Content uploaded by Sylwia Smolinska
Author content
All content in this area was uploaded by Sylwia Smolinska on Dec 18, 2017
Content may be subject to copyright.
REVIEW ARTICLE
Histamine and gut mucosal immune regulation
S. Smolinska
1,2
, M. Jutel
1,2
, R. Crameri
3
& L. O’Mahony
3
1
Department of Clinical Immunology, Wroclaw Medical University, Wroclaw;
2
‘ALL-MED’ Medical Research Institute, Wroclaw, Poland;
3
Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland
To cite this article: Smolinska S, Jutel M, Crameri R, O’Mahony L. Histamine and gut mucosal immune regulation. Allergy 2013; DOI: 10.1111/all.12330.
Keywords
allergy; histamine; inflammation; microbial
metabolites; mucosal immunology.
Correspondence
Dr. Liam O’Mahony, SIAF, Obere Strasse
22, 7270 Davos Platz, Switzerland.
Tel.: +41-81-4100853
Fax: +41-81-4100840
E-mail: liam.omahony@siaf.uzh.ch
Accepted for publication 21 October 2013
DOI:10.1111/all.12330
Edited by: Hans-Uwe Simon
Abstract
Histamine is a biogenic amine with extensive effects on many cell types, mediated
by the activation of its four receptors (H1R–H4R). Distinct effects are dependent
on receptor subtypes and their differential expression. Within the gastrointestinal
tract, histamine is present at relatively high concentrations, particularly during
inflammatory responses. In this review, we discuss the immunoregulatory influ-
ence of histamine on a number of gastrointestinal disorders, including food
allergy, scombroid food poisoning, histamine intolerance, irritable bowel syn-
drome, and inflammatory bowel disease. It is clear that the effects of histamine
on mucosal immune homeostasis are dependent on expression and activity of the
four currently known histamine receptors; however, the relative protective or
pathogenic effects of histamine on inflammatory processes within the gut are still
poorly defined and require further investigation.
Histamine [2-(4-imidazolyl)-ethylamine] is a short-acting
endogenous amine, which is widely distributed throughout
the body (1, 2). Histamine is synthesized by the enzyme histi-
dine decarboxylase (HDC), which decarboxylates the semi-
essential amino acid L-histidine. Originally discovered more
than 100 years ago, histamine was first chemically synthe-
sized by Windaus and Vogt in 1907. Soon afterward in 1910,
Dale and Laidlaw reported the first biological functions of
histamine, whereby they recognized that histamine had the
ability to mimic smooth muscle-stimulating and vasodepres-
sor action previously observed during anaphylaxis (3, 4).
Subsequently, histamine was isolated from many different tis-
sues, and thus, its name was based on the Greek word ‘his-
tos’, which means tissue. Studies utilizing HDC-knockout
animals 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 (5).
Histamine can be produced by a wide variety of different
cell types (6–10). Mast cells, basophils, gastric enterochro-
maffin-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, and these will be discussed
further below. HDC expression and histamine release is influ-
enced by cytokines including IL-1, IL-3, IL-12, IL-18,
GM-CSF, macrophage colony-stimulating factor, and tumor
necrosis factor (TNF)-a(1, 11, 12). Mast cells and basophils
store large quantities of histamine, which is released upon
degranulation in response to immunological and nonimmu-
nological stimuli. However, other cell types such as DCs and
lymphocytes do not store histamine intracellularly, but
secrete it following synthesis (13–15).
An important aspect of histamine biology are the enzymes
that degrade histamine. Histamine can be metabolized by
oxidative deamination (diamine oxidase –DAO) or by ring
methylation (histamine-N-methyltransferase –HNMT) (16).
Diamine oxidase is stored in plasma membrane-associated
vesicular structures in epithelial cells and is secreted into the
circulation following stimulation. Histamine-N-methyltrans-
ferase is a cytosolic enzyme, which can convert histamine
Abbreviations
CD, Crohn’s disease; DAO, diamine oxidase; DC, dendritic cells;
GM-CSF, granulocyte–macrophage colony-stimulating factor;
GPCR, G-protein-coupled receptors; HDC, histidine decarboxylase;
HNMT, histamine-N-methyltransferase; HR, histamine receptor;
IBD, inflammatory bowel disease; IBS, irritable bowel syndrome;
IL, interleukin; iNKT, invariant natural killer T cell; OVA, ovalbumin;
RAST, radioallergosorbent test; SNPs, single-nucleotide
polymorphisms; T
H
, T helper cell; TNF, tumor necrosis factor;
UC, ulcerative colitis.
©2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Allergy
only in the intracellular space of cells. Thus, it has been pro-
posed that DAO may be responsible for scavenging extracel-
lular histamine, while HNMT metabolizes intracellular
histamine. Histamine-N-methyltransferase has a slightly
higher affinity for histamine [Michaelis–Menten constant
(kM): 6–13 lM] compared to DAO (kM: 20 lM). In mam-
mals, DAO expression is restricted to specific tissues; the
highest activities are in the small bowel, colon, placenta, and
kidney (17). Histamine-N-methyltransferase is widely
expressed in human tissues; the greatest expression is in kid-
ney and liver, followed by spleen, colon, prostate, ovary,
spinal cord cells, bronchi, and trachea. Histamine-N-methyl-
transferase is regarded as the key enzyme for histamine
degradation in the bronchial epithelium (18).
While histamine is well recognized for its effects in the
immediate-type hypersensitivity response (i.e., increased vas-
cular permeability, smooth muscle contraction, activation of
nociceptive nerves, wheal and flare reaction and itch
response), the pathological relevance of increased histamine
levels at diseased sites is less well understood in other disor-
ders such as inflammatory bowel disease (IBD) and irritable
bowel syndrome (IBS) (19, 20). Indeed, histamine may nega-
tively or positively influence parasitic and bacterial infections
(21, 22). Within the gastrointestinal tract, histamine levels
can be influenced by host allergic and inflammatory
responses, altered activity of degradative enzymes, dietary
intake, and microbial processes (Fig. 1). In this review,
we will discuss the potential pathological and potential
Figure 1 Histamine within the mucosa. The major cellular sources of
histamine within the gastrointestinal tract are illustrated. Histamine
alters the dendritic cell response to microbes by enhancing IL-12
secretion via H1R, while H2R activation promotes IL-10 secretion and
inhibits IL-12, TNF-a, and IL-23 secretion. In addition, the activation of
H1R on lymphocytes promotes TH1 polarization, while the activation
of H2R suppresses TH1 and TH2 polarization, favoring polarization to
TREGs. H4R may aid TH2 polarization, and H4R displays chemotactic
properties. Activation of epithelial cells with histamine influences bar-
rier function. Enteric neurons are activated via H3R.
©2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Histamine Smolinska et al.
protective roles of histamine in gastrointestinal disorders. In
addition, we will highlight some of the limitations regarding
the diagnosis of and treatment for these ailments.
Immunomodulatory effects of histamine
The immune response is strictly controlled by effector and
regulatory processes, which normally result in protection
from infection and tolerance of innocuous environmental
antigens. However, in inflammatory diseases, the activated
immune response results in a chronic pro-inflammatory state
characterized by activated innate pathways with aberrant
expansion and polarization of T
H
1, T
H
2, T
H
9, T
H
17, T
H
22,
or T
REG
lymphocyte populations. Thus, the ongoing identifi-
cation of appropriate controlling factors that augment pro-
tective immune responses while limiting tissue damage is
being intensively investigated. Many host-derived and envi-
ronment metabolites can influence immune reactivity, for
example microbiota and dietary factors significantly influence
mucosal immune homeostasis (23).
Cells of both the innate and adaptive immune system can
be regulated by histamine (24–26). The regulatory nature of
histamine in immunology is dependent on its binding to four
subtypes of histamine receptors, which are named chronolog-
ically in order of their discovery –H1R–H4R. These four
receptors belong to the rhodopsin-like family of G-protein-
coupled receptors, which are differentially expressed in
numerous cell types and contain seven transmembrane
domains (27). The different receptor molecular responses to
histamine are primarily due to the activation of specific Ga
subunits, as each Gasubunit activates distinct molecular sig-
naling cascades. H1R binding leads to the activation of Gaq
and H2R is coupled to Gas, while H3R and H4R are both
activators of Gai/0. Simultaneous activation of more than
one receptor on a specific cell can lead to altered effects, for
example H1R signaling can antagonize or amplify H2R-
mediated responses depending on the time and context of
receptor activation (28).
H1R is expressed by a broad range of cell types including
neurons, airway and vascular smooth muscle cells, epithelial
cells, hepatocytes, chondrocytes, endothelial cells, DCs,
monocytes, neutrophils, T cells, and B cells (29, 30). H1R
gene expression can be upregulated by IL-3, IL-4, and hista-
mine, while H1R activation is responsible for many of the
features associated with the allergic immediate-type hypersen-
sitivity response, such as redness, itching, and swelling.
Peripheral H1R-mediated effects include rhinorrhea, bron-
choconstriction, anaphylaxis, conjunctivitis, and urticaria,
while central-associated H1R effects include the regulation of
food and water intake, convulsion, attention, and sleep regu-
lation. H1R antagonists have been shown to have multiple
effects on the allergic inflammatory response, and murine
H1R-knockout models have revealed significant immunologi-
cal (impairment of T- and B-cell responses), metabolic, and
behavioral abnormalities (31–33).
Similar to H1R, expression of H2R is found in a variety of
tissues and cells including brain, gastric parietal cell, smooth
muscle cells, T and B cells, DCs, and cardiac tissue. H2R can
modulate a range of immune system activities such as mast
cell degranulation, antibody synthesis, cytokine production,
and T-cell polarization. In particular, DC responses to micro-
bial ligands were significantly altered by histamine in a H2R-
dependent manner (34). Other effects, such as the suppression
of IL-27 secretion, were mediated via H2R and H4R (35).
Murine H2R-knockout mice display defects in gastric and
immune regulatory functions as well as selective cognitive
defects and abnormalities in nociception (36, 37).
H3R is a presynaptical autoreceptor in the peripheral and
central nervous system and has been shown to be involved in
the sleep–wake cycle, cognition, homeostatic regulation of
energy levels, and inflammation. H3R-knockout mice display
a metabolic syndrome characterized by hyperphagia, late-
onset obesity, increased insulin and leptin levels (38). In addi-
tion, H3R knockouts had an increased severity of neuroin-
flammatory diseases associated with enhanced expression of
MIP-2, IP-10, and CXCR3 by peripheral T cells (39).
The H4R is the most recent receptor to be discovered, and
it shares some molecular and pharmacological properties
with the H3R. However, in contrast to H3R, H4R is
expressed by a wide range of cells including keratinocytes,
Langerhans cells, DCs, neutrophils, and lymphocytes
(40–42). Invariant NK T (iNKT) cells are numerically and
functionally impaired in HDC-knockout mice with dimin-
ished secretion of IL-4 and IFN-afollowing stimulation.
H4R signaling was essential for the histamine effect on iNKT
cytokine secretion (43). An exciting new development
suggests that the combined treatment with H1R and H4R
antagonists may have a significant therapeutic effect on
chronic dermatitis through the synergistic inhibition of
pruritus and skin inflammation (44).
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 hista-
mine may be caused by endogenous histamine overproduc-
tion (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 (45).
Histamine intolerance is associated with a range of symptoms
that mimic an allergic reaction, such as diarrhea, headache,
rhinoconjunctival symptoms, asthma, hypotension, arrhyth-
mia, urticaria, pruritus, and flushing (46, 47). Some estimates
suggest that approximately 1% of the population is histamine
intolerant, and 80% of those patients are middle-aged (45).
However, these estimates are controversial and the exact pro-
portion of individuals exhibiting histamine intolerance is still
unknown.
©2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Smolinska et al. Histamine
Due to the various symptoms observed in multiple organs,
the diagnosis of histamine intolerance is difficult. Diagnosis
of histamine intolerance requires the presentation of ≥2 typi-
cal symptoms of histamine intolerance and improvement fol-
lowing the introduction of a histamine-free diet and the use
of antihistamines. Potential food allergies should be excluded
by skin prick test or by the determination of specific IgE for
food allergens. Occult systemic mastocytosis should be also
excluded, for example by measuring serum tryptase levels.
The accurate diagnosis of histamine intolerance should be
based on the well-documented association between food con-
sumption and symptoms, identification of food causing
symptoms, determination of histamine content of the food
causing the symptoms, exclusion of other causes (e.g., allergy,
toxins, metabolites), oral histamine provocation (if possible),
determination of DAO and HNMT contents and activity in
intestinal mucosa (not in peripheral blood), and the analysis
of DAO and HNMT genetic polymorphisms (48).
For histamine-intolerant patients, alcohol and long-ripened
or fermented (and therefore histamine-rich) foods, for exam-
ple aged cheese, cured meat, yeast products, spinach, toma-
toes, and histamine liberators, such as citrus fruit, should be
avoided (49). A histamine-free diet can be complemented
with adjuvant administration of antihistamine receptor drugs.
In addition, histamine degradation can be supported by the
administration of vitamin C and B-6, which may increase
DAO activity (50, 51). The use of drugs that interfere with
histamine metabolism should be avoided. Recently, capsules
containing DAO isolated from pig kidneys have been gener-
ated to supplement the proposed deficit of endogenous
human DAO in patients with histamine intolerance (45).
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 sea-
food allergies (52). Scombroid poisoning results from the
consumption of mishandled fish. Histamine and other decom-
position products are generated in fish tissues by bacterial
conversion of free histidine (53). Scombrid fish have high
levels of free histidine in their muscle tissues, compared to
nonscombroid species, which have lower levels. However,
nonscombroid fish species have also been implicated in scom-
broid poisoning. Histamine is produced by a wide range of
bacteria, but the major histamine-producing bacteria in fish
are Gram-negative mesophilic enteric and marine bacteria
(54, 55). Examples include strains of Morganella morganii,
Enterobacter aerogenes,Raoultella planticola,Raoultella orni-
thinolytica, and Photobacterium damselae, some of which can
secrete ≥1000 ppm histamine during optimal in vitro culture
conditions. Strains of other species, including Hafnia alvei,
Citrobacter freundi,Vibrio alginolyticus, and Escherichia coli,
are weak histamine producers (or nonproducers), yielding
concentrations <500 ppm under similar in vitro culture condi-
tions (56, 57). 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. Treatment
for scombroid poisoning includes the administration of anti-
histamines, while corticosteroids are ineffective (52). The
proper handling and storage of fish is the most effective pre-
ventive measure as cooking contaminated fish does not pre-
vent histamine poisoning because the toxins are heat stable.
In addition to the presence of histamine, other mechanisms
have also been proposed that contribute to scombroid poi-
soning. Firstly, histamine toxicity could be potentiated by
toxins, which inhibit histamine-metabolizing enzymes. Hista-
mine toxicity is potentiated by the action of DAO and
HNMT inhibitors that are also present together with dietary
histamine in the ingested fish. Inhibition of HNMT and
DAO, which usually degrade histamine, leads to increased
histamine levels within the gut, and subsequently, increased
amounts of histamine are available for absorption to extra-
intestinal tissues (58). Secondly, the induction of mast cell
degranulation will release endogenous histamine. The second
hypothesis is based on ‘scombrotoxins’ that are mast cell
degranulators associated with the spoiled fish. This hypothesis
is significantly different from the first in that dietary histamine
in the implicated fish is not solely required. Rather, the
observed toxicity may be due to the endogenous release of
histamine (59). Finally, currently unknown histamine recep-
tor agonists may be present within the decomposed fish. For
example, gizzerosine is a small peptide found in poor-quality
feed produced by overheating decomposed fish material (60).
It is a potent H2R agonist, approximately 200 times more
potent than histamine itself, and gizzerosine kills poultry by
causing excessive excretion of digestive acids (60). Although
certainly not implicated in scombroid poisoning, gizzerosine
provides an excellent example of a previously unknown and
histidine-derived agonist active at a histamine receptor. Based
on this precedent, there may be other histidine-derived com-
pounds in scombroid poisoning-implicated fish that could
bind to histaminergic receptors, and thus, it is not possible to
rule out the existence of other agonists without comparing
the total histamine receptor bioactivity with the predicted
activity based on known histamine concentrations in out-
break-implicated sample extracts. If there were other hista-
minergic receptor agonists for the various histaminergic
receptors with activity comparable to that shown by gizzero-
sine for H2 receptors, low levels of bioactive compounds
could be enough to cause illness.
Food allergy
The gut immune system is exposed daily to a large number
and variety of foreign proteins, and the ability to avoid aller-
gic reactions to food is significantly influenced by the way
these potential allergens are transported, presented, and
responded to (61). The influence of histamine on altering the
©2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Histamine Smolinska et al.
gut immune response to food antigens has not been defini-
tively examined; however given the immunoregulatory func-
tions of histamine described above, it is tempting to
speculate that histamine and its receptors could be involved
either directly or indirectly in food antigen tolerance and sen-
sitization mechanisms. In addition to eliciting the major
symptoms of IgE-mediated food allergy, the ingestion of his-
tamine-rich food, alcohol, or drugs that release histamine or
block DAO may induce diarrhea, hypotension, arrhythmia,
bronchial constriction, rhinoconjunctivitis, urticaria, or head-
ache, 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 (62–64). From the duodenal mast cells of
food-allergic patients, the anti-IgE-mediated mast cell hista-
mine release was increased compared with nonallergics. His-
tamine release from basophils was positively correlated with
the test scores of the RAST analysis, skin prick test, and
food challenge (65). This result was confirmed in other stud-
ies, whereby incubation of biopsies from food-allergic
patients with anti-human IgE antibodies or allergens induced
a ninefold increase in histamine release. Stimulation of biop-
sies ex vivo with histamine itself induced a concentration-
dependent NO response only in food-allergic subjects (66). It
has been postulated that this method can also be utilized
diagnostically to quantify allergen-induced histamine secre-
tion in live human colorectal biopsy tissue and has been sug-
gested to correlate with alterations in transepithelial
resistance (67).
It is important to note that not only mast cells or baso-
philes are cellular sources of histamine. Other host cells and
an altered microbiome may also contribute to increased his-
tamine levels and the associated response to food allergens.
However, this has not been studied in detail for food-allergic
patients.
The relative contribution of the different histamine recep-
tors to the induction of food allergy has also not been ade-
quately studied. In mice, intraperitoneal administration of
cimetidine (H2R antagonist) together with ovalbumin (OVA)
resulted in enhanced T
H
2 cytokine secretion by spleen cells
stimulated with OVA in vitro and increased IgE levels in the
sera (68). In humans, treatment with H2R antagonists results
in enhanced IgE production against food antigens (69, 70).
These results indicate that H2R antagonists may contribute
to the development of IgE-mediated food allergies; however,
the use of other non-H2R targeting antacids is also a risk
factor for the development of food allergies.
Current therapy for food allergy is not curative. The
effectiveness of antihistamines and mast cell stabilizers in
ameliorating food allergy symptoms is very limited. Single-
nucleotide polymorphisms in the DAO gene have been
detected in patients with food allergy symptoms; however,
the IgE status of these patients was not described and this
group could potentially include histamine-intolerant, rather
than food-allergic, individuals (71). Current DAO prepara-
tions did not reduce mast cell degranulation in response to
allergens; however, porcine kidney DAO shows antihista-
minic activity in vivo and protects against pig anaphylactic
shock in an experimental model, which is directly related to
the inactivation of histamine (72). A new concept for the
treatment of food allergy is based on the oral administration
of DAO associated with catalase. An oral bi-enzymatic ther-
apy with DAO and catalase was suggested to reduce the lev-
els of intestinal histamine via degradation by DAO, with the
production of H
2
O
2
,NH
3
, and imidazole acetaldehyde. As
H
2
O
2
, a by-product of degradation, is toxic due to its pro-
oxidant effects on intestinal cells, catalase has been included
to decompose H
2
O
2
.
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 dis-
rupted mucosal immune responses play a role (73, 74). In
addition, the composition of the gastrointestinal microbiota is
altered and the administration of specific microbes has thera-
peutic effects (75–77). Frequently patients with IBS experience
postprandial worsening of their symptoms, and patients typi-
cally 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 (78). Interesting, the use of spherical car-
bon absorbent (which adsorbs molecules such as histamine
from the gut lumen) has been beneficial for some patients (79).
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 (80). Mucosal biopsy
supernatants from patients with IBS contained higher levels of
histamine compared to biopsy supernatants from healthy
volunteers, while the mast cell stabilizer and H1R antagonist
ketotifen reduces some IBS symptoms (20, 81).
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 (82). Ulcerative colitis is characterized by
inflammation with superficial ulcerations limited to the
mucosa of the colon. Inflammation usually starts in the rec-
tum and continuously spreads throughout the colon. Crohn’s
disease, however, is characterized by a discontinuous pattern,
potentially affecting the entire gastrointestinal tract. In con-
trast to ulcerative colitis, inflammation in patients with CD is
transmural with large ulcerations, and occasionally, granulo-
mas are observed. The precise mechanisms causing these dis-
eases remain unknown but complex interactions between the
immune system, enteric microbiota, and host genotype under-
lie the development of IBD. Some studies have demonstrated
©2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Smolinska et al. Histamine
that components of the intestinal microbiota can drive pro-
tective or pathological responses in IBD models, highlighting
the importance of host–microbe communication in the devel-
opment of these diseases.
The importance of mast cells has been well documented in
patients with IBD. In 1980, Dvorak and colleagues reported
that the number of mast cells was markedly increased in the
involved area of the ileum of patients with CD (83). In 1990,
Nolte et al. found that the mast cell count in patients with
ulcerative colitis was increased compared with that in control
subjects and patients with CD. In addition, more mast cells
were present in inflamed tissue compared to adjacent nonin-
flamed tissue (84). Additional studies confirmed the finding
that mast cell number was significantly increased in inflamed
tissue from patients with ulcerative colitis, particularly at the
line of demarcation between inflamed and normal mucosa.
The accumulation of mast cells at the visible line of demarca-
tion between normal and abnormal mucosa suggested that
mast cells played a crucial role in the pathogenesis of the dis-
ease, either causing further damage or limiting the expansion
of damage (85). Nishida and colleagues found that there were
greater numbers of mast cells than macrophages in the lam-
ina propria of patients with IBD, although this was not
found in patients with collagenous colitis (86). Interestingly,
increased numbers of mast cells were observed throughout
the lamina propria, particularly in the upper part of lamina
propria, whereas increased numbers of macrophages were
only seen in the lower part of lamina propria in patients with
IBD. This suggests that the release of pro-inflammatory
mediators from accumulated mast cells could have led to the
recruitment of macrophages to the lamina propria. Dramati-
cally increased numbers of mast cells were also observed in
the hypertrophied and fibrotic muscularis propria of stric-
tures in CD compared with normal bowel (87).
The rate of histamine secretion from the jejunum was
increased in patients with CD compared with normal con-
trols, and the secretion of histamine was related to disease
activity, indicating that degranulation of mast cells may be
important in active CD (88). Highly increased mucosal hista-
mine levels were also observed in allergic enteropathy and
ulcerative colitis (63). Increased levels of N-methylhistamine,
a stable histamine metabolite, were detected in the urine of
patients with active CD or ulcerative colitis (89). Because an
increased level of N-methylhistamine was significantly corre-
lated with clinical disease activity, the above findings further
suggest that histamine plays an important role in the patho-
genesis of these diseases. Mast cells isolated from the resected
colon of active CD or ulcerative colitis patients were able to
release more histamine than those from normal colon when
being stimulated with epithelial proteins (90). Similarly, cul-
tured colorectal biopsies from patients with IBD secreted
more histamine toward substance P alone or substance P
with anti-IgE compared to the samples from control subjects
cultured under the same conditions (91). Histamine-N-meth-
yltransferase gene expression is reduced in inflamed mucosa
and DAO polymorphisms have been identified for patients
with IBD, suggesting that there could be dysregulated metab-
olism of histamine within the inflamed gut (71, 92).
While it is clear that histamine is present at higher levels
within the mucosa of patients with IBD, the potential protec-
tive or pathological role for histamine signaling through its
different receptors has not been determined in patients with
IBD. Recently, the use of H2R antagonists, but not proton
pump inhibitors, significantly increased the risk of hospital-
ization or surgery in patients with CD (93). Although these
results should be interpreted with caution, one could hypoth-
esize that histamine signaling through the H2R may have
some protective effects within the mucosa of patients with
IBD. In contrast, inhibition of the H1R may have some pro-
tective effects in a subset of patients with IBD, but these
studies need to be repeated in larger cohorts (94, 95).
The role for microbial-derived histamine
There are many new examples, appearing regularly in the lit-
erature, which describe novel microbe–host interactions that
impact the immunological health of the host. Specific
microbes within the microbiota have been described to release
the biogenic amine histamine. In bacteria, the expression and
activity of amino acid decarboxylases is enhanced in acidic
environments, such as in the stomach. This leads to a local
increase in pH around the bacteria and protects it from the
acidic, chloride-rich environment. Furthermore, expression
and activity of decarboxylases in bacteria is regulated by the
presence of fermentable carbohydrates and oxygen, the redox
potential of the medium, the temperature, and the sodium
chloride concentration. The biological consequences of biogenic
amine secretion in vivo by the resident microbiota are largely
unknown. Histamine can have both pro-inflammatory and anti-
inflammatory effects on immunoregulatory processes, depending
on which histamine receptor is activated. With the exception of
scombroid poisoning, it is currently unknown whether histamine
secretion by the microbiota is altered during, or contributes to,
mucosal inflammatory disorders. Maintenance of mucosal
homeostasis is heavily dependent on appropriate sampling and
processing of microbial ligands by the innate immune system, in
particular DCs. We have demonstrated that histamine signifi-
cantly alters the DC response to microbial ligands via the H2R
and administration of a histamine-secreting Lactobacillus
rhamnosus strain to H2R-knockout mice results in a loss of the
microbe’s immunoregulatory activities (32). Other in vitro stud-
ies have also confirmed this finding, for example histamine
secretion by a Lactobacillus reuteri strain modulates TLR-2-
induced TNF-asecretion in vitro (96). These observations
suggest that histamine from the enteric microbes might exert
immunoregulatory effects in vivo; however, it remains to be
determined whether these effects are protective or pathological.
Future perspectives and conclusions
It is clear that histamine is present within the gastrointestinal
mucosa and increased levels are associated with a range of
mucosal inflammatory disorders. Due to the obvious overlap
in symptoms, great care needs to be exercised in the differen-
tial diagnosis of these disorders. Treatment strategies that
promote H2R expression and activity, with decreased H1R or
©2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Histamine Smolinska et al.
H4R activity, may improve mucosal immunoregulatory activ-
ity and protect against allergic sensitization and inflammatory
disorders. The contribution of the microbiota to the histamine
content of the gut and histamine receptor activation is cur-
rently unknown. Even though histamine was first discovered
more than 100 years ago, there remain substantial gaps in our
knowledge concerning the immunoregulatory activity of hista-
mine, particularly within the gastrointestinal tract.
Funding
The authors are supported by Swiss National Foundation
grants (project numbers: 310030-127356 and 310030-144219),
Allergiestiftung Ulrich M€
uller-Gierok, European Union
research grants, EU Marie Curie grants, and Polish National
Science Centre grants No. 2011/01/B/NZ6/01872, 2012/04/M/
NZ6/00355 and 2012/04/A/NZ6/00407.
Conflicts of interest
Liam O’Mahony is a consultant to Alimentary Health Ltd
and has received research funding from GSK. Marek Jutel is
a consultant to Allergopharma, GER, Anergis, CH, Biomay,
and received lecture fees from GSK, Allergopharma, Staller-
gens, ALK. Sylwia Smolinska and Reto Crameri have no
conflict of interests to declare.
References
1. Jutel M, Akdis M, Akdis CA. Histamine,
histamine receptors and their role in immune
pathology. Clin Exp Allergy 2009;39:1786–
1800.
2. Westly E. Nothing to sneeze at. Nat Med
2010;16:1063–1065.
3. Barger G, Dale HH. Chemical structure and
sympathomimetic action of amines. J Physiol
1910;41:19–59.
4. Dale HH, Laidlaw PP. The physiological
action of beta-iminazolylethylamine. J Phys-
iol 1910;41:318–344.
5. Ohtsu H. Pathophysiologic role of hista-
mine: evidence clarified by histidine decar-
boxylase gene knockout mice. Int Arch
Allergy Immunol 2012;158(Suppl 1):2–6.
6. Akdis CA, Blaser K. Histamine in the
immune regulation of allergic inflammation.
J Allergy Clin Immunol 2003;112:15–22.
7. Jutel M, Watanabe T, Akdis M, Blaser K,
Akdis CA. Immune regulation by histamine.
Curr Opin Immunol 2002;14:735–740.
8. Dy M, Schneider E. Histamine-cytokine con-
nection in immunity and hematopoiesis.
Cytokine Growth Factor Rev 2004;15:393–
410.
9. Schneider E, Rolli-Derkinderen M, Arock
M, Dy M. Trends in histamine research: new
functions during immune responses and
hematopoiesis. Trends Immunol 2002;23:255–
263.
10. MacGlashan D Jr. Histamine: a mediator of
inflammation. J Allergy Clin Immunol
2003;112(4 Suppl):S53–S59.
11. Yoshimoto T, Tsutsui H, Tominaga K,
Hoshino K, Okamura H, Akira S et al.
IL-18, although antiallergic when
administered with IL-12, stimulates IL-4
and histamine release by basophils. Proc
Natl Acad Sci U S A 1999;96:13962–13966.
12. Miadonna A, Salmaso C, Marco MP, Pugni
L, Milazzo N, Tedeschi A et al. Priming and
inducing effects of interleukin-3 on histamine
release from cord-blood basophils. Allergy
1997;52:992–998.
13. Saxena SP, McNicol A, Brandes LJ, Becker
AB, Gerrard JM. Histamine formed in
stimulated human platelets is cytoplasmic.
Biochem Biophys Res Commun
1989;164:164–168.
14. Kubo Y, Nakano K. Regulation of hista-
mine synthesis in mouse CD4+and CD8+T
lymphocytes. Inflamm Res 1999;48:149–153.
15. Radvany Z, Darvas Z, Kerekes K, Prechl J,
Szalai C, Pallinger E et al. H1 histamine
receptor antagonist inhibits constitutive
growth of Jurkat T cells and antigen-specific
proliferation of ovalbumin-specific murine T
cells. Semin Cancer Biol 2000;10:41–45.
16. Klocker J, Matzler SA, Huetz GN, Drasche
A, Kolbitsch C, Schwelberger HG. Expres-
sion of histamine degrading enzymes in por-
cine tissues. Inflamm Res 2005;54(Suppl 1):
S54–S57.
17. Schwelberger HG, Hittmair A, Kohlwein
SD. Analysis of tissue and subcellular locali-
zation of mammalian diamine oxidase by
confocal laser scanning fluorescence micros-
copy. Inflamm Res 1998;47(Suppl 1):S60–
S61.
18. Yamauchi K, Sekizawa K, Suzuki H, Nak-
azawa H, Ohkawara Y, Katayose D et al.
Structure and function of human histamine
N-methyltransferase: critical enzyme in hista-
mine metabolism in airway. Am J Physiol
1994;267(3 Pt 1):L342–L349.
19. He SH. Key role of mast cells and their
major secretory products in inflammatory
bowel disease. World J Gastroenterol
2004;10:309–318.
20. Buhner S, Li Q, Vignali S, Barbara G,
De Giorgio R, Stanghellini V et al.
Activation of human enteric neurons by
supernatants of colonic biopsy specimens
from patients with irritable bowel syndrome.
Gastroenterology 2009;137:1425–1434.
21. Beghdadi W, Porcherie A, Schneider BS,
Dubayle D, Peronet R, Huerre M et al.
Inhibition of histamine-mediated signaling
confers significant protection against severe
malaria in mouse models of disease. J Exp
Med 2008;205:395–408.
22. Metz M, Doyle E, Bindslev-Jensen C,
Watanabe T, Zuberbier T, Maurer M.
Effects of antihistamines on innate immune
responses to severe bacterial infection in
mice. Int Arch Allergy Immunol
2011;155:355–360.
23. Frei R, Lauener RP, Crameri R, O’Mahony
L. Microbiota and dietary interactions: an
update to the hygiene hypothesis? Allergy
2012;67:451–461.
24. O’Mahony L, Akdis M, Akdis CA. Regula-
tion of the immune response and inflamma-
tion by histamine and histamine receptors.
J Allergy Clin Immunol 2011;128:1153–1162.
25. Ferstl R, Akdis CA, O’Mahony L. Hista-
mine regulation of innate and adaptive
immunity. Front Biosci 2012;17:40–53.
26. Bachert C. The role of histamine in allergic
disease: re-appraisal of its inflammatory
potential. Allergy 2002;57:287–296.
27. Akdis CA, Simons FE. Histamine receptors
are hot in immunopharmacology. Eur
J Pharmacol 2006;533:69–76.
28. Garbarg MSJ. Synergism between histamine
H1- and H2-receptors in the cAMP response
in guinea pig brain slices: effects of phorbol
esters and calcium. Mol Pharmacol
1988;33:38–43.
29. Gschwandtner M, Mildner M, Mlitz V,
Gruber F, Eckhart L, Werfel T et al. Hista-
mine suppresses epidermal keratinocyte dif-
ferentiation and impairs skin barrier
function in a human skin model. Allergy
2013;68:37–47.
30. Togias A. H1-receptors: localization and role
in airway physiology and in immune
functions. J Allergy Clin Immunol
2003;112(Suppl 4):S60–S68.
31. Baroody FM, Naclerio RM. Antiallergic
effects of H1-receptor antagonists. Allergy
2000;55(Suppl 64):17–27.
32. Masaki T, Yoshimatsu H. The hypothalamic
H1 receptor: a novel therapeutic target for
©2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Smolinska et al. Histamine
disrupting diurnal feeding rhythm and obes-
ity. Trends Pharmacol Sci 2006;27:279–284.
33. Jutel M, Watanabe T, Klunker S, Akdis M,
Thomet OA, Malolepszy J et al. Histamine
regulates T-cell and antibody responses by
differential expression of H1 and H2 recep-
tors. Nature 2001;413:420–425.
34. Frei R, Ferstl R, Konieczna P, Ziegler M,
Simon T, Rugeles TM et al. Histamine
receptor 2 modifies dendritic cell responses
to microbial ligands. J Allergy Clin Immunol
2013;132:194–204.
35. Gschwandtner M, Bunk H, Kother B, Thur-
mond RL, Kietzmann M, Werfel T et al.
Histamine down-regulates IL-27 production
in antigen-presenting cells. J Leukoc Biol
2012;92:21–29.
36. Teuscher C, Poynter ME, Offner H, Zamora
A, Watanabe T, Fillmore PD et al. Attenua-
tion of Th1 effector cell responses and sus-
ceptibility to experimental allergic
encephalomyelitis in histamine H2 receptor
knockout mice is due to dysregulation of
cytokine production by antigen-presenting
cells. Am J Pathol 2004;164:883–892.
37. Dai H, Kaneko K, Kato H, Fujii S, Jing Y,
Xu A et al. Selective cognitive dysfunction
in mice lacking histamine H1 and H2 recep-
tors. Neurosci Res 2007;57:306–313.
38. Yoshimoto R, Miyamoto Y, Shimamura K,
Ishihara A, Takahashi K, Kotani H et al.
Therapeutic potential of histamine H3 recep-
tor agonist for the treatment of obesity and
diabetes mellitus. Proc Natl Acad Sci U S A
2006;103:13866–13871.
39. Teuscher C, Subramanian M, Noubade R,
Gao JF, Offner H, Zachary JF et al. Central
histamine H3 receptor signaling negatively
regulates susceptibility to autoimmune
inflammatory disease of the CNS. Proc Natl
Acad Sci U S A 2007;104:10146–10151.
40. Glatzer F, Gschwandtner M, Ehling S,
Rossbach K, Janik K, Klos A et al. Hista-
mine induces proliferation in keratinocytes
from patients with atopic dermatitis through
the histamine 4 receptor. J Allergy Clin
Immunol 2013; doi: 10.1016/j.jaci.2013.
06.023. [Epub ahead of print]
41. Gschwandtner M, Rossbach K, Dijkstra D,
Baumer W, Kietzmann M, Stark H et al.
Murine and human Langerhans cells express
a functional histamine H4 receptor: modula-
tion of cell migration and function. Allergy
2010;65:840–849.
42. Baumer W, Wendorff S, Gutzmer R, Werfel
T, Dijkstra D, Chazot P et al. Histamine H4
receptors modulate dendritic cell migration
through skin–immunomodulatory role of
histamine. Allergy 2008;63:1387–1394.
43. Leite-de-Moraes MC, Diem S, Michel ML,
Ohtsu H, Thurmond RL, Schneider E et al.
Cutting edge: histamine receptor H4 activa-
tion positively regulates in vivo IL-4 and
IFN-gamma production by invariant NKT
cells. J Immunol 2009;182:1233–1236.
44. Ohsawa Y, Hirasawa N. The antagonism of
histamine H1 and H4 receptors ameliorates
chronic allergic dermatitis via anti-pruritic
and anti-inflammatory effects in NC/Nga
mice. Allergy 2012;67:1014–1022.
45. Maintz L, Novak N. Histamine and hista-
mine intolerance. Am J Clin Nutr
2007;85:1185–1196.
46. Lessof MH, Gant V, Hinuma K, Murphy
GM, Dowling RH. Recurrent urticaria and
reduced diamine oxidase activity. Clin Exp
Allergy 1990;20:373–376.
47. Wantke F, Hemmer W, Haglmuller T, Gotz
M, Jarisch R. Histamine in wine. Broncho-
constriction after a double-blind placebo-
controlled red wine provocation test. Int
Arch Allergy Immunol 1996;110:397–400.
48. Schwelberger HG. Histamine intolerance: a
metabolic disease? Inflamm Res 2010;59:
S219–S221.
49. Wantke F, Gotz M, Jarisch R. Histamine-
free diet: treatment of choice for histamine-
induced food intolerance and supporting
treatment for chronic headaches. Clin Exp
Allergy 1993;23:982–985.
50. Johnston CS. The antihistamine action of
ascorbic acid. Subcell Biochem 1996;25:189–
213.
51. Martner-Hewes PM, Hunt IF, Murphy NJ,
Swendseid ME, Settlage RH. Vitamin B-6
nutriture and plasma diamine oxidase activ-
ity in pregnant Hispanic teenagers. Am
J Clin Nutr 1986;44:907–913.
52. Hungerford JM. Scombroid poisoning: a
review. Toxicon 2010;56:231–243.
53. Rawles DD, Flick GJ, Martin RE. Biogenic
amines in fish and shellfish. Adv Food Nutr
Res 1996;39:329–365.
54. Kim SH, Barros-Velazquez J, Ben-Gigrey B,
Eun JB, Jun SH, Wie CI et al. Identification
of the main bacteria contributing to hista-
mine formation in seafood to ensure product
safety. Food Sci Biotechnol 2003;12:451–460.
55. Bjornsdottir-Butler K, Bolton GE, Jaykus
LA, McClellan-Green PD, Green DP. Devel-
opment of molecular-based methods for
determination of high histamine producing
bacteria in fish. Intl J Food Microbiol
2010;139:161–167.
56. Kim SH, Field KG, Chang DS, Wei CI, An
HJ. Identification of bacteria crucial to his-
tamine accumulation in Pacific mackerel
during storage. J Food Protect 2001;64:1556–
1564.
57. Takahashi H, Kimura B, Yoshikawa M,
Fujii T. Cloning and sequencing of the histi-
dine decarboxylase genes of gram-negative,
histamine-producing bacteria and their
application in detection and identification of
these organisms in fish. Appl Environ
Microbiol 2003;69:2568–2579.
58. Hui JY, Taylor SL. Inhibition of in vivo his-
tamine-metabolism in rats by foodborne and
pharmacologic inhibitors of diamine oxidase,
histamine N-methyltransferase, and mono-
amine-oxidase. Toxicol Appl Pharm
1985;81:241–249.
59. Ijomah P, Clifford MN, Walker R, Wright
J, Hardy R, Murray CK. The importance of
endogenous histamine relative to dietary his-
tamine in the etiology of scombrotoxicosis.
Food Addit Contam 1991;8:531–542.
60. Okazaki T, Noguchi T, Igarashi K, Saka-
gami Y, Seto H, Mori K et al. Gizzerosine,
a new toxic-substance in fish-meal, causes
severe gizzard erosion in chicks. J Agric
Food Chem 1983;47:2949–2952.
61. Cochrane S, Beyer K, Clausen M, Wjst M,
Hiller R, Nicoletti C et al. Factors influenc-
ing the incidence and prevalence of food
allergy. Allergy 2009;64:1246–1255.
62. Raithel M, Weidenhiller M, Abel R, Baen-
kler HW, Hahn EG. Colorectal mucosal his-
tamine release by mucosa oxygenation in
comparison with other established clinical
tests in patients with gastrointestinally medi-
ated allergy. World J Gastroenterol
2006;12:4699–4705.
63. Raithel M, Matek M, Baenkler HW, Jorde
W, Hahn EG. Mucosal histamine content
and histamine secretion in Crohn’s disease,
ulcerative colitis and allergic enteropathy.
Int Arch Allergy Immunol 1995;108:127–133.
64. Bijlsma PB, Backhaus B, Weidenhiller M,
Donhauser N, Hahn EG, Raithel M. Food
allergy diagnosis by detection of antigen-
induced electrophysiological changes and
histamine release in human intestinal biop-
sies during mucosa-oxygenation. Inflamm
Res 2004;53(Suppl 1):S29–S30.
65. Nolte H, Schiotz PO, Kruse A, Skov PS.
Comparison of intestinal mast-cell and baso-
phil histamine-release in children with food
allergic reactions. Allergy 1989;44:554–565.
66. Raithel M, Hagel AF, Zopf Y, Bijlsma PB,
De Rossi TM, Gabriel S et al. Analysis of
immediate ex vivo release of nitric oxide
from human colonic mucosa in gastrointesti-
nally mediated allergy, inflammatory bowel
disease and controls. J Physiol Pharmacol
2012;63:317–325.
67. Bijlsma PB, Backhaus B, Weidenhiller M,
Donhauser N, Hahn EG, Raithel M. Food
allergy diagnosis by detection of antigen-
induced electrophysiological changes and
histamine release in human intestinal biop-
sies during mucosa-oxygenation. Inflamm
Res 2004;53:S29–S30.
68. Arae K, Oboki K, Ohno T, Hirata M,
Nakae S, Taguchi H et al. Cimetidine
enhances antigen-specific IgE and Th2 cyto-
kine production. Allergol Int 2011;60:339–344.
69. Untersmayr E, Bakos N, Scholl I, Kundi M,
Roth-Walter F, Szalai K et al. Anti-ulcer
©2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Histamine Smolinska et al.
drugs promote IgE formation toward dietary
antigens in adult patients. FASEB J
2005;19:656–658.
70. Scholl I, Untersmayr E, Bakos N, Roth-
Walter F, Gleiss A, Boltz-Nitulescu G et al.
Antiulcer drugs promote oral sensitization
and hypersensitivity to hazelnut allergens in
BALB/c mice and humans. Am J Clin Nutr
2005;81:154–160.
71. Petersen J, Raithel M, Schwelberger HG.
Characterisation of functional polymor-
phisms of the human diamine oxidase gene.
Inflamm Res 2005;54(Suppl 1):S58–S59.
72. Masini E, Vannacci A, Marzocca C, Man-
naioni PF, Befani O, Federico R et al. A
plant histaminase modulates cardiac
anaphylactic response in guinea pig. Biochem
Biophys Res Commun 2002;296:840–846.
73. Macsharry J, O’Mahony L, Fanning A,
Bairead E, Sherlock G, Tiesman J et al.
Mucosal cytokine imbalance in irritable
bowel syndrome. Scand J Gastroenterol
2008;43:1467–1476.
74. Dinan TG, Quigley EM, Ahmed SM, Scully
P, O’Brien S, O’Mahony L et al. Hypotha-
lamic-pituitary-gut axis dysregulation in irri-
table bowel syndrome: plasma cytokines as a
potential biomarker? Gastroenterology
2006;130:304–311.
75. Codling C, O’Mahony L, Shanahan F, Quig-
ley EM, Marchesi JR. A molecular analysis
of fecal and mucosal bacterial communities
in irritable bowel syndrome. Dig Dis Sci
2010;55:392–397.
76. O’Mahony L, McCarthy J, Kelly P, Hurley
G, Luo F, Chen K et al. Lactobacillus and
bifidobacterium in irritable bowel syndrome:
symptom responses and relationship to cyto-
kine profiles. Gastroenterology 2005;128:541–
551.
77. Whorwell PJ, Altringer L, Morel J, Bond Y,
Charbonneau D, O’Mahony L et al. Efficacy
of an encapsulated probiotic Bifidobacterium
infantis 35624 in women with irritable bowel
syndrome. Am J Gastroenterol
2006;101:1581–1590.
78. Bohn L, Storsrud S, Tornblom H, Bengtsson
U, Simren M. Self-reported food-related gas-
trointestinal symptoms in IBS are common
and associated with more severe symptoms
and reduced quality of life. Am J Gastroen-
terol 2013;108:634–641.
79. Tack JF, Miner PB Jr, Fischer L, Harris
MS. Randomised clinical trial: the safety
and efficacy of AST-120 in non-constipating
irritable bowel syndrome –a double-blind,
placebo-controlled study. Aliment Pharmacol
Ther 2011;34:868–877.
80. Barbara G, Stanghellini V, De Giorgio R,
Cremon C, Cottrell GS, Santini D et al.
Activated mast cells in proximity to colonic
nerves correlate with abdominal pain in irri-
table bowel syndrome. Gastroenterology
2004;126:693–702.
81. Klooker TK, Braak B, Koopman KE, Wel-
ting O, Wouters MM, van der Heide S et al.
The mast cell stabiliser ketotifen decreases
visceral hypersensitivity and improves intesti-
nal symptoms in patients with irritable
bowel syndrome. Gut 2010;59:1213–1221.
82. Sheil B, Shanahan F, O’Mahony L. Probiot-
ic effects on inflammatory bowel disease.
J Nutr 2007;137(3 Suppl 2):819S–824S.
83. Dvorak AM, Monahan RA, Osage JE,
Dickersin GR. Crohn’s disease: transmission
electron microscopic studies. II. Immuno-
logic inflammatory response. Alterations of
mast cells, basophils, eosinophils, and the
microvasculature. Hum Pathol 1980;11:606–
619.
84. Nolte H, Spjeldnaes N, Kruse A, Windel-
borg B. Histamine release from gut mast
cells from patients with inflammatory bowel
diseases. Gut 1990;31:791–794.
85. King T, Biddle W, Bhatia P, Moore J,
Miner PB Jr. Colonic mucosal mast cell dis-
tribution at line of demarcation of active
ulcerative colitis. Dig Dis Sci 1992;37:490–
495.
86. Nishida Y, Murase K, Isomoto H, Furusu
H, Mizuta Y, Riddell RH et al. Different
distribution of mast cells and macrophages
in colonic mucosa of patients with collage-
nous colitis and inflammatory bowel dis-
ease. Hepatogastroenterology 2002;49:678–
682.
87. Gelbmann CM, Mestermann S, Gross V,
Kollinger M, Scholmerich J, Falk W. Stric-
tures in Crohn’s disease are characterised by
an accumulation of mast cells colocalised
with laminin but not with fibronectin or
vitronectin. Gut 1999;45:210–217.
88. Knutson L, Ahrenstedt O, Odlind B, Hall-
gren R. The jejunal secretion of histamine is
increased in active Crohn’s disease. Gastro-
enterology 1990;98:849–854.
89. Winterkamp S, Weidenhiller M, Otte P,
Stolper J, Schwab D, Hahn EG et al. Uri-
nary excretion of N-methylhistamine as a
marker of disease activity in inflammatory
bowel disease. Am J Gastroenterol
2002;97:3071–3077.
90. Fox CC, Lichtenstein LM, Roche JK. Intes-
tinal mast cell responses in idiopathic inflam-
matory bowel disease. Histamine release
from human intestinal mast cells in response
to gut epithelial proteins. Dig Dis Sci
1993;38:1105–1112.
91. Raithel M, Schneider HT, Hahn EG. Effect
of substance P on histamine secretion from
gut mucosa in inflammatory bowel disease.
Scand J Gastroenterol 1999;34:496–503.
92. Schulze HA, Hasler R, Mah N, Lu T,
Nikolaus S, Costello CM et al. From model
cell line to in vivo gene expression:
disease-related intestinal gene expression in
IBD. Genes Immun 2008;9:240–248.
93. Juillerat P, Schneeweiss S, Cook EF, Anan-
thakrishnan AN, Mogun H, Korzenik JR.
Drugs that inhibit gastric acid secretion may
alter the course of inflammatory bowel dis-
ease. Aliment Pharmacol Ther 2012;36:239–
247.
94. Raithel M, Nagel A, Zopf Y, deRossi T,
Stengel C, Hagel A et al. Plasma histamine
levels (H) during adjunctive H1-receptor
antagonist treatment with loratadine in
patients with active inflammatory bowel dis-
ease (IBD). Inflamm Res 2010;59(Suppl 2):
S257–S258.
95. Jones NL, Roifman CM, Griffiths AM,
Sherman P. Ketotifen therapy for acute
ulcerative colitis in children: a pilot study.
Dig Dis Sci 1998;43:609–615.
96. Thomas CM, Hong T, van Pijkeren JP,
Hemarajata P, Trinh DV, Hu W et al. His-
tamine derived from probiotic Lactobacillus
reuteri suppresses TNF via modulation of
PKA and ERK signaling. PLoS One 2012;7:
e31951.
©2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Smolinska et al. Histamine
