol, or from bacteria), but the main cause is currently thought to be due to impaired enzymatic degradation of histamine, possibly due to genetic or acquired impairment of the enzymatic functions of DAO or HNMT. Diamine oxidase is the primary enzyme required for the degradation of ingested histamine. Histamine intolerance is associated with a range of symptoms that mimic an allergic reaction, such as diarrhea, headache, rhino-conjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, and flushing. Some estimates suggest that approximately 1% of the population is histamine intolerant, and 80% of those patients are middle-aged.

Scombroid poisoning

Scombroid poisoning (the term ‘scombroid’ is derived from the type of fish Scombridae, which were first implicated), or histamine fish poisoning, is a type of food poisoning with symptoms and treatment similar to those associated with seafood allergies. Scombroid poisoning results from the consumption of mishandled fish. Histamine and other decomposition products are generated in fish tissues by bacterial conversion of free histidine. Scombrid fish have high levels of free histidine in their muscle tissues, compared to non-scombroid species, which have lower levels. However, non-scombroid fish species have also been implicated in scombroid poisoning. 

The symptoms of scombroid poisoning are variable and can include a peppery or metallic taste, oral numbness, headache, dizziness, palpitations, rapid and weak pulse, low blood pressure, difficulty in swallowing, thirst, hives, rash, flushing, and facial swelling. Sometimes nausea, vomiting, and diarrhea are also observed. The symptoms of scombroid poisoning typically are rapid in onset following the consumption of fish and recovery is usually complete within 24 h, but in rare cases can last for days. 

Food allergy

The gut immune system is exposed daily to a large number and variety of foreign proteins, and the ability to avoid allergic reactions to food is significantly influenced by the way these potential allergens are transported, presented, and responded to. The influence of histamine on altering the gut immune response to food antigens has not been definitively examined; however, given the immunoregulatory functions of histamine, it is tempting to speculate that histamine and its receptors could be involved either directly or indirectly in food antigen tolerance and sensitization mechanisms. In addition to eliciting the major symptoms of IgE-mediated food allergy, the ingestion of histamine-rich food, alcohol, or drugs that release histamine or block DAO may induce diarrhea, hypotension, arrhythmia, bronchial constriction, rhinoconjunctivitis, urticaria, or headache, which can confuse the diagnosis of food allergy.

In food-allergic subjects, enhanced secretion of histamine and increased numbers of mast cells in the intestines have been demonstrated

Irritable bowel syndrome

Irritable bowel syndrome is a chronic condition that affects 10–20% of the population. Patients experience recurrent abdominal discomfort or pain, in combination with altered bowel habits. The etiology and the pathophysiology are only partly understood, with some evidence suggesting that disrupted mucosal immune responses play a role. In addition, the composition of the gastrointestinal microbiota is altered and the administration of specific microbes has therapeutic effects. Frequently patients with IBS experience postprandial worsening of their symptoms, and patients typically avoid certain foods to reduce symptoms. Thus, the majority of patients with IBS feel that specific foods are important triggers of their symptoms. In a recent study, 58% of the patients with IBS studied experienced gastrointestinal symptoms from histamine-releasing food items and foods rich in biogenic amines. Interesting, the use of spherical carbon absorbent (which adsorbs molecules such as histamine from the gut lumen) has been beneficial for some patients.

Endogenous histamine has been implicated as an important mediator associated with symptom severity in IBS. Activated mast cells, which were spontaneously secreting higher amounts of histamine, in proximity to colonic nerves were correlated with abdominal pain in patients with IBS. 

Inflammatory bowel diseases

Crohn's disease (CD) and ulcerative colitis (UC) are the two major forms of IBD, and both diseases are associated with high morbidity and healthcare costs. The two disorders have distinct features. Ulcerative colitis is characterized by inflammation with superficial ulcerations limited to the mucosa of the colon. Inflammation usually starts in the rectum and continuously spreads throughout the colon. Crohn's disease, however, is characterized by a discontinuous pattern, potentially affecting the entire gastrointestinal tract. In contrast to ulcerative colitis, inflammation in patients with CD is transmural with large ulcerations, and occasionally, granulomas are observed. The precise mechanisms causing these diseases remain unknown but complex interactions between the immune system, enteric microbiota, and host genotype underlie the development of IBD. Some studies have demonstrated that components of the intestinal microbiota can drive protective or pathological responses in IBD models, highlighting the importance of host-microbe communication in the development of these diseases.

The importance of mast cells has been well documented in patients with IBD. The rate of histamine secretion from the jejunum was increased in patients with CD compared with normal controls, and the secretion of histamine was related to disease activity, indicating that degranulation of mast cells may be important in active CD.

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