ArticlePDF AvailableLiterature Review

Histamine and gut mucosal immune regulation

Authors:
  • ALL-MED Medical Research Institute
  • National University of Ireland, Cork, Ireland

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 influence of histamine on a number of gastrointestinal disorders, including food allergy, scombroid food poisoning, histamine intolerance, irritable bowel syndrome, 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.
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 (H1RH4R). 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 (610). 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 (1315).
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, granulocytemacrophage 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 [MichaelisMenten constant
(kM): 613 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 (2426). 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 H1RH4R. 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 (3133).
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 sleepwake 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
(4042). 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 (6264). 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
1020% 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 (7577). 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 hostmicrobe 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 microbehost 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.
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Smolinska et al. Histamine
... In general, low amounts of SCFAs in the stool suggest their binding by gut receptors and use by enterocytes indicating a state of eubiosis [54]. Furthermore, other dysbiosis-associated compounds, such as inflammation-related metabolites were absent or decreased in B+ individuals [55]. ...
... In the gut, histamine release is influenced by numerous factors including the host, diet and the overall microbiota composition. Its increase in the gut has also been noted in IBS and IBD sufferers [55,58,59]. The observed decrease in B+ samples may link Blastocystis to anti-inflammatory responses in the gut. ...
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Blastocystis is an obligate anaerobic microbial eukaryote that frequently inhabits the gastrointestinal tract. Despite this prevalence, very little is known about the extent of its genetic diversity, pathogenicity, and interaction with the rest of the microbiome and its host. Although the organism is morphologically static, it has no less than 28 genetically distinct subtypes (STs). Reports on the pathogenicity of Blastocystis are conflicting. The association between Blastocystis and intestinal bacterial communities is being increasingly explored. Nonetheless, similar investigations extending to the metabolome are non-existent.Using established NMR metabolomics protocols in 149 faecal samples from individuals from South Korea (n = 38), Thailand (n = 44) and Turkey (n = 69), we have provided a snapshot of the core metabolic compounds present in human stools with (B+) and without (B−) Blastocystis. Samples included hosts with gastrointestinal symptoms and asymptomatics. A total of nine, 62 and 98 significant metabolites were associated with Blastocystis carriage in the South Korean, Thai and Turkish sample sets respectively, with a number of metabolites increased in colonised groups. The metabolic profiles of B+ and B− samples from all countries were distinct and grouped separately in the partial least squares-discriminant analysis (PLS-DA). Typical inflammation-related metabolites negatively associated with Blastocystis positive samples. This data will assist in directing future studies underlying the involvement of Blastocystis in physiological processes of both the gut microbiome and the host. Future studies using metabolome and microbiome data along with host physiology and immune responses information will contribute significantly towards elucidating the role of Blastocystis in health and disease.
... представили данные иммунорегуляторного влияния гистамина в кишечнике и обсудили в том числе не только непереносимость гистамина, истинную пищевую аллергию, но и влияние микробиоты, т.к. существуют микробы выделяющие гистамин [16]. ...
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Chronic urticaria is a polyetiological disease proceeding by various immunological and non-immunological (pseudo-allergic) mechanisms. Food intolerance is a distinct type of pseudo-allergies, manifesting, e.g., with histamine intolerance syndrome, caused by imbalance between the histamine accumulation and the ability to degrade it. The purpose of this article was to summarize results of recent studies, to discuss the difficulties of diagnosing this pathology, which primarily depends on the degree of impaired histamine degradation under the influence of diamine oxidase. Diamine oxidase is the main enzyme required for histamine destruction in the intestines, being synthesized by apical enterocytes. The review draws attention to the reasons leading to increased level of histamine not only with consumed food, given its different concentration in the same food products, depending, for example, on their processing and storage, but also with suppressing activity of the enzymes required for metabolism of histamine by various food additives, by the influence of microbiota. The results of studies in which the levels of histamine and/or diamine oxidase activity were determined, which depend on adherence to the diet confirming the association of diamine oxidase with the symptoms of histamine intolerance. According to most studies, the compliance with diet led to increased level of diamine oxidase. However, in some studies, no changes in the activity of this enzyme were found. There are several studies that have evaluated the levels of diamine oxidase in patients with true allergies. Moreover, some authors, in addition to adherence to the diet, evaluated the effectiveness of drugs containing diamine oxidase in patients with low levels of this enzyme in blood serum. The workers also confirm high proportion of histamine intolerance syndrome among various food reactions, suggesting a need for differential diagnosis with other non-immune reactions, including disorders of gastrointestinal tract and psychosomatic reactions. Thus, all the authors confirm the need for laboratory diagnosis of histamine intolerance syndrome, since this will not only increase the efficiency of dietary adherence, but also substantiate the usage of drugs containing diamine oxidase, which will improve quality of life in these cohorts. However, these patients are still treated with low-histamine diets. The literature data confirm the opportunity of using this histamine degradation enzyme as a biological marker of histamine intolerance syndrome, and recommend its assays for inclusion into the diagnostic algorithm for chronic urticaria.
... In addition to the main symptoms that cause IgE-mediated food allergies, the ingestion of histamine-rich foods, alcohol, or drugs that release histamine or conduction block diamine oxidase may cause diarrhea; hypotension; arrhythmia; bronchoconstriction and nasal conjunctiva inflammation; urticaria; or headache. These may confuse the diagnosis of food allergy [27]. ...
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Biological amines are organic nitrogen compounds that can be produced by the decomposition of spoiled food. As an important biological amine, histamine has played an important role in food safety. Many methods have been used to detect histamine in foods. Compared with traditional analysis methods, fluorescence sensors as an adaptable detection tool for histamine in foods have the advantages of low cost, convenience, less operation, high sensitivity, and good visibility. In terms of food safety, fluorescence sensors have shown great utilization potential. In this review, we will introduce the applications and development of fluorescence sensors in food safety based on various types of materials. The performance and effectiveness of the fluorescence sensors are discussed in detail regarding their structure, luminescence mechanism, and recognition mechanism. This review may contribute to the exploration of the application of fluorescence sensors in food-related work.
... It gets formed by decarboxylation of histidine via L-histidine decarboxylase (HDC) and acts on four different receptors, namely H1, H2, H3 and H4 [22]. H2 receptors are present in various cells and tissues such as gastric parietal cells, smooth muscle cells, epithelial, endothelial, neuronal, hepatocyte, immune cells, dendritic cells, and the brain and cardiac tissueswhere it acts through Gs protein-coupled receptors via cAMP second messenger system [23,24]. Recently it has been found that that H2 receptor blockers such as famotidine, cimetidine, ranitidine and tiotidine show their effects by affecting the biased agonism signaling pathwayof histamine besides the conventional molecular mechanism [25][26][27][28][29]. ...
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the anti-nociceptive activity of a new non-steroidal anti-inflammatory compound Zaltoprofen vs. Piroxicam in murine models
... Mice supplemented with probiotic L. rhamnosus were found to have decreased anxiety levels in addition to increased gene expression of both GABAAα1 and GABAAα2 in the hippocampus [432]. Histamine, synthesized by both microbiota and epithelial gut cells of the host have essential roles for mediating gut microbiome and host neurocommunication [447,448]. Application of the probiotic L.reuteri activates histamine receptor 2, thereby modulating host mucosal responses to inflammation and highlighting the role of probiotic microbiota in gut-brain communication [449]. ...
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Parkinson’s Disease (PD) is a neurodegenerative disease, leading to motor and non-motor complications. Autonomic alterations, including gastrointestinal symptoms, precede motor defects and act as early warning signs. Chronic exposure to dietary, environmental heavy metals impacts the gastrointestinal system and host-associated microbiome, eventually affecting the central nervous system. The correlation between dysbiosis and PD suggests a functional and bidirectional communication between the gut and the brain. The bioaccumulation of metals promotes stress mechanisms by increasing reactive oxygen species, likely altering the bidirectional gut–brain link. To better understand the differing molecular mechanisms underlying PD, integrative modeling approaches are necessary to connect multifactorial perturbations in this heterogeneous disorder. By exploring the effects of gut microbiota modulation on dietary heavy metal exposure in relation to PD onset, the modification of the host-associated microbiome to mitigate neurological stress may be a future treatment option against neurodegeneration through bioremediation. The progressive movement towards a systems toxicology framework for precision medicine can uncover molecular mechanisms underlying PD onset such as metal regulation and microbial community interactions by developing predictive models to better understand PD etiology to identify options for novel treatments and beyond. Several methodologies recently addressed the complexity of this interaction from different perspectives; however, to date, a comprehensive review of these approaches is still lacking. Therefore, our main aim through this manuscript is to fill this gap in the scientific literature by reviewing recently published papers to address the surrounding questions regarding the underlying molecular mechanisms between metals, microbiota, and the gut–brain-axis, as well as the regulation of this system to prevent neurodegeneration.
... Based on a recent study, butyrate, which helps induce IL10-secreting T cells and Treg cells, induces the regulatory activity of the DCs, which is mediated on colonic DCs and macrophages by the G-protein-coupled receptor, Gpr109a [85,86]. It has been shown that Butyrate induces IL23 secretion by mouse DCs, which activates the TH17 response under certain conditions and also increases mucosal histamine levels in patients with inflammatory bowel disorder and intestinal syndrome [87]. It can reduce the secretion of proinflammatory chemokines and cytokines that are stimulated by TLR-stimulated DCs, albeit raising IL10 production [88]. ...
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Due to the importance of using cost-effective methods for therapeutic purposes, the function of probiotics as safe microorganisms and the study of their relevant functional mechanisms have recently been in the spotlight. Finding the mechanisms of attachment and stability and their beneficial effects on the immune system can be useful in identifying and increasing the therapeutic effects of probiotics. In this review, the functional mechanisms of probiotics were comprehensively investigated. Relevant articles were searched in scientific sources, documents, and databases, including PubMed, NCBI, Bactibace, OptiBac, and Bagel4. The most important functional mechanisms of probiotics and their effects on strengthening the epithelial barrier, competitive inhibition of pathogenic microorganisms, production of antimicrobials, binding and interaction with the host, and regulatory effects on the immune system were discussed. In this regard, the attachment of probiotics to the epithelium is very important because the prerequisite for their proper functioning is to establish a proper connection to the epithelium. Therefore, more attention should be paid to the binding effect of probiotics, including sortase A, a significant factor involved in the expression of sortase-dependent proteins (SDP), on their surface as mediators of intestinal epithelial cell binding. In general, by investigating the functional mechanisms of probiotics, it was concluded that the mechanism by which probiotics regulate the immune system and adhesion capacity can directly and indirectly have preventive and therapeutic effects on a wide range of diseases. However, further study of these mechanisms requires extensive research on various aspects.
... It also plays important roles in other immune responses, neurotransmissions and disease pathogenesis (Benly, 2015;Mirjam and Donald, 2012;Shahid et al., 2009;Carlos et al., 2009;Polazzi and Monti, 2010;Nuutinen and Panula, 2010;Passani et al., 2014;Benly, 2015;Kenedy et al., 2012;Steven et al., 2008). Histamine was first discovered in 1910 but its role as a mediator of allergic reaction was first described in 1932 (Smolinska et al., 2013). ...
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Food processing and storage increase the value chain of food items, both for commercial purposes and for future use by peasant producers. The roles of lactic acid bacteria (LAB) and yeasts in the processing of dairy, brewed, bakery and traditionally fermented foods cannot be over-emphasized. These organisms improve the nutritional contents and organoleptic properties of these foods. However, certain undesired products, especially from protein-rich foods, notably, biogenic amines often characterize the process. This is usually a physiologic response by the organisms to the food environments such as pH, and is often influenced by temperature, time and salt concentration. Histamine production during such a process often results in the accumulation of exogenous histamine in the foods, thereby constituting health hazards to the consumers. Histamine food poisoning affects virtually every system of the body due to the widespread physiological roles of histamine in the body, presenting a wide range of symptoms that make diagnosis difficult. More regulated scientific approaches should be adopted by food processors and handlers especially in the developing countries where technologies may not be available.
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Background & Aims Pro-inflammtory diet interacting with gut microbiome might trigger for Crohn's disease (CD). We aimed to investigate the relationship between dietary inflammatory potential and microflora/metabolites change and their link with CD. Methods The dietary inflammatory potential was assessed using a dietary inflammatory index (DII) based on the Food Frequency Questionnaire from 150 new-onset CD patients and 285 healthy controls (HCs). We selected 41 CD patients and 89 HCs who had not received medication for metagenomic and targeted metabolomic sequencing to profile their gut microbial composition as well as fecal and serum metabolites. DII scores were classified into quartiles to investigate associations among different variables. Results DII scores of CD patients were significantly higher than HCs (0.56 ± 1.20 vs 0.23±1.02, p = 0.017). With adjustment for confounders, a higher DII score was significantly associated with higher risk of CD (OR: 1.420; 95% CI: 1.049, 1.923, p = 0.023). DII score also was positively correlated with disease activity (p = 0.001). Morganella morganii and Veillonella parvula were increased while Coprococcus eutactus was decreased in the pro-inflammatory diets group, as well as in CD. DII-related bacteria were associated with disease activity and inflammatory markers in CD patients. Among the metabolic change, pro-inflammatory diet induced metabolites change were largely involved in amino acid metabolic pathways that were also observed in CD. Conclusions Pro-inflammatory diet might be associated with increased risk and disease activity of CD. Diet with high DII potentially involves in CD by mediating alterations in gut microbiota and metabolites.
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Histamine intolerance (HIT) is a common disorder associated with impaired histamine metabolism. Notwithstanding, it is often misdiagnosed as other diseases because of its lack of specific clinical manifestations. HIT did not gain traction until the early 21st century. In this review, we will focus on the latest research and elaborate on the clinical manifestations of HIT, including its manifestations in special populations such as atopic dermatitis (AD) and chronic urticaria (CU), as well as the latest understanding of its etiology and pathogenesis. In addition, we will explore the latest treatment strategies for HIT and the treatment of specific cases.
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This study integrated metagenomics and metabolomics to evaluate the effects of diets with different starch sources on the microbial community, metabolic functions, and resultant metabolites in the cecum of finishing pigs. In this study, 48 crossbred growing barrows were randomly allocated to 2 treatment groups with eight replicate pens of 3 pigs each. Pigs were fed a tapioca starch (TS) diet or a pea starch (PS) diet (the ratio between amylose and amylopectin of the two diets were 0.11 and 0.44, respectively) for 44 days. The results showed that, compared with the TS diet, the PS diet increased (P <0.05) the relative abundance of amylolytic bacteria, such as Lactobacillus spp., and Streptococcus spp., and decreased (P <0.05) the relative abundance of some inflammatory bacteria, such as Tyzzerella, Porphyromonas, and Tannerella in the cecum of pigs. In addition, analysis of microbial functions showed that 11 carbohydrate-active enzymes, such as GH73, AA3, and AA6, were enriched in the PS group (P < 0.05), while 26 other enzymes, such as GH2, GH35, and GH53, were enriched in the TS group (P < 0.05). Meanwhile, KEGG pathway analysis showed a decreasing trend (P < 0.1) for energy metabolism and amino acid metabolism pathways, and a significant increase (P < 0.05) in the lipid metabolism pathways in the PS group. Correspondingly, the resultant metabolites related to amino acids and their derivatives (such as decreased histamine and indole, while increased γ-aminobutyric acid and pyroglutamic acid), and fatty acids and lipids (such as increased tetradecanoylcarnitine and monoacylglycerol) were also changed (P < 0.05) in the cecum of pigs fed the PS diet. In summary, these findings indicated that the cecal microbiota and metabolism underwent responsive changes to diets with different starch sources, and a high ratio of amylose to amylopectin in diets may be beneficial to intestinal health of pigs.
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Components of the commensal flora, including Bifidobacteria and Lactobacilli, have been associated with beneficial effects on the host. These beneficial effects include maintenance of intestinal homeostasis, competitive exclusion of pathogens, production of antimicrobial compounds, promotion of gut barrier function, and immune modulation. Probiotics currently can be administered in dairy yogurts and drinks and also in the form of sachets or capsules. Although preliminary studies are clearly promising, placebo-controlled, randomized, double-blind clinical trials are required to clarify the role of probiotic bacteria in the treatment of inflammatory bowel disease. The choice of probiotic bacteria, the optimal dose, mode of administration, and duration of therapy still need to be established. Detailed strain characterization is also required for all potential probiotic strains. As evidence accumulates to suggest a breakdown in tolerance toward ubiquitous intestinal bacteria, it appears logical to intervene by modulating the enteric flora. Increasingly, research suggests that probiotics may offer an alternative or adjuvant approach to conventional therapy by altering the intestinal microflora and modulating the host immune system.
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Histamine is the main causative agent of hazard of seafood products. It is the causative agent of scombroid poisoning and a chemical hazard regulated by scombroid poisoning, and is formed by time/temperature the FDA according to the HACCP guideline. Although the abuse of fish muscle (l). The outbreak of scombroid mechanism of histamine formation is well understood, poisoning associated with the consumption of seafood outbreaks of scombroid poisoning continue to occur in has consistently been reported through the foodborne association with the consumption of seafoods. Since disease outbreak surveillance of the Centers for Disease accumulation of histamine in seafood products requires Control and Prevention (2). Furthermore, the FDA has the proliferation of histidine decarboxylase-possessing established the 50 ppm (5 mg/100 g) guideline for histamine bacteria, it is possible to control and prevent …
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Background Epidermal hyperproliferation resulting in acanthosis is an important clinical observation in patients with atopic dermatitis, and its underlying mechanisms are not completely understood. Objective Because increased levels of histamine are present in lesional skin, we investigated the effect of histamine, especially with regard to histamine 4 receptor (H4R) activation, on the proliferation of human and murine keratinocytes. Methods The expression of H4R on human and murine keratinocytes was detected by using real-time PCR. Keratinocyte proliferation was evaluated by using different in vitro cell proliferation assays, scratch assays, and measurement of the epidermal thickness of murine skin. Results We detected H4R mRNA on foreskin keratinocytes and on outer root sheath keratinocytes; H4R mRNA was more abundant in keratinocytes from patients with atopic dermatitis compared with those from nonatopic donors. Stimulation of foreskin keratinocytes, atopic dermatitis outer root sheath keratinocytes, and H4R-transfected HaCaT cells with histamine and H4R agonist resulted in an increase in proliferation, which was blocked with the H4R-specific antagonist JNJ7777120. Abdominal epidermis of H4R-deficient mice was significantly thinner, and the in vitro proliferation of keratinocytes derived from H4R-deficient mice was lower compared with that seen in control mice. Interestingly, we only detected H4R expression on murine keratinocytes after stimulation with LPS and peptidoglycan. Conclusion H4R is highly expressed on keratinocytes from patients with atopic dermatitis, and its stimulation induces keratinocyte proliferation. This might represent a mechanism that contributes to the epidermal hyperplasia observed in patients with atopic dermatitis.
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Components of the commensal flora, including Bifidobacteria and Lactobacilli, have been associated with beneficial effects on the host. These beneficial effects include maintenance of intestinal homeostasis, competitive exclusion of pathogens, production of antimicrobial compounds, promotion of gut barrier function, and immune modulation. Probiotics currently can be administered in dairy yogurts and drinks and also in the form of sachets or capsules. Although preliminary studies are clearly promising, placebo-controlled, randomized, double-blind clinical trials are required to clarify the role of probiotic bacteria in the treatment of inflammatory bowel disease. The choice of probiotic bacteria, the optimal dose, mode of administration, and duration of therapy still need to be established. Detailed strain characterization is also required for all potential probiotic strains. As evidence accumulates to suggest a breakdown in tolerance toward ubiquitous intestinal bacteria, it appears logical to intervene by modulating the enteric flora. Increasingly, research suggests that probiotics may offer an alternative or adjuvant approach to conventional therapy by altering the intestinal microflora and modulating the host immune system.
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Transmission electron microscopy was done using surgically resected specimens from 12 patients with Crohn's disease and three control subjects. Nonulcerated involved areas of ileum as well as proximal, grossly uninvolved resection margins were chosen for study. Specimens for transmission electron microscopy were prepared for viewing by a variety of techniques. Six hundred five Epon embedded blocks were studied by light microscopy, and 112 of these were viewed in the transmission electron microscope.
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“Black vomit” is a serious disease in chicks and is caused by some kinds of fish meal in the diet. However, the causative compound has not been identified. In the present study, a new substance, 2-amino-9-(4-imidazolyl)-7-azanonanoic acid, has been isolated from mackerel meal and named Gizzerosine. This compound caused severe gizzard erosion in chiks within a week when it was fed to them at the level of 2.2 ppm in the diet. Gizzerosine is produced during fish meal manufacturing by the reaction between histidine and protein in the fish meat. The discovery of Gizzerosine raises a new problem in food chemistry and animal nutrition.