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Histamine is an imidazole characterized by the presence of a two-nitrogen atom ring called a diazole. The monoamine is synthesized from histidine by histidine decarboxylase, an enzyme that decarboxylates the amino acid at the carboxyl terminus1. Histamine release plays an important role in the immune response to allergens including pet dander, mold, or food particles, which can lead to symptoms such as a runny nose and watery eyes.
A subset of the body’s immune system cells, mast cells, and basophils produce most of the body’s histamine2. These cells release histamine after IgE binds to Fc receptors in response to an allergen3. When histamine is released, it can bind to receptors on dendritic cells, another group of white blood cells that help activate the immune system. This can lead to a cascade of events mediated in part by cytokine production that results in an allergic reaction and can lead to allergic conditions.
The central nervous system also produces histamine, primarily from the tuberomammillary nucleus. From there, C-sensitive nerve fibers on human skin enable the body to respond to burning pain and itch4. Members of the gut microbiome can also produce histamine with their array of histidine decarboxylases5. Regardless of the source, histamine binds to four different kinds of histamine receptors in cells, all of which are G protein-coupled receptors: H1R, H2R, H3R, and H4R6.
Histamine and allergic diseases
While histamine helps maintain normal bodily functions, overproduction of histamine is related to many immune and inflammatory disorders. Allergic inflammation of the skin can occur when histamine binds to histamine receptors such as H2R, causing allergy symptoms such as itchy skin welts that are characteristic of urticaria7. Histamine also binds to H4R on immune cells in the skin, suggesting a role for histamine in atopic dermatitis8.
Histamine also contributes to aberrant immune responses in other parts of the body, leading to inflammatory diseases. In mouse models, histamine has been shown to activate Th2-expressing cells and macrophages together, inducing allergic rhinitis9. Researchers have also been working on new therapeutic targets for allergic asthma based on H1R antagonism10. Bronchial smooth muscle cells express all four histamine receptors, with H1R as the primary site of histamine activity. Such binding activity drives allergic reactions in the lung, producing symptoms such as coughing from smooth muscle contractions.
Histamine and neurodegenerative diseases
As a neurotransmitter, histamine plays an important role in normal nervous system function. In the central nervous system, the molecule operates through histaminergic neurons networked across the brain11. As a result, histamine regulates the sleep-wake cycle, learning and memory, feeding, and energy levels12. Its activity in the central nervous system also helps ensure normal cognitive function. This is accomplished from the tuberomammillary nucleus, which also harbors histamine receptors and acts as a neural center for processing information13.
Histamine imbalances have been associated with neurodegenerative diseases. Reduced histamine levels are associated with sleepiness due to disrupted sleep-wake cycles14. Conversely, overactivation of the H1R and H4R receptors can induce microglial phagocytosis, a characteristic of neuroinflammation in Parkinson’s Disease15. Histamine overactivity and hypersensitivity have also been associated with hallucinations and other symptoms in schizophrenia16.
Histamine and gastrointestinal diseases
Increased histamine production has been associated with different gastrointestinal diseases. Enrichment of gut microbes that produce histamine has been observed among patients with inflammatory bowel disease (IBD)5. Histamine production by the gut microbiome has also been associated with abdominal pain in mouse models of irritable bowel syndrome (IBS)17.
In the stomach, histamine mediates gastric acid secretion. However, excess gastric acid secretion is a major cause of gastroesophageal reflux disease (GERD)18. Histamine contributes to GERD by binding to H2R receptors produced by gastric parietal cells, inducing gastric acid secretion19. As a GERD treatment strategy, clinicians use H2 receptor antagonists to prevent histamine binding to H2R and reduce gastric acid levels in the stomach.
Histamine overabundance is also associated with histamine intolerance. Histamine intolerance occurs when people eat foods rich in histamine. This produces symptoms such as diarrhea, nausea, and high blood pressure. In the small intestine, histamine intolerance arises from reduced expression of diamine oxidase (DAO)20. DAO in the small intestinal mucosa helps regulate histamine levels in the small intestine. When not enough DAO is produced, excess histamine levels occur, driving a wide range of digestive issues such as abdominal pain, bloating, flatulence, nausea, and diarrhea.
Histamine in research
As of July 2023, there are over 15,000 citations for “histamine” in research publications (*excluding books and documents) on PubMed. The extensive number of publications linking histamine to gut disorders and, more recently, the gut microbiome, suggests that any studies aiming to better understand how the microbiome influences health and disease may benefit from histamine quantification. Histamine’s key roles in allergic responses and in neurodegenerative diseases also suggest that any research program focused on these areas may benefit from quantitative analysis of histamine.
- Huang H, Li Y, Liang J et al. Molecular Regulation of Histamine Synthesis. Front Immunol 2018;9:1392. doi: 10.3389/fimmu.2018.01392
- Borriello F, Iannone R, and Marone G. Histamine Release from Mast Cells and Basophils. Handb Exp Pharmacol. 2017;241:121–139. doi:10.1007/164_2017_18
- Stone KD, Prussin C, and Metcalfe DD. IgE, Mast Cells, Basophils, and Eosinophils. J Allergy Clin Immunol 2010;125(2 Suppl 2):S73–S80. doi:10.1016/j.jaci.2009.11.017
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- Mou Z, Yang Y, Hall AB et al. The taxonomic distribution of histamine-secreting bacteria in the human gut microbiome. BMC Genomics. 2021;22(1):695. doi:10.1186/s12864-021-08004-3
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- Borro M, Negrini S, Long A et al. H2-antagonist in IgE-mediated type I hypersensitivity reactions: what literature says so far? Clin Mol Allergy 2021;19(1):4. doi:10.1186/s12948-021-00143-y
- Schaper‐Gerhardt K, Rossbach K, Nikolouli E et al. The role of the histamine H4 receptor in atopic dermatitis and psoriasis. Br J Pharmacol 2020;177(3):490–502. doi:10.1111/bph.14550
- Naclerio R. Clinical manifestations of the release of histamine and other inflammatory mediators. J Allergy ClinImmunol 1999;103(3 Pt 2):S382–S385. doi:10.1016/S0091-6749(99)70216-2
- Yamauchi K and Ogasawara M. The Role of Histamine in the Pathophysiology of Asthma and the Clinical Efficacy of Antihistamines in Asthma Therapy. Int J Mol Sci 2019;20(7):1733. doi:10.3390/ijms20071733
- Haas HL, Sergeeva OA, and Selbach O. Histamine in the Nervous System. Physiol Rev 2008;88(3):1183–1241. doi:10.1152/physrev.00043.2007
- Hu W and Chen Z. The roles of histamine and its receptor ligands in central nervous system disorders: An update. Pharmacol Ther 2017;175:116–132. doi:10.1016/j.pharmthera.2017.02.039
- Alvarez EO. The role of histamine on cognition. Behav Brain Res 2009;199(2):183–189. doi:10.1016/j.bbr.2008.12.010
- Scammell TE, Jackson AC, Franks NP et al. Histamine: neural circuits and new medications. Sleep 2018;42(1):zsy183. doi:10.1093/sleep/zsy183
- Rocha SM, Saraiva T, Cristóvão AC, et al. Histamine induces microglia activation and dopaminergic neuronal toxicity via H1 receptor activation. J Neuroinflammation 2016;13(1):137. doi:10.1186/s12974-016-0600-0
- Howes OD, Williams M, Ibrahim K, et al. Midbrain dopamine function in schizophrenia and depression: a post-mortem and positron emission tomographic imaging study. Brain 2013;136(Pt 11):3242-3251. doi:10.1093/brain/awt264
- De Palma G, Shimbori C, Reed DE, et al. Histamine production by the gut microbiota induces visceral hyperalgesia through histamine 4 receptor signaling in mice. Sci Transl Med 2022;14(655):eabj1895. doi:10.1126/scitranslmed.abj1895
- Alnouri G, Cha N, and Sataloff RT. Histamine Sensitivity: An Uncommon Recognized Cause of Living Laryngopharyngeal Reflux Symptoms and Signs—A Case Report. Ear Nose Throat J 2022;101(4):NP155-NP157. doi:10.1177/0145561320951071
- Nugent CC, Falkson SR, and Terrell JM. H2 Blockers. In: StatPearls. StatPearls Publishing; 2023. http://www.ncbi.nlm.nih.gov/books/NBK525994/ ; Accessed July 11, 2023.
- Schnedl WJ and Enko D. Histamine Intolerance Originates in the Gut. Nutrients 2021;13(4):1262. doi:10.3390/nu13041262