Histamine Intolerance

Histamine Foods

The major exogenous source of histamine is from food, and the concentration of histamine in various foods is highly variable. The main pathway for histamine formation in substances is the decarboxylation of histidine in the presence of an L-histidine decarboxylase (HDC). In addition to histamine, foods may contain other biogenic amines, mainly tyramine, putrescine and cadaverine, which are formed by enzymatic deamination of amino acids such as tyrosine, ornithine and lysine, respectively. These decarboxylation reactions are thought to be a survival strategy for microorganisms in acidic environments and an alternative source of metabolic energy in the presence of inadequate substrate supply.

Foods that may be high in histamine contain microbiologically altered foods, such as fish and meat, or derived products that have been cured or processed under inadequate sanitary conditions, or fermented products, where the bacteria responsible for the fermentation process may also have amine-causing ability.

Table 1. Histamine content in different food categories

(Source: Comas-Basté O, et al. 2020)

Histamine Function

Inflammation is commonly thought to be mediated by activation of histamine receptor 1 (H1R), however the use of selective H4R ligands or modulation of the synergistic action of H1 and H4 receptors has been found to be potentially more effective in the treatment of disorders such as chronic itch, asthma and allergic rhinitis for these pathophysiological conditions. Histamine exhibits two sides of the coin, promoting both inflammatory and regulatory responses that contribute to pathological processes and homeostatic functions in the body.

As an inflammatory mediator, histamine is commonly associated with allergic reactions, promotes vascular and tissue changes, and has strong chemotactic activity. Histamine aids in the migration of eosinophils from the bloodstream to the site of inflammation, and it induces an increase in the expression of macrophage-1 antigen (Mac1) and ICAM-1 adhesion molecules by binding to the H4R of eosinophils, in addition to promoting the rearrangement of actin filaments. In mast cells, histamine binding to the same receptor promotes intracellular calcium release and mast cell recruitment to tissues. These cells that accumulate to the site of inflammation amplify the inflammatory response mediated by histamine and may favor the establishment of a chronic inflammatory response. In addition, histamine modulates the inflammatory response by acting on other cell populations.

In the nervous system, histamine regulates the activation of microglia, leading to the production of pro-inflammatory cytokines such as IL-6 and TNF-α. Histamine promotes loss of mitochondrial membrane potential and ROS production in microglia. In summary, the accumulation of these cytokines and pro-inflammatory molecules may lead to nerve damage. When histamine is present, dendritic cells (DCs) secrete more IL-6, IL-8, and CCL2 and induce IL-1β, CCL5, and CCL4. However, the H2R pathway promotes IL-10 production and inhibits IL-12 synthesis in immature DCs, thereby favoring the Th2 response profile. This modulation of cytokine production suggests that histamine indirectly alters the Th1/Th2 balance by stimulating DCs. In a food allergy model, when animals are exposed to allergens, the development of intestinal inflammation and diarrhea can be suppressed by inhibiting histamine-mediated antigen presentation and chemotaxis of DCs, while blocking H1R and H4R.

In addition to its classical role in inflammatory processes, histamine is recognized as a key player in immune regulation. For example, although histamine is usually associated with inflammatory processes in the skin, it may also play a regulatory role in other clinical diseases. HER agonists in a mouse model of psoriasis improved clinical scores in psoriasis mice by inhibiting Th1 cytokines and simultaneously inducing Treg cells. These findings suggest that histamine targeting has pharmacologic potential.

Histamine is involved in maintaining homeostasis in the gut. The researchers found that in a chemically induced carcinogenesis model, mice with HDC knocked out were more susceptible to inflammation and had a higher tumor load at mucosal sites, but administration of histamine treatment attenuated this phenotype. The expression levels of HDC and H2R were positively correlated with increased survival in colorectal cancer patients. In addition to tumor biology, histamine has a regulatory function in intestinal inflammatory diseases, and researchers have demonstrated that histamine protects animals from increased responses to colonic inflammation.

Gut microbes provide the host with many metabolites such as short-chain fatty acids, tryptophan metabolites, and histamine. L. reuteri-derived histamine can act via H2R on the human monocyte cell line THP-1 to promote activation of the cAMP/PKA cascade and blockade of ERK signaling, thereby modulating its inflammatory response. Histamine production by Lactobacillus rhamnosus promotes regulatory responses of Foxp3-T cells in intestinal Peyer plaques while inhibiting Th1 polarization in an H2R-dependent manner.

Although histamine is associated with deleterious inflammation in asthmatics, its contribution to lung homeostasis has also been reported. The effect of this action depends on the receptor and cell type involved, e.g., H1R antagonists are beneficial for asthma treatment. However, H2R deficiency or pharmacological blockade exacerbates lung inflammation in OVA-sensitized mice. This is due to increased activation of iNKT cells, which promotes macrophage and neutrophil recruitment as well as T-cell production of IL-4, IL-17, and IFN-γ.

Figure 3. Inflammatory and regulatory functions of histamine on different body sites
(Source: Branco ACCC, et al. 2018)