Histamine and Gut Mucosal Immune Regulation S

REVIEW ARTICLE Histamine and gut mucosal immune regulation S. Smolinska1,2, M. Jutel1,2, R. Crameri3 & L. O’Mahony3

1Department of Clinical Immunology, Wroclaw Medical University, Wroclaw; 2‘ALL-MED’ Medical Research Institute, Wroclaw, Poland; 3Swiss 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 Abstract allergy; histamine; inflammation; microbial Histamine is a biogenic amine with extensive effects on many cell types, mediated metabolites; mucosal immunology. by the activation of its four receptors (H1R–H4R). Distinct effects are dependent Correspondence on receptor subtypes and their differential expression. Within the gastrointestinal Dr. Liam O’Mahony, SIAF, Obere Strasse tract, histamine is present at relatively high concentrations, particularly during 22, 7270 Davos Platz, Switzerland. inflammatory responses. In this review, we discuss the immunoregulatory influ- Tel.: +41-81-4100853 ence of histamine on a number of gastrointestinal disorders, including food Fax: +41-81-4100840 allergy, scombroid food poisoning, histamine intolerance, irritable bowel syn- E-mail: [email protected] 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 Accepted for publication 21 October 2013 four currently known histamine receptors; however, the relative protective or pathogenic effects of histamine on inflammatory processes within the gut are still DOI:10.1111/all.12330 poorly defined and require further investigation. Edited by: Hans-Uwe Simon

Histamine [2-(4-imidazolyl)-ethylamine] is a short-acting studies demonstrate the influence of histamine on wound endogenous amine, which is widely distributed throughout healing, circulatory disease, immunology, oncology, and the body (1, 2). Histamine is synthesized by the enzyme histi- infectious disease (5). dine decarboxylase (HDC), which decarboxylates the semi- Histamine can be produced by a wide variety of different essential amino acid L-histidine. Originally discovered more cell types (6–10). Mast cells, basophils, gastric enterochro- than 100 years ago, histamine was first chemically synthe- maffin-like cells, and histaminergic neurons are the best sized by Windaus and Vogt in 1907. Soon afterward in 1910, described cellular sources of histamine, but other cell types, Dale and Laidlaw reported the first biological functions of for example platelets, dendritic cells (DCs), and T cells, can histamine, whereby they recognized that histamine had the also express HDC following stimulation. In addition, certain ability to mimic smooth muscle-stimulating and vasodepres- microbes can express HDC, and these will be discussed sor action previously observed during anaphylaxis (3, 4). further below. HDC expression and histamine release is influ- Subsequently, histamine was isolated from many different tis- enced by cytokines including IL-1, IL-3, IL-12, IL-18, sues, and thus, its name was based on the Greek word ‘his- GM-CSF, macrophage colony-stimulating factor, and tumor tos’, which means tissue. Studies utilizing HDC-knockout necrosis factor (TNF)-a (1, 11, 12). Mast cells and basophils animals have revealed the multiple effects of histamine on store large quantities of histamine, which is released upon allergic, peptic, and neurologic functions, while more recent degranulation in response to immunological and nonimmu- nological stimuli. However, other cell types such as DCs and lymphocytes do not store histamine intracellularly, but Abbreviations secrete it following synthesis (13–15). CD, Crohn’s disease; DAO, diamine oxidase; DC, dendritic cells; An important aspect of histamine biology are the enzymes GM-CSF, granulocyte–macrophage colony-stimulating factor; that degrade histamine. Histamine can be metabolized by GPCR, G-protein-coupled receptors; HDC, histidine decarboxylase; oxidative deamination (diamine oxidase – DAO) or by ring HNMT, histamine-N-methyltransferase; HR, histamine receptor; methylation (histamine-N-methyltransferase – HNMT) (16). IBD, inflammatory bowel disease; IBS, irritable bowel syndrome; Diamine oxidase is stored in plasma membrane-associated IL, interleukin; iNKT, invariant natural killer T cell; OVA, ovalbumin; vesicular structures in epithelial cells and is secreted into the RAST, radioallergosorbent test; SNPs, single-nucleotide circulation following stimulation. Histamine-N-methyltrans- polymorphisms; TH, T helper cell; TNF, tumor necrosis factor; ferase is a cytosolic enzyme, which can convert histamine UC, ulcerative colitis.

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Histamine Smolinska et al. only in the intracellular space of cells. Thus, it has been pro- While histamine is well recognized for its effects in the posed that DAO may be responsible for scavenging extracel- immediate-type hypersensitivity response (i.e., increased vas- lular histamine, while HNMT metabolizes intracellular cular permeability, smooth muscle contraction, activation of histamine. Histamine-N-methyltransferase has a slightly nociceptive nerves, wheal and flare reaction and itch higher affinity for histamine [Michaelis–Menten constant response), the pathological relevance of increased histamine (kM): 6–13 lM] compared to DAO (kM: 20 lM). In mam- levels at diseased sites is less well understood in other disor- mals, DAO expression is restricted to specific tissues; the ders such as inflammatory bowel disease (IBD) and irritable highest activities are in the small bowel, colon, placenta, and bowel syndrome (IBS) (19, 20). Indeed, histamine may nega- kidney (17). Histamine-N-methyltransferase is widely tively or positively influence parasitic and bacterial infections expressed in human tissues; the greatest expression is in kid- (21, 22). Within the gastrointestinal tract, histamine levels ney and liver, followed by spleen, colon, prostate, ovary, can be influenced by host allergic and inflammatory spinal cord cells, bronchi, and trachea. Histamine-N-methyl- responses, altered activity of degradative enzymes, dietary transferase is regarded as the key enzyme for histamine intake, and microbial processes (Fig. 1). In this review, degradation in the bronchial epithelium (18). we will discuss the potential pathological and potential

Figure 1 Histamine within the mucosa. The major cellular sources of H1R on lymphocytes promotes TH1 polarization, while the activation histamine within the gastrointestinal tract are illustrated. Histamine of H2R suppresses TH1 and TH2 polarization, favoring polarization to alters the dendritic cell response to microbes by enhancing IL-12 TREGs. H4R may aid TH2 polarization, and H4R displays chemotactic secretion via H1R, while H2R activation promotes IL-10 secretion and properties. Activation of epithelial cells with histamine inﬂuences bar- inhibits IL-12, TNF-a, and IL-23 secretion. In addition, the activation of rier function. Enteric neurons are activated via H3R.

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Smolinska et al. Histamine protective roles of histamine in gastrointestinal disorders. In modulate a range of immune system activities such as mast addition, we will highlight some of the limitations regarding cell degranulation, antibody synthesis, cytokine production, the diagnosis of and treatment for these ailments. and T-cell polarization. In particular, DC responses to microbial ligands were significantly altered by histamine in a H2R- dependent manner (34). Other effects, such as the suppression Immunomodulatory effects of histamine of IL-27 secretion, were mediated via H2R and H4R (35). The immune response is strictly controlled by effector and Murine H2R-knockout mice display defects in gastric and regulatory processes, which normally result in protection immune regulatory functions as well as selective cognitive from infection and tolerance of innocuous environmental defects and abnormalities in nociception (36, 37). antigens. However, in inflammatory diseases, the activated H3R is a presynaptical autoreceptor in the peripheral and immune response results in a chronic pro-inflammatory state central nervous system and has been shown to be involved in characterized by activated innate pathways with aberrant the sleep–wake cycle, cognition, homeostatic regulation of expansion and polarization of TH1, TH2, TH9, TH17, TH22, energy levels, and inflammation. H3R-knockout mice display or TREG lymphocyte populations. Thus, the ongoing identifi- a metabolic syndrome characterized by hyperphagia, late- cation of appropriate controlling factors that augment pro- onset obesity, increased insulin and leptin levels (38). In addi- tective immune responses while limiting tissue damage is tion, H3R knockouts had an increased severity of neuroin- being intensively investigated. Many host-derived and envi- flammatory diseases associated with enhanced expression of ronment metabolites can influence immune reactivity, for MIP-2, IP-10, and CXCR3 by peripheral T cells (39). example microbiota and dietary factors significantly influence The H4R is the most recent receptor to be discovered, and mucosal immune homeostasis (23). it shares some molecular and pharmacological properties Cells of both the innate and adaptive immune system can with the H3R. However, in contrast to H3R, H4R is be regulated by histamine (24–26). The regulatory nature of expressed by a wide range of cells including keratinocytes, histamine in immunology is dependent on its binding to four Langerhans cells, DCs, neutrophils, and lymphocytes subtypes of histamine receptors, which are named chronolog- (40–42). Invariant NK T (iNKT) cells are numerically and ically in order of their discovery – H1R–H4R. These four functionally impaired in HDC-knockout mice with dimin- receptors belong to the rhodopsin-like family of G-protein- ished secretion of IL-4 and IFN-a following stimulation. coupled receptors, which are differentially expressed in H4R signaling was essential for the histamine effect on iNKT numerous cell types and contain seven transmembrane cytokine secretion (43). An exciting new development domains (27). The different receptor molecular responses to suggests that the combined treatment with H1R and H4R histamine are primarily due to the activation of specific Ga antagonists may have a significant therapeutic effect on subunits, as each Ga subunit activates distinct molecular sig- chronic dermatitis through the synergistic inhibition of naling cascades. H1R binding leads to the activation of Gaq pruritus and skin inflammation (44). 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 The role of histamine in inflammatory disorders of example H1R signaling can antagonize or amplify H2R- the gut mediated responses depending on the time and context of Histamine intolerance receptor activation (28). H1R is expressed by a broad range of cell types including Histamine intolerance is thought to result from an incorrect neurons, airway and vascular smooth muscle cells, epithelial balance between accumulated histamine and the capacity for cells, hepatocytes, chondrocytes, endothelial cells, DCs, histamine degradation. The increased availability of hista- monocytes, neutrophils, T cells, and B cells (29, 30). H1R mine may be caused by endogenous histamine overproduc- gene expression can be upregulated by IL-3, IL-4, and hista- tion (e.g., allergies or mastocytosis) or increased exogenous mine, while H1R activation is responsible for many of the ingestion of histidine or histamine (in food, alcohol, or from features associated with the allergic immediate-type hypersen- bacteria), but the main cause is currently thought to be due sitivity response, such as redness, itching, and swelling. to impaired enzymatic degradation of histamine, possibly due Peripheral H1R-mediated effects include rhinorrhea, bron- to genetic or acquired impairment of the enzymatic functions choconstriction, anaphylaxis, conjunctivitis, and urticaria, of DAO or HNMT. Diamine oxidase is the primary enzyme while central-associated H1R effects include the regulation of required for the degradation of ingested histamine (45). food and water intake, convulsion, attention, and sleep regu- Histamine intolerance is associated with a range of symptoms lation. H1R antagonists have been shown to have multiple that mimic an allergic reaction, such as diarrhea, headache, effects on the allergic inflammatory response, and murine rhinoconjunctival symptoms, asthma, hypotension, arrhyth- H1R-knockout models have revealed significant immunologi- mia, urticaria, pruritus, and flushing (46, 47). Some estimates cal (impairment of T- and B-cell responses), metabolic, and suggest that approximately 1% of the population is histamine behavioral abnormalities (31–33). intolerant, and 80% of those patients are middle-aged (45). Similar to H1R, expression of H2R is found in a variety of However, these estimates are controversial and the exact pro- tissues and cells including brain, gastric parietal cell, smooth portion of individuals exhibiting histamine intolerance is still muscle cells, T and B cells, DCs, and cardiac tissue. H2R can unknown.

Due to the various symptoms observed in multiple organs, numbness, headache, dizziness, palpitations, rapid and weak the diagnosis of histamine intolerance is difficult. Diagnosis pulse, low blood pressure, difficulty in swallowing, thirst, of histamine intolerance requires the presentation of ≥2 typi- hives, rash, flushing, and facial swelling. Sometimes nausea, cal symptoms of histamine intolerance and improvement fol- vomiting, and diarrhea are also observed. The symptoms of lowing the introduction of a histamine-free diet and the use scombroid poisoning typically are rapid in onset following of antihistamines. Potential food allergies should be excluded the consumption of fish and recovery is usually complete by skin prick test or by the determination of specific IgE for within 24 h, but in rare cases can last for days. Treatment food allergens. Occult systemic mastocytosis should be also for scombroid poisoning includes the administration of anti- excluded, for example by measuring serum tryptase levels. histamines, while corticosteroids are ineffective (52). The The accurate diagnosis of histamine intolerance should be proper handling and storage of fish is the most effective pre- based on the well-documented association between food con- ventive measure as cooking contaminated fish does not pre- sumption and symptoms, identification of food causing vent histamine poisoning because the toxins are heat stable. symptoms, determination of histamine content of the food In addition to the presence of histamine, other mechanisms causing the symptoms, exclusion of other causes (e.g., allergy, have also been proposed that contribute to scombroid poi- toxins, metabolites), oral histamine provocation (if possible), soning. Firstly, histamine toxicity could be potentiated by determination of DAO and HNMT contents and activity in toxins, which inhibit histamine-metabolizing enzymes. Hista- intestinal mucosa (not in peripheral blood), and the analysis mine toxicity is potentiated by the action of DAO and of DAO and HNMT genetic polymorphisms (48). HNMT inhibitors that are also present together with dietary For histamine-intolerant patients, alcohol and long-ripened histamine in the ingested fish. Inhibition of HNMT and or fermented (and therefore histamine-rich) foods, for exam- DAO, which usually degrade histamine, leads to increased ple aged cheese, cured meat, yeast products, spinach, toma- histamine levels within the gut, and subsequently, increased toes, and histamine liberators, such as citrus fruit, should be amounts of histamine are available for absorption to extra- avoided (49). A histamine-free diet can be complemented intestinal tissues (58). Secondly, the induction of mast cell with adjuvant administration of antihistamine receptor drugs. degranulation will release endogenous histamine. The second In addition, histamine degradation can be supported by the hypothesis is based on ‘scombrotoxins’ that are mast cell administration of vitamin C and B-6, which may increase degranulators associated with the spoiled fish. This hypothesis DAO activity (50, 51). The use of drugs that interfere with is significantly different from the first in that dietary histamine histamine metabolism should be avoided. Recently, capsules in the implicated fish is not solely required. Rather, the containing DAO isolated from pig kidneys have been gener- observed toxicity may be due to the endogenous release of ated to supplement the proposed deficit of endogenous histamine (59). Finally, currently unknown histamine recep- human DAO in patients with histamine intolerance (45). 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). Scombroid poisoning It is a potent H2R agonist, approximately 200 times more Scombroid poisoning (the term ‘scombroid’ is derived from potent than histamine itself, and gizzerosine kills poultry by the type of fish Scombridae, which were first implicated), or causing excessive excretion of digestive acids (60). Although histamine fish poisoning, is a type of food poisoning with certainly not implicated in scombroid poisoning, gizzerosine symptoms and treatment similar to those associated with sea- provides an excellent example of a previously unknown and food allergies (52). Scombroid poisoning results from the histidine-derived agonist active at a histamine receptor. Based consumption of mishandled fish. Histamine and other decom- on this precedent, there may be other histidine-derived composition products are generated in fish tissues by bacterial pounds in scombroid poisoning-implicated fish that could conversion of free histidine (53). Scombrid fish have high bind to histaminergic receptors, and thus, it is not possible to levels of free histidine in their muscle tissues, compared to rule out the existence of other agonists without comparing nonscombroid species, which have lower levels. However, the total histamine receptor bioactivity with the predicted nonscombroid fish species have also been implicated in scom- activity based on known histamine concentrations in out- broid poisoning. Histamine is produced by a wide range of break-implicated sample extracts. If there were other hista- bacteria, but the major histamine-producing bacteria in fish minergic receptor agonists for the various histaminergic are Gram-negative mesophilic enteric and marine bacteria receptors with activity comparable to that shown by gizzero- (54, 55). Examples include strains of Morganella morganii, sine for H2 receptors, low levels of bioactive compounds Enterobacter aerogenes, Raoultella planticola, Raoultella orni- could be enough to cause illness. thinolytica, and Photobacterium damselae, some of which can secrete ≥1000 ppm histamine during optimal in vitro culture Food allergy conditions. Strains of other species, including Hafnia alvei, Citrobacter freundi, Vibrio alginolyticus, and Escherichia coli, The gut immune system is exposed daily to a large number are weak histamine producers (or nonproducers), yielding and variety of foreign proteins, and the ability to avoid aller- concentrations <500 ppm under similar in vitro culture condi- gic reactions to food is significantly influenced by the way tions (56, 57). The symptoms of scombroid poisoning are these potential allergens are transported, presented, and variable and can include a peppery or metallic taste, oral responded to (61). The influence of histamine on altering the

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Smolinska et al. Histamine gut immune response to food antigens has not been defini- shock in an experimental model, which is directly related to tively examined; however given the immunoregulatory func- the inactivation of histamine (72). A new concept for the tions of histamine described above, it is tempting to treatment of food allergy is based on the oral administration speculate that histamine and its receptors could be involved of DAO associated with catalase. An oral bi-enzymatic ther- either directly or indirectly in food antigen tolerance and sen- apy with DAO and catalase was suggested to reduce the lev- sitization mechanisms. In addition to eliciting the major els of intestinal histamine via degradation by DAO, with the symptoms of IgE-mediated food allergy, the ingestion of his- production of H2O2,NH3, and imidazole acetaldehyde. As tamine-rich food, alcohol, or drugs that release histamine or H2O2, a by-product of degradation, is toxic due to its pro- block DAO may induce diarrhea, hypotension, arrhythmia, oxidant effects on intestinal cells, catalase has been included bronchial constriction, rhinoconjunctivitis, urticaria, or head- to decompose H2O2. ache, which can confuse the diagnosis of food allergy. In food-allergic subjects, enhanced secretion of histamine Irritable bowel syndrome and increased numbers of mast cells in the intestines have been demonstrated (62–64). From the duodenal mast cells of Irritable bowel syndrome is a chronic condition that affects food-allergic patients, the anti-IgE-mediated mast cell hista- 10–20% of the population. Patients experience recurrent mine release was increased compared with nonallergics. His- abdominal discomfort or pain, in combination with altered tamine release from basophils was positively correlated with bowel habits. The etiology and the pathophysiology are only the test scores of the RAST analysis, skin prick test, and partly understood, with some evidence suggesting that dis- food challenge (65). This result was confirmed in other stud- rupted mucosal immune responses play a role (73, 74). In ies, whereby incubation of biopsies from food-allergic addition, the composition of the gastrointestinal microbiota is patients with anti-human IgE antibodies or allergens induced altered and the administration of specific microbes has thera- a ninefold increase in histamine release. Stimulation of biop- peutic effects (75–77). Frequently patients with IBS experience sies ex vivo with histamine itself induced a concentration- postprandial worsening of their symptoms, and patients typi- dependent NO response only in food-allergic subjects (66). It cally avoid certain foods to reduce symptoms. Thus, the has been postulated that this method can also be utilized majority of patients with IBS feel that specific foods are diagnostically to quantify allergen-induced histamine secre- important triggers of their symptoms. In a recent study, 58% tion in live human colorectal biopsy tissue and has been sug- of the patients with IBS studied experienced gastrointestinal gested to correlate with alterations in transepithelial symptoms from histamine-releasing food items and foods rich resistance (67). in biogenic amines (78). Interesting, the use of spherical car- It is important to note that not only mast cells or baso- bon absorbent (which adsorbs molecules such as histamine philes are cellular sources of histamine. Other host cells and from the gut lumen) has been beneficial for some patients (79). an altered microbiome may also contribute to increased his- Endogenous histamine has been implicated as an important tamine levels and the associated response to food allergens. mediator associated with symptom severity in IBS. Activated However, this has not been studied in detail for food-allergic mast cells, which were spontaneously secreting higher amounts patients. of histamine, in proximity to colonic nerves were correlated The relative contribution of the different histamine recep- with abdominal pain in patients with IBS (80). Mucosal biopsy tors to the induction of food allergy has also not been ade- supernatants from patients with IBS contained higher levels of quately studied. In mice, intraperitoneal administration of histamine compared to biopsy supernatants from healthy cimetidine (H2R antagonist) together with ovalbumin (OVA) volunteers, while the mast cell stabilizer and H1R antagonist resulted in enhanced TH2 cytokine secretion by spleen cells ketotifen reduces some IBS symptoms (20, 81). stimulated with OVA in vitro and increased IgE levels in the sera (68). In humans, treatment with H2R antagonists results Inflammatory bowel diseases in enhanced IgE production against food antigens (69, 70). These results indicate that H2R antagonists may contribute Crohn’s disease (CD) and ulcerative colitis (UC) are the two to the development of IgE-mediated food allergies; however, major forms of IBD, and both diseases are associated with the use of other non-H2R targeting antacids is also a risk high morbidity and healthcare costs. The two disorders have factor for the development of food allergies. distinct features (82). Ulcerative colitis is characterized by Current therapy for food allergy is not curative. The inflammation with superficial ulcerations limited to the effectiveness of antihistamines and mast cell stabilizers in mucosa of the colon. Inflammation usually starts in the rec- ameliorating food allergy symptoms is very limited. Single- tum and continuously spreads throughout the colon. Crohn’s nucleotide polymorphisms in the DAO gene have been disease, however, is characterized by a discontinuous pattern, detected in patients with food allergy symptoms; however, potentially affecting the entire gastrointestinal tract. In con- the IgE status of these patients was not described and this trast to ulcerative colitis, inflammation in patients with CD is group could potentially include histamine-intolerant, rather transmural with large ulcerations, and occasionally, granulo- than food-allergic, individuals (71). Current DAO prepara- mas are observed. The precise mechanisms causing these dis- tions did not reduce mast cell degranulation in response to eases remain unknown but complex interactions between the allergens; however, porcine kidney DAO shows antihista- immune system, enteric microbiota, and host genotype under- minic activity in vivo and protects against pig anaphylactic lie the development of IBD. Some studies have demonstrated

© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd Histamine Smolinska et al. that components of the intestinal microbiota can drive pro- While it is clear that histamine is present at higher levels tective or pathological responses in IBD models, highlighting within the mucosa of patients with IBD, the potential protec- the importance of host–microbe communication in the devel- tive or pathological role for histamine signaling through its opment of these diseases. different receptors has not been determined in patients with The importance of mast cells has been well documented in IBD. Recently, the use of H2R antagonists, but not proton patients with IBD. In 1980, Dvorak and colleagues reported pump inhibitors, significantly increased the risk of hospital- that the number of mast cells was markedly increased in the ization or surgery in patients with CD (93). Although these involved area of the ileum of patients with CD (83). In 1990, results should be interpreted with caution, one could hypoth- Nolte et al. found that the mast cell count in patients with esize that histamine signaling through the H2R may have ulcerative colitis was increased compared with that in control some protective effects within the mucosa of patients with subjects and patients with CD. In addition, more mast cells IBD. In contrast, inhibition of the H1R may have some pro- were present in inflamed tissue compared to adjacent nonin- tective effects in a subset of patients with IBD, but these flamed tissue (84). Additional studies confirmed the finding studies need to be repeated in larger cohorts (94, 95). that mast cell number was significantly increased in inflamed tissue from patients with ulcerative colitis, particularly at the The role for microbial-derived histamine line of demarcation between inflamed and normal mucosa. The accumulation of mast cells at the visible line of demarca- There are many new examples, appearing regularly in the lit- tion between normal and abnormal mucosa suggested that erature, which describe novel microbe–host interactions that mast cells played a crucial role in the pathogenesis of the dis- impact the immunological health of the host. Specific ease, either causing further damage or limiting the expansion microbes within the microbiota have been described to release of damage (85). Nishida and colleagues found that there were the biogenic amine histamine. In bacteria, the expression and greater numbers of mast cells than macrophages in the lam- activity of amino acid decarboxylases is enhanced in acidic ina propria of patients with IBD, although this was not environments, such as in the stomach. This leads to a local found in patients with collagenous colitis (86). Interestingly, increase in pH around the bacteria and protects it from the increased numbers of mast cells were observed throughout acidic, chloride-rich environment. Furthermore, expression the lamina propria, particularly in the upper part of lamina and activity of decarboxylases in bacteria is regulated by the propria, whereas increased numbers of macrophages were presence of fermentable carbohydrates and oxygen, the redox only seen in the lower part of lamina propria in patients with potential of the medium, the temperature, and the sodium IBD. This suggests that the release of pro-inflammatory chloride concentration. The biological consequences of biogenic mediators from accumulated mast cells could have led to the amine secretion in vivo by the resident microbiota are largely recruitment of macrophages to the lamina propria. Dramati- unknown. Histamine can have both pro-inflammatory and anti- cally increased numbers of mast cells were also observed in inflammatory effects on immunoregulatory processes, depending the hypertrophied and fibrotic muscularis propria of stric- on which histamine receptor is activated. With the exception of tures in CD compared with normal bowel (87). scombroid poisoning, it is currently unknown whether histamine The rate of histamine secretion from the jejunum was secretion by the microbiota is altered during, or contributes to, increased in patients with CD compared with normal con- mucosal inflammatory disorders. Maintenance of mucosal trols, and the secretion of histamine was related to disease homeostasis is heavily dependent on appropriate sampling and activity, indicating that degranulation of mast cells may be processing of microbial ligands by the innate immune system, in important in active CD (88). Highly increased mucosal hista- particular DCs. We have demonstrated that histamine signifi- mine levels were also observed in allergic enteropathy and cantly alters the DC response to microbial ligands via the H2R ulcerative colitis (63). Increased levels of N-methylhistamine, and administration of a histamine-secreting Lactobacillus a stable histamine metabolite, were detected in the urine of rhamnosus strain to H2R-knockout mice results in a loss of the patients with active CD or ulcerative colitis (89). Because an microbe’s immunoregulatory activities (32). Other in vitro stud- increased level of N-methylhistamine was significantly corre- ies have also confirmed this finding, for example histamine lated with clinical disease activity, the above findings further secretion by a Lactobacillus reuteri strain modulates TLR-2- suggest that histamine plays an important role in the patho- induced TNF-a secretion in vitro (96). These observations genesis of these diseases. Mast cells isolated from the resected suggest that histamine from the enteric microbes might exert colon of active CD or ulcerative colitis patients were able to immunoregulatory effects in vivo; however, it remains to be release more histamine than those from normal colon when determined whether these effects are protective or pathological. being stimulated with epithelial proteins (90). Similarly, cultured colorectal biopsies from patients with IBD secreted Future perspectives and conclusions more histamine toward substance P alone or substance P with anti-IgE compared to the samples from control subjects It is clear that histamine is present within the gastrointestinal cultured under the same conditions (91). Histamine-N-meth- mucosa and increased levels are associated with a range of yltransferase gene expression is reduced in inflamed mucosa mucosal inflammatory disorders. Due to the obvious overlap and DAO polymorphisms have been identified for patients in symptoms, great care needs to be exercised in the differen- with IBD, suggesting that there could be dysregulated metab- tial diagnosis of these disorders. Treatment strategies that olism of histamine within the inflamed gut (71, 92). promote H2R expression and activity, with decreased H1R or

H4R activity, may improve mucosal immunoregulatory activ- Allergiestiftung Ulrich Muller-Gierok,€ European Union ity and protect against allergic sensitization and inflammatory research grants, EU Marie Curie grants, and Polish National disorders. The contribution of the microbiota to the histamine Science Centre grants No. 2011/01/B/NZ6/01872, 2012/04/M/ content of the gut and histamine receptor activation is cur- NZ6/00355 and 2012/04/A/NZ6/00407. rently unknown. Even though histamine was first discovered more than 100 years ago, there remain substantial gaps in our Conflicts of interest knowledge concerning the immunoregulatory activity of histamine, particularly within the gastrointestinal tract. 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, Funding and received lecture fees from GSK, Allergopharma, Staller- The authors are supported by Swiss National Foundation gens, ALK. Sylwia Smolinska and Reto Crameri have no grants (project numbers: 310030-127356 and 310030-144219), conflict of interests to declare.

References 1. Jutel M, Akdis M, Akdis CA. Histamine, 13. Saxena SP, McNicol A, Brandes LJ, Becker malaria in mouse models of disease. J Exp histamine receptors and their role in immune AB, Gerrard JM. Histamine formed in Med 2008;205:395–408. pathology. Clin Exp Allergy 2009;39:1786– stimulated human platelets is cytoplasmic. 22. Metz M, Doyle E, Bindslev-Jensen C, 1800. Biochem Biophys Res Commun Watanabe T, Zuberbier T, Maurer M. 2. Westly E. Nothing to sneeze at. Nat Med 1989;164:164–168. Effects of antihistamines on innate immune 2010;16:1063–1065. 14. Kubo Y, Nakano K. Regulation of hista- responses to severe bacterial infection in 3. Barger G, Dale HH. Chemical structure and mine synthesis in mouse CD4+ and CD8+ T mice. Int Arch Allergy Immunol sympathomimetic action of amines. J Physiol lymphocytes. Inflamm Res 1999;48:149–153. 2011;155:355–360. 1910;41:19–59. 15. Radvany Z, Darvas Z, Kerekes K, Prechl J, 23. Frei R, Lauener RP, Crameri R, O’Mahony 4. Dale HH, Laidlaw PP. The physiological Szalai C, Pallinger E et al. H1 histamine L. Microbiota and dietary interactions: an action of beta-iminazolylethylamine. J Phys- receptor antagonist inhibits constitutive update to the hygiene hypothesis? Allergy iol 1910;41:318–344. growth of Jurkat T cells and antigen-specific 2012;67:451–461. 5. Ohtsu H. Pathophysiologic role of hista- proliferation of ovalbumin-specific murine T 24. O’Mahony L, Akdis M, Akdis CA. Regula- mine: evidence clarified by histidine decar- cells. Semin Cancer Biol 2000;10:41–45. tion of the immune response and inflamma- boxylase gene knockout mice. Int Arch 16. Klocker J, Matzler SA, Huetz GN, Drasche tion by histamine and histamine receptors. Allergy Immunol 2012;158(Suppl 1):2–6. A, Kolbitsch C, Schwelberger HG. Expres- J Allergy Clin Immunol 2011;128:1153–1162. 6. Akdis CA, Blaser K. Histamine in the sion of histamine degrading enzymes in por- 25. Ferstl R, Akdis CA, O’Mahony L. Hista- immune regulation of allergic inflammation. cine tissues. Inflamm Res 2005;54(Suppl 1): mine regulation of innate and adaptive J Allergy Clin Immunol 2003;112:15–22. S54–S57. immunity. Front Biosci 2012;17:40–53. 7. Jutel M, Watanabe T, Akdis M, Blaser K, 17. Schwelberger HG, Hittmair A, Kohlwein 26. Bachert C. The role of histamine in allergic Akdis CA. Immune regulation by histamine. SD. Analysis of tissue and subcellular locali- disease: re-appraisal of its inflammatory Curr Opin Immunol 2002;14:735–740. zation of mammalian diamine oxidase by potential. Allergy 2002;57:287–296. 8. Dy M, Schneider E. Histamine-cytokine con- confocal laser scanning fluorescence micros- 27. Akdis CA, Simons FE. Histamine receptors nection in immunity and hematopoiesis. copy. Inflamm Res 1998;47(Suppl 1):S60– are hot in immunopharmacology. Eur Cytokine Growth Factor Rev 2004;15:393– S61. J Pharmacol 2006;533:69–76. 410. 18. Yamauchi K, Sekizawa K, Suzuki H, Nak- 28. Garbarg MSJ. Synergism between histamine 9. Schneider E, Rolli-Derkinderen M, Arock azawa H, Ohkawara Y, Katayose D et al. H1- and H2-receptors in the cAMP response M, Dy M. Trends in histamine research: new Structure and function of human histamine in guinea pig brain slices: effects of phorbol functions during immune responses and N-methyltransferase: critical enzyme in hista- esters and calcium. Mol Pharmacol hematopoiesis. Trends Immunol 2002;23:255– mine metabolism in airway. Am J Physiol 1988;33:38–43. 263. 1994;267(3 Pt 1):L342–L349. 29. Gschwandtner M, Mildner M, Mlitz V, 10. MacGlashan D Jr. Histamine: a mediator of 19. He SH. Key role of mast cells and their Gruber F, Eckhart L, Werfel T et al. Hista- inflammation. J Allergy Clin Immunol major secretory products in inflammatory mine suppresses epidermal keratinocyte dif- 2003;112(4 Suppl):S53–S59. bowel disease. World J Gastroenterol ferentiation and impairs skin barrier 11. Yoshimoto T, Tsutsui H, Tominaga K, 2004;10:309–318. function in a human skin model. Allergy Hoshino K, Okamura H, Akira S et al. 20. Buhner S, Li Q, Vignali S, Barbara G, 2013;68:37–47. IL-18, although antiallergic when De Giorgio R, Stanghellini V et al. 30. Togias A. H1-receptors: localization and role administered with IL-12, stimulates IL-4 Activation of human enteric neurons by in airway physiology and in immune and histamine release by basophils. Proc supernatants of colonic biopsy specimens functions. J Allergy Clin Immunol Natl Acad Sci U S A 1999;96:13962–13966. from patients with irritable bowel syndrome. 2003;112(Suppl 4):S60–S68. 12. Miadonna A, Salmaso C, Marco MP, Pugni Gastroenterology 2009;137:1425–1434. 31. Baroody FM, Naclerio RM. Antiallergic L, Milazzo N, Tedeschi A et al. Priming and 21. Beghdadi W, Porcherie A, Schneider BS, effects of H1-receptor antagonists. Allergy inducing effects of interleukin-3 on histamine Dubayle D, Peronet R, Huerre M et al. 2000;55(Suppl 64):17–27. release from cord-blood basophils. Allergy Inhibition of histamine-mediated signaling 32. Masaki T, Yoshimatsu H. The hypothalamic 1997;52:992–998. confers significant protection against severe H1 receptor: a novel therapeutic target for

disrupting diurnal feeding rhythm and obes- IFN-gamma production by invariant NKT 58. Hui JY, Taylor SL. Inhibition of in vivo his- ity. Trends Pharmacol Sci 2006;27:279–284. cells. J Immunol 2009;182:1233–1236. tamine-metabolism in rats by foodborne and 33. Jutel M, Watanabe T, Klunker S, Akdis M, 44. Ohsawa Y, Hirasawa N. The antagonism of pharmacologic inhibitors of diamine oxidase, Thomet OA, Malolepszy J et al. Histamine histamine H1 and H4 receptors ameliorates histamine N-methyltransferase, and mono- regulates T-cell and antibody responses by chronic allergic dermatitis via anti-pruritic amine-oxidase. Toxicol Appl Pharm differential expression of H1 and H2 recep- and anti-inflammatory effects in NC/Nga 1985;81:241–249. tors. Nature 2001;413:420–425. mice. Allergy 2012;67:1014–1022. 59. Ijomah P, Clifford MN, Walker R, Wright 34. Frei R, Ferstl R, Konieczna P, Ziegler M, 45. Maintz L, Novak N. Histamine and hista- J, Hardy R, Murray CK. The importance of Simon T, Rugeles TM et al. Histamine mine intolerance. Am J Clin Nutr endogenous histamine relative to dietary his- receptor 2 modifies dendritic cell responses 2007;85:1185–1196. tamine in the etiology of scombrotoxicosis. to microbial ligands. J Allergy Clin Immunol 46. Lessof MH, Gant V, Hinuma K, Murphy Food Addit Contam 1991;8:531–542. 2013;132:194–204. GM, Dowling RH. Recurrent urticaria and 60. Okazaki T, Noguchi T, Igarashi K, Saka- 35. Gschwandtner M, Bunk H, Kother B, Thur- reduced diamine oxidase activity. Clin Exp gami Y, Seto H, Mori K et al. Gizzerosine, mond RL, Kietzmann M, Werfel T et al. Allergy 1990;20:373–376. a new toxic-substance in fish-meal, causes Histamine down-regulates IL-27 production 47. Wantke F, Hemmer W, Haglmuller T, Gotz severe gizzard erosion in chicks. J Agric in antigen-presenting cells. J Leukoc Biol M, Jarisch R. Histamine in wine. Broncho- Food Chem 1983;47:2949–2952. 2012;92:21–29. constriction after a double-blind placebo- 61. Cochrane S, Beyer K, Clausen M, Wjst M, 36. Teuscher C, Poynter ME, Offner H, Zamora controlled red wine provocation test. Int Hiller R, Nicoletti C et al. Factors influenc- A, Watanabe T, Fillmore PD et al. Attenua- Arch Allergy Immunol 1996;110:397–400. ing the incidence and prevalence of food tion of Th1 effector cell responses and sus- 48. Schwelberger HG. Histamine intolerance: a allergy. Allergy 2009;64:1246–1255. ceptibility to experimental allergic metabolic disease? Inflamm Res 2010;59: 62. Raithel M, Weidenhiller M, Abel R, Baen- encephalomyelitis in histamine H2 receptor S219–S221. kler HW, Hahn EG. Colorectal mucosal his- knockout mice is due to dysregulation of 49. Wantke F, Gotz M, Jarisch R. Histamine- tamine release by mucosa oxygenation in cytokine production by antigen-presenting free diet: treatment of choice for histamine- comparison with other established clinical cells. Am J Pathol 2004;164:883–892. induced food intolerance and supporting tests in patients with gastrointestinally medi- 37. Dai H, Kaneko K, Kato H, Fujii S, Jing Y, treatment for chronic headaches. Clin Exp ated allergy. World J Gastroenterol Xu A et al. Selective cognitive dysfunction Allergy 1993;23:982–985. 2006;12:4699–4705. in mice lacking histamine H1 and H2 recep- 50. Johnston CS. The antihistamine action of 63. Raithel M, Matek M, Baenkler HW, Jorde tors. Neurosci Res 2007;57:306–313. ascorbic acid. Subcell Biochem 1996;25:189– W, Hahn EG. Mucosal histamine content 38. Yoshimoto R, Miyamoto Y, Shimamura K, 213. and histamine secretion in Crohn’s disease, Ishihara A, Takahashi K, Kotani H et al. 51. Martner-Hewes PM, Hunt IF, Murphy NJ, ulcerative colitis and allergic enteropathy. Therapeutic potential of histamine H3 recep- Swendseid ME, Settlage RH. Vitamin B-6 Int Arch Allergy Immunol 1995;108:127–133. tor agonist for the treatment of obesity and nutriture and plasma diamine oxidase activ- 64. Bijlsma PB, Backhaus B, Weidenhiller M, diabetes mellitus. Proc Natl Acad Sci U S A ity in pregnant Hispanic teenagers. Am Donhauser N, Hahn EG, Raithel M. Food 2006;103:13866–13871. J Clin Nutr 1986;44:907–913. allergy diagnosis by detection of antigen- 39. Teuscher C, Subramanian M, Noubade R, 52. Hungerford JM. Scombroid poisoning: a induced electrophysiological changes and Gao JF, Offner H, Zachary JF et al. Central review. Toxicon 2010;56:231–243. histamine release in human intestinal biop- histamine H3 receptor signaling negatively 53. Rawles DD, Flick GJ, Martin RE. Biogenic sies during mucosa-oxygenation. Inflamm regulates susceptibility to autoimmune amines in fish and shellfish. Adv Food Nutr Res 2004;53(Suppl 1):S29–S30. inflammatory disease of the CNS. Proc Natl Res 1996;39:329–365. 65. Nolte H, Schiotz PO, Kruse A, Skov PS. Acad Sci U S A 2007;104:10146–10151. 54. Kim SH, Barros-Velazquez J, Ben-Gigrey B, Comparison of intestinal mast-cell and baso- 40. Glatzer F, Gschwandtner M, Ehling S, Eun JB, Jun SH, Wie CI et al. Identification phil histamine-release in children with food Rossbach K, Janik K, Klos A et al. Hista- of the main bacteria contributing to hista- allergic reactions. Allergy 1989;44:554–565. mine induces proliferation in keratinocytes mine formation in seafood to ensure product 66. Raithel M, Hagel AF, Zopf Y, Bijlsma PB, from patients with atopic dermatitis through safety. Food Sci Biotechnol 2003;12:451–460. De Rossi TM, Gabriel S et al. Analysis of the histamine 4 receptor. J Allergy Clin 55. Bjornsdottir-Butler K, Bolton GE, Jaykus immediate ex vivo release of nitric oxide Immunol 2013; doi: 10.1016/j.jaci.2013. LA, McClellan-Green PD, Green DP. Devel- from human colonic mucosa in gastrointesti- 06.023. [Epub ahead of print] opment of molecular-based methods for nally mediated allergy, inflammatory bowel 41. Gschwandtner M, Rossbach K, Dijkstra D, determination of high histamine producing disease and controls. J Physiol Pharmacol Baumer W, Kietzmann M, Stark H et al. bacteria in fish. Intl J Food Microbiol 2012;63:317–325. Murine and human Langerhans cells express 2010;139:161–167. 67. Bijlsma PB, Backhaus B, Weidenhiller M, a functional histamine H4 receptor: modula- 56. Kim SH, Field KG, Chang DS, Wei CI, An Donhauser N, Hahn EG, Raithel M. Food tion of cell migration and function. Allergy HJ. Identification of bacteria crucial to his- allergy diagnosis by detection of antigen- 2010;65:840–849. tamine accumulation in Pacific mackerel induced electrophysiological changes and 42. Baumer W, Wendorff S, Gutzmer R, Werfel during storage. J Food Protect 2001;64:1556– histamine release in human intestinal biop- T, Dijkstra D, Chazot P et al. Histamine H4 1564. sies during mucosa-oxygenation. Inflamm receptors modulate dendritic cell migration 57. Takahashi H, Kimura B, Yoshikawa M, Res 2004;53:S29–S30. through skin–immunomodulatory role of Fujii T. Cloning and sequencing of the histi- 68. Arae K, Oboki K, Ohno T, Hirata M, histamine. Allergy 2008;63:1387–1394. dine decarboxylase genes of gram-negative, Nakae S, Taguchi H et al. Cimetidine 43. Leite-de-Moraes MC, Diem S, Michel ML, histamine-producing bacteria and their enhances antigen-specific IgE and Th2 cyto- Ohtsu H, Thurmond RL, Schneider E et al. application in detection and identification of kine production. Allergol Int 2011;60:339–344. Cutting edge: histamine receptor H4 activa- these organisms in fish. Appl Environ 69. Untersmayr E, Bakos N, Scholl I, Kundi M, tion positively regulates in vivo IL-4 and Microbiol 2003;69:2568–2579. Roth-Walter F, Szalai K et al. Anti-ulcer

drugs promote IgE formation toward dietary and reduced quality of life. Am J Gastroen- with laminin but not with fibronectin or antigens in adult patients. FASEB J terol 2013;108:634–641. vitronectin. Gut 1999;45:210–217. 2005;19:656–658. 79. Tack JF, Miner PB Jr, Fischer L, Harris 88. Knutson L, Ahrenstedt O, Odlind B, Hall- 70. Scholl I, Untersmayr E, Bakos N, Roth- MS. Randomised clinical trial: the safety gren R. The jejunal secretion of histamine is Walter F, Gleiss A, Boltz-Nitulescu G et al. and efficacy of AST-120 in non-constipating increased in active Crohn’s disease. Gastro- Antiulcer drugs promote oral sensitization irritable bowel syndrome – a double-blind, enterology 1990;98:849–854. and hypersensitivity to hazelnut allergens in placebo-controlled study. Aliment Pharmacol 89. Winterkamp S, Weidenhiller M, Otte P, BALB/c mice and humans. Am J Clin Nutr Ther 2011;34:868–877. Stolper J, Schwab D, Hahn EG et al. Uri- 2005;81:154–160. 80. Barbara G, Stanghellini V, De Giorgio R, nary excretion of N-methylhistamine as a 71. Petersen J, Raithel M, Schwelberger HG. Cremon C, Cottrell GS, Santini D et al. marker of disease activity in inflammatory Characterisation of functional polymor- Activated mast cells in proximity to colonic bowel disease. Am J Gastroenterol phisms of the human diamine oxidase gene. nerves correlate with abdominal pain in irri- 2002;97:3071–3077. Inflamm Res 2005;54(Suppl 1):S58–S59. table bowel syndrome. Gastroenterology 90. Fox CC, Lichtenstein LM, Roche JK. Intes- 72. Masini E, Vannacci A, Marzocca C, Man- 2004;126:693–702. tinal mast cell responses in idiopathic inflam- naioni PF, Befani O, Federico R et al. A 81. Klooker TK, Braak B, Koopman KE, Wel- matory bowel disease. Histamine release plant histaminase modulates cardiac ting O, Wouters MM, van der Heide S et al. from human intestinal mast cells in response anaphylactic response in guinea pig. Biochem The mast cell stabiliser ketotifen decreases to gut epithelial proteins. Dig Dis Sci Biophys Res Commun 2002;296:840–846. visceral hypersensitivity and improves intesti- 1993;38:1105–1112. 73. Macsharry J, O’Mahony L, Fanning A, nal symptoms in patients with irritable 91. Raithel M, Schneider HT, Hahn EG. Effect Bairead E, Sherlock G, Tiesman J et al. bowel syndrome. Gut 2010;59:1213–1221. of substance P on histamine secretion from Mucosal cytokine imbalance in irritable 82. Sheil B, Shanahan F, O’Mahony L. Probiot- gut mucosa in inflammatory bowel disease. bowel syndrome. Scand J Gastroenterol ic effects on inflammatory bowel disease. Scand J Gastroenterol 1999;34:496–503. 2008;43:1467–1476. J Nutr 2007;137(3 Suppl 2):819S–824S. 92. Schulze HA, Hasler R, Mah N, Lu T, 74. Dinan TG, Quigley EM, Ahmed SM, Scully 83. Dvorak AM, Monahan RA, Osage JE, Nikolaus S, Costello CM et al. From model P, O’Brien S, O’Mahony L et al. Hypotha- Dickersin GR. Crohn’s disease: transmission cell line to in vivo gene expression: lamic-pituitary-gut axis dysregulation in irri- electron microscopic studies. II. Immuno- disease-related intestinal gene expression in table bowel syndrome: plasma cytokines as a logic inflammatory response. Alterations of IBD. Genes Immun 2008;9:240–248. potential biomarker? Gastroenterology mast cells, basophils, eosinophils, and the 93. Juillerat P, Schneeweiss S, Cook EF, Anan- 2006;130:304–311. microvasculature. Hum Pathol 1980;11:606– thakrishnan AN, Mogun H, Korzenik JR. 75. Codling C, O’Mahony L, Shanahan F, Quig- 619. Drugs that inhibit gastric acid secretion may ley EM, Marchesi JR. A molecular analysis 84. Nolte H, Spjeldnaes N, Kruse A, Windel- alter the course of inflammatory bowel dis- of fecal and mucosal bacterial communities borg B. Histamine release from gut mast ease. Aliment Pharmacol Ther 2012;36:239– in irritable bowel syndrome. Dig Dis Sci cells from patients with inflammatory bowel 247. 2010;55:392–397. diseases. Gut 1990;31:791–794. 94. Raithel M, Nagel A, Zopf Y, deRossi T, 76. O’Mahony L, McCarthy J, Kelly P, Hurley 85. King T, Biddle W, Bhatia P, Moore J, Stengel C, Hagel A et al. Plasma histamine G, Luo F, Chen K et al. Lactobacillus and Miner PB Jr. Colonic mucosal mast cell dis- levels (H) during adjunctive H1-receptor bifidobacterium in irritable bowel syndrome: tribution at line of demarcation of active antagonist treatment with loratadine in symptom responses and relationship to cyto- ulcerative colitis. Dig Dis Sci 1992;37:490– patients with active inflammatory bowel dis- kine profiles. Gastroenterology 2005;128:541– 495. ease (IBD). Inflamm Res 2010;59(Suppl 2): 551. 86. Nishida Y, Murase K, Isomoto H, Furusu S257–S258. 77. Whorwell PJ, Altringer L, Morel J, Bond Y, H, Mizuta Y, Riddell RH et al. Different 95. Jones NL, Roifman CM, Griffiths AM, Charbonneau D, O’Mahony L et al. Efficacy distribution of mast cells and macrophages Sherman P. Ketotifen therapy for acute of an encapsulated probiotic Bifidobacterium in colonic mucosa of patients with collage- ulcerative colitis in children: a pilot study. infantis 35624 in women with irritable bowel nous colitis and inflammatory bowel dis- Dig Dis Sci 1998;43:609–615. syndrome. Am J Gastroenterol ease. Hepatogastroenterology 2002;49:678– 96. Thomas CM, Hong T, van Pijkeren JP, 2006;101:1581–1590. 682. Hemarajata P, Trinh DV, Hu W et al. His- 78. Bohn L, Storsrud S, Tornblom H, Bengtsson 87. Gelbmann CM, Mestermann S, Gross V, tamine derived from probiotic Lactobacillus U, Simren M. Self-reported food-related gas- Kollinger M, Scholmerich J, Falk W. Stric- reuteri suppresses TNF via modulation of trointestinal symptoms in IBS are common tures in Crohn’s disease are characterised by PKA and ERK signaling. PLoS One 2012;7: and associated with more severe symptoms an accumulation of mast cells colocalised e31951.