Histamine intolerance is a hot topic at the moment within the wholistic and functional medicine field. Research is still emerging, however with the current research at hand, we are starting to get a solid understanding of the exact mechanisms behind this interesting food intolerance, which is often misdiagnosed and underestimated due to its multifaceted symptom presentation.
Research is starting to show that a disrupted gut microbiome may be the main driver behind histamine intolerance, which is no surprise due to what we already know about the role of the gut flora in food allergies and intolerances. This once again highlights the significant connection between the gut microbiome and our health.
What is histamine intolerance?
Histamine intolerance results from a disequilibrium of accumulated histamine and the capacity for histamine degradation. Approximately 1% of the population has histamine intolerance and 80% of those patients are middle-aged.
Histamine is a biogenic amine that is endogenously produced by mast cells and basophils as part of inflammatory immune responses. Recent evidence also suggests that certain gut bacteria can convert histidine in food to histamine via histamine decarboxylase (HDC) enzyme production. Numerous bacterias in food have been shown to display high HDC activity and thus have the capacity to form histamine.
High concentrations of histamine can be found in food products of microbial fermentation such as aged cheese, sauerkraut, wine, beer and processed meat, as well as microbially-spoiled food (i.e. fish and seafood left uncooked). Histamines are also found in various fruits and vegetables. Lastly, in addition to histamine-rich food, many foods such as citrus are considered to have the capacity to release histamine directly from tissue mast cells.
Diamine oxidase (DAO) is the main enzyme required for the metabolism of ingested histamine. In healthy people, dietary histamine can be rapidly detoxified by DAO, whereas those with low DAO activity are at risk of histamine accumulation, which over time (not always immediately) may result in numerous symptoms mimicking an allergic reaction.
Histamine receptors are located in multiple areas of the body such as the gut, skin, epithelium, blood vessels, nervous system and bronchioles. This is why histamine intolerance can manifest in such a wide variety of symptoms, affecting many body systems. This is also why it is difficult to diagnose because clinical symptoms and their provocation by certain foods and beverages appear similar in other diseases, such as food allergy and intolerance of sulfites or other biogenic amines (e.g. tyramine).
Research has shown that reducing histamine-rich foods in the diet dramatically reduces symptoms.[1,2] However, as functional medicine practitioners, we are always concerned about treating the underlying cause(s) of health issues. While symptomatic treatment is necessary, it is imperative to address the causes in order to achieve long-term health. This is especially true for histamine intolerance because foods high in histamine tend to be nutrient dense foods such as fish, seafood, various fermented foods and some varieties of fruits and vegetables. Therefore removing them from the diet permanently may not be ideal for long-term health. This means that as practitioners, one potential question we need to ask is, why are DAO enzymes not being produced in sufficient amounts? Looking to the gut might give us some answers.
The gut microbiome and histamine intolerance
The fact that histamine intolerance is a food intolerance, it should come as no surprise that the gut microbiome has a large role to play in its pathogenesis.
DAO enzymes are synthesised and stored within the epithelium of the small intestine and colon. Upon histamine ingestion, the enzymes work to metabolise histamine and therefore reduce the amount absorbed into the blood stream. Decreased DAO production leads to increased histamine absorption, resulting in histamine accumulation.
A potential genetic background of reduced histamine metabolism has been investigated. Various single nucleotide polymorphisms (SNPs) in the DAO gene have been shown to be associated with inflammatory and neoplastic gastrointestinal diseases, such as food allergy, gluten-sensitive enteropathy, Crohn’s disease, ulcerative colitis and colon adenoma. Thus, histamine intolerance seems to be acquired mostly through the impairment of DAO activity caused by gastrointestinal diseases (GIDs).
These GIDs are characterised by high amounts of inflammation in the gut wall, which causes damage to the epithelial cells of the mucosa that produce and store DAO, suggesting that there could be dysregulated metabolism of histamine with an inflamed gut.[1,3]
The association of SNPs in the DAO gene with GIDs provides evidence for a genetic predisposition in a subgroup of patients with histamine intolerance.[1,3] This is also why individuals with inflammatory bowel disease (IBD) have been shown to have increased levels of histamine as well as increased mast cell numbers in their gut.
While not everyone with histamine intolerance has GIDs, these findings may allow us to make theoretical conclusions about the role of the gut bacteria in DAO production and therefore its role in histamine intolerance.
It is well established in the scientific literature that there is a strong correlation between the diseases listed above and an altered gut microbiome, i.e. small intestine bacterial overgrowth (SIBO) and dysbiosis.[4-7]
It is also known that both SIBO and dysbiosis can cause considerable amounts of inflammation in the gut mucosa due to increased lipopolysaccharide (LPS) release, inflammatory cytokine production and immune activation.[4,5] Therefore the manifesting inflammation may cause a dysfunction in DAO production for those who have a genetic predisposition. Also, inflammatory cytokines, LPS and stress increase mast cell degranulation leading to excessive production of histamine.[1,2,8-10]
Excessive production, combined with decreased degradation of histamine from impaired DAO activity, can then lead to symptomatology. This demonstrates that the inflammation resulting from a disrupted gut microbiome may be an underlying driving factor behind histamine intolerance.
Studies on irritable bowel syndrome (IBS) patients seem to support the role of a disrupted microflora in the pathogenesis of histamine intolerance. This may be because patients with IBS have a strong association with SIBO and tend to have higher amounts of histamine levels, which are correlated with their abdominal pain.[3,12] Also, people with IBS tend to report a worsening of their symptoms from histamine-rich and histamine-releasing foods. Thus, increased histamine levels may be a contributing factor behind their gastrointestinal symptoms.
Alcohol, nonsteroidal anti-inflammatory drugs (NSAIDs) and antibiotics have also been shown to suppress DAO production and are associated with histamine intolerance. They all have the potential to cause inflammation to the gut mucosa, which further supports the role of mucosal inflammation as a potential cause of diminished DAO activity and histamine intolerance.
Lastly, some bacterial species in the gut have the potential to produce HDC, which can convert histidine to histamine in food leading to excess production, e.g. Lactobacillus caseiparacasei, Streptococcus thermophiles, L. delbrueckii, L. bulgaricus, L. reuteri, L. brevis and Lactococcus lactis.[14-17]
Many of these species are found in fermented foods and dairy, which is why these foods can exacerbate the symptoms of histamine intolerant individuals. These strains can be found in probiotic supplements too, therefore caution must be taken when prescribing probiotics in those who are histamine intolerant.
Various species of Escherichia coli have also been shown to increase histamine production via the release of LPS, which induces HDC activity. E. coli forms part of the commensal gut microbiota, however when they become over represented (e.g. dysbiosis) they can cause issues. E. coli tends to thrive in dysbiotic environments because it is hypothesised that the presence of nitric oxide (a byproduct of an inflammatory habitat that results from dysbiosis), stimulates the growth of E. coli in the large intestine.[18,19]
This means that dysbiosis can predispose a person to an overgrowth of E. coli, which in turn leads to increased production of histamine, thus contributing to the symptomatology of histamine intolerance.
What does this all mean?
In patients with histamine intolerance symptomatology that are triggered by certain foods, and who have a negative diagnosis of allergy or other disorders, histamine intolerance should be considered as an underlying mechanism.
Histamine levels can be measured in plasma or urine. Serum DAO levels can also be measured. Elevated histamine concentrations and reduced DAO levels are both classically found in histamine intolerance and can be used as diagnostic tools along with a food diary.
Typical treatment includes removing foods that the patient reacts to, supplementing with DAO enzymes (including DAO cofactors such as vitamin C and B6) as well as using natural antihistamine substances that stabilise mast cells such as quercetin and vitamin C. Also, any drugs that decrease DAO activity should be avoided (e.g. NSAIDS and antibiotics).
Lastly, supplementing with probiotic strains that degrade histamine may be beneficial. These include bifidobacteria species (particularly Bifidobacterium infantis), L. plantarum, L. rhamnosus, L. salivarius and L. gasseri.
It is also important to address the underlying causes of histamine intolerance. Therefore addressing conditions like SIBO and dysbiosis may be necessary and are also likely to be an underlying factor to other health issues that a histamine intolerant patient may be suffering from.
Importantly, as practitioners, our understanding of the role of the gut microbiome in histamine intolerance gives us a deeper understanding of why certain foods may exacerbate conditions affecting other body systems and provides us with an effective basis for meaningful treatment.
- Maintz L, Novak N. Histamine and histamine intolerance. Am J Clin Nutr 2007;85(5)1185-1196. [Full text]
- Hanusková E, Plevková J. [Histamine intolerance]. Cesk Fysiol 2013;62(1):26-33. [Abstract]
- Smolinska S, Jutel M, Crameri R, et al. Histamine and gut mucosal immune regulation. Euro J Allergy Clin Immun 2013;69(3):273-281. [Full text]
- Bures J, Cyrany J, Kohoutova D, et al. Small intestinal bacterial overgrowth syndrome. World J Gastroenterol 2010;16(24):2978-2990. [Full text]
- Dukowicz A, Lacy B, Levine J. Small intestinal bacterial overgrowth. Gastroenterol Hepatol 2007;3(2):112-122. [Full text]
- Rana SV, Sharma S, Malik A, et al. Small intestinal bacterial overgrowth and orocecal transit time in patients of inflammatory bowel disease. Dig Dis Sci 2013;58(9):2594-2598. [Abstract]
- Rana S, Sharma S, Kaur J, et al. Relationship of cytokines, oxidative stress and GI motility with bacterial overgrowth in ulcerative colitis patients. J Crohns Colitis 2014;8(8):859-865. [Abstract]
- Smith TF, Aelvoet M, Morrison DC. The effect of bacterial lipopolysaccharide (LPS) on histamine release from human basophils. I. Enhancement of immunologic release by LPS. Clin Immunol Immunopathol 1985;34(3):355-365. [Abstract]
- Kim TH, Yoon HJ, Lim CM, et al. The role of endogenous histamine on the pathogenesis of the lipopolysaccharide (LPS)-induced, acute lung injury: a pilot study. Inflammation 2005;29(2-3):72-80. [Abstract]
- Cao J, Papadopoulou N, Kempuraj D, et al. Human mast cells express corticotropin-releasing hormone (CRH) receptors and CRH leads to selective secretion of vascular endothelial growth factor. J Immunol 2005;174(12):7665-7675. [Full text]
- Ghoshal U, Srivastava D. Irritable bowel syndrome and small intestinal bacterial overgrowth: Meaningful association or unnecessary hype. World J Gastroenterol 2014;20(10):2482-2491. [Full text]
- Barbara G, Stanghellini V, De Giorgio R, et al. Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology 2004;126(3):693-702. [Abstract]
- Boehn B, Störsrud S, Törnblom H, et al. Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life. Am J Gastro 2013;108(5);634-641. [Full text]
- Hemarajata P, Spinler J, Balderas M, et al. Identification of a proton-chloride antiporter (EriC) by Himar1 transposon mutagenesis in Lactobacillus reuteri and its role in histamine production. Antonie Van Leeuwenhoek 2014;105(3):579-592. [Full text]
- Tabanelli G. Effect of chemico-physical parameters on the histidine decarboxylase (HdcA) enzymatic activity in Streptococcus thermophilus PRI60. J Food Sci 2012;77(4):M231-M237. [Abstract]
- Moon J. Isolation and characterization of histamine-producing bacteria from fermented fish products. J Microbiol 2013;51(6):881-885. [Abstract]
- Komprda T, Sládková P, Petirová E, et al. Tyrosine- and histidine-decarboxylase positive lactic acid bacteria and enterococci in dry fermented sausages. Meat Sci 2010;86(3):870-877. [Abstract]
- Shoji N, Yoshida A, Yu Z, et al. Lipopolysaccharide stimulates histamine-forming enzyme (histidine decarboxylase) activity in murine dental pulp and gingiva. Arch Oral Biol 2006;51(10):856-860. [Abstract]
- Schippa S, Conte M. Dysbiotic events in gut microbiota: impact on human health. Nutrients 2014;6(12):5786-5805. [Full text]