Histamine

Endogenous synthesis of histamine in the gastrointestinal tract

As noted earlier, histamine not only enters our bodies from food or is formed from histidine by bacteria, it is also synthesized by cells in the gastrointestinal tract. The APUD system (Amine Precursor Uptake and Decarboxylation) is a group of cells (G cells, enterochromaffin-like cells (ECL) and others) that are distributed throughout the body, especially in the GI tract, lungs, pancreas and other tissues. These cells are capable of synthesizing and secreting substances such as hormones, neuropeptides, biogenic amines (histamine, gastrin, serotonin), etc.

The role of enterochromaffin-like cells

Enterochromaffin-like cells (ECL cells) are located in the gastric mucosa and are the main sources of histamine in the gastrointestinal tract. They synthesize histamine under the influence of the following stimuli:

• Gastrin: a hormone produced by G cells in the stomach and duodenum. Gastrin activates ECL cells via the gastrin receptor SSC-B and stimulates them to release histamine.

• Acetylcholine: a neurotransmitter of the parasympathetic nervous system that also stimulates ECL cells.

The histamine produced acts on the parietal (lining) cells of the stomach via H2-histamine receptors, stimulating the secretion of hydrochloric acid (HCl). This is an important mechanism to ensure the acidity of gastric juice and hence efficient digestion.

G cells and gastrin

G cells are APUD-system cells located in the antral (lower) portion of the stomach connecting it to the duodenum. They produce gastrin in response to:

• The presence of food in the stomach, especially proteins.

• Stretching of the stomach walls.

• Nervous stimuli associated with food intake.

Gastrin has several functions:

• Stimulates ECL cells to produce histamine.

• Directly stimulates parietal cells to secrete hydrochloric acid.

• Promotes the growth of gastric mucosa and maintenance of its structure.

Thus there is a close interaction between G-cells, ECL-cells and parietal cells that regulates gastric juice secretion and maintains optimal conditions for digestion.

Histamine formation in the intestine

Histamine in the intestine can be formed not only from food sources, but also by microbiota, especially bacteria, which can synthesize histamine from the amino acid L-histidine. In inflammatory processes in the gastrointestinal tract, histamine levels increase.

Histidine decarboxylase (HDC), an enzyme that catalyzes the conversion of histidine to histamine, can be expressed both by cells of the immune system (e.g., dendritic cells and T lymphocytes) and by members of the gut microbiota. This confirms the key role of the microbiota in the regulation of the immune response through histamine production.

High concentrations of histamine are most often found in microbial fermentation products, where its synthesis depends on the presence of free histidine, HDC activity, and other favorable conditions. In the gut, genes encoding HDC are found in a wide range of bacteria, including Gram-positive and Gram-negative bacteria. For example, in members of the genera Lactobacillus, Pediococcus, and Oenococcus, HDC expression is stimulated by the presence of histidine, while histamine inhibits this process. Gram-negative bacteria require the coenzyme pyridoxal phosphate for HDC activity, whereas Gram-positive enzymes use covalently bound pyruvate as a cofactor.

Environmental factors such as carbohydrate availability, oxygen and chloride concentrations, and the acidity of the medium significantly affect decarboxylase secretion by bacteria. In an acidic environment, amino acid decarboxylase is activated, which contributes to a localized increase in pH around the bacteria, providing protection to the microorganisms and maintaining their metabolic activity. High concentrations of HDC are observed in the bacteria Morganella morganii, Escherichia coli, Proteus vulgaris, Enterobacter aerogenes and others. Some bacteria are able not only to synthesize histamine but also to metabolize it. For example, Pseudomonas putida processes histamine in several steps to form asparagic and fumaric acids, which requires the participation of 11 specialized proteins. These processes are unique to the genus Pseudomonas and are absent in Gram-positive bacteria.

An imbalance of the gut microbiota (dysbiosis) may increase the content of histamine-secreting bacteria such as Staphylococcus, Proteus, Clostridium perfringens, which is associated with histamine accumulation, its absorption into plasma and systemic effects. In people with histamine intolerance there is a decrease in the proportion of beneficial bacteria (Faecalibacterium prausnitzii, Ruminococcus) and an increase in the number of histamine-secreting microorganisms, which confirms the link between dysbiosis and intestinal pathology.

Consequences of increased histamine formation in the gut:

• Increased peristalsis, which can lead to diarrhea.

• Inflammatory processes in the intestine, contributing to the development of irritable bowel syndrome and other gastroenterological diseases.

• Systemic inflammatory reactions as a consequence of increased intestinal.

• Allergic reactions and food intolerances.

• Microbiota imbalance.

Biological activity of histamine

For most of us, histamine is primarily associated with allergic reactions. However, its negative effects on our well-being are much more extensive. Histamine can cause not only yesterday's itching, but also today's migraine, swelling, and can also provoke a sudden stomach upset. For some people, this biogenic amine is a serious health threat. Normally, histamine is always present in the body and participates in regulatory processes. And its intolerance occurs when the balance between consumption and destruction is disturbed.

Despite its low molecular mass compared to other biological molecules (only 17 atoms), histamine plays an important role in the body. Histamine is known to be involved in more than 23 different physiological functions due to its flexible chemical binding structure. This flexibility allows the histamine molecule to easily change its shape or configuration and thereby effectively bind to different types of receptors, adapting to their structures. Histamine receptors are distributed throughout the body and perform many important functions, from regulating vascular tone to controlling immune responses.

The main functions of histamine in the body:

• Stimulation of gastric juice production: acts on H2-receptors of gastric parietal cells, stimulating the secretion of hydrochloric acid necessary for digestion.

• Stimulation of intestinal peristalsis: increases the contraction of the intestinal smooth muscle, promoting the efficient movement of the food clump along the gastrointestinal tract.

• Involvement in allergic reactions: It plays a key role in the development of immediate (IgE-mediated) allergic reactions. Upon contact with an allergen, mast cells release histamine, resulting in allergy symptoms such as itching, swelling and urticaria, a skin reaction resembling a nettle burn.

• Immunomodulatory effect: participates in the immune response to pathogens, regulating the activity of various immune cells and contributing to the body's defense against infections.

• Vasodilation and regulation of vascular tone: causes blood vessels to dilate (vasodilation) by binding to H1 receptors on the vessel walls, which in turn increases blood flow in the area of histamine release, improving the supply of oxygen and nutrients to the tissues. This is especially important in inflammation or allergic reactions when the body needs to quickly deliver immune cells to the affected tissue.

• Blood pressure regulation: able to reduce blood pressure by affecting vascular tone.

• Regulation of body temperature: involved in thermoregulatory processes, contributing to the maintenance of a constant body temperature through the same vasodilation, sweating and activation of the hypothalamus, which controls body temperature.

• Circadian rhythm regulation: influences sleep and wake cycles by participating in the regulation of the body's circadian rhythms as a neurotransmitter. Histamine concentrations are highest in the morning and afternoon hours and decrease in the evening. In addition, histamine interacts with the hypothalamus, where the "biological" clock is located.

• Stimulation of the local inflammatory response: when injured or exposed to allergens, histamine promotes local inflammation manifested by swelling, redness and pain. This is a defense mechanism that prevents the spread of infection and promotes tissue healing.

• Initiation of inflammatory processes: attracts immune cells to the site of injury and increases capillary permeability, promoting the escape of plasma from cells into tissues.

• Neurotransmitter function: acts as a neurotransmitter in the central nervous system, participating in the regulation of wakefulness, attention, and other cognitive functions.

An example of the effects on the nervous system:

Drowsiness may occur when taking first-generation antihistamines that penetrate the blood-brain barrier and block H1 receptors in the brain. This is due to suppression of histaminergic activity, which is responsible for maintaining wakefulness.

The involvement of histamine in physiological processes such as digestion, immune response, regulation of vascular tone and central nervous system function emphasizes its importance in maintaining homeostasis.

Understanding the biological activity of histamine and its interaction with various receptors allows for more effective diagnosis and treatment of conditions associated with its imbalance, including allergic reactions and some neurological disorders.