Journal of Neurogastroenterology and Motility 2017; 23(3): 341-348  https://doi.org/10.5056/jnm16203
Targeting Histamine Receptors in Irritable Bowel Syndrome: A Critical Appraisal
Adam Fabisiak1, Jakub Włodarczyk1, Natalia Fabisiak1, Martin Storr2,3, and Jakub Fichna1,*
1Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Lodz, Poland, 2Center of Endoscopy, Starnberg, Germany, 3Walter Brendel Center of Experimental Medicine, Ludwig Maximilians University of Munich, Munich, Germany
Correspondence to: Jakub Fichna, PhD, DSc, Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland, Tel: +48-42-272-5707, Fax: +48-42-272-5694, E-mail: jakub.fichna@umed.lodz.pl
Received: November 24, 2016; Revised: March 10, 2017; Accepted: April 7, 2017; Published online: July 1, 2017.
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract

Irritable bowel syndrome is a group of functional gastrointestinal disorders with not yet fully clarified etiology. Recent evidence suggesting that mast cells may play a central role in the pathogenesis of irritable bowel syndrome paves the way for agents targeting histamine receptors as a potential therapeutic option in clinical treatment. In this review, the role of histamine and histamine receptors is debated. Moreover, the clinical evidence of anti-histamine therapeutics in irritable bowel syndrome is discussed.

Keywords: Ebastine, Irritable bowel syndrome, Mast cells, Receptors, histamine
Introduction

Irritable bowel syndrome (IBS) is a functional gastrointestinal (GI) disorder without completely elucidated etiology. The typical symptoms are abdominal pain and change in bowel habits. Additionally, bloating, tenesmus, bowel urgency, and abdominal distension can occur. A recent meta-analysis estimated the international prevalence of IBS at 11.2%1 based on the Rome III criteria; however, a recent study in China showed that the number of patients diagnosed based on the Rome IV criteria is nearly half the number of patients diagnosed according to the Rome III criteria.2 However, only one-third of those who suffer from IBS-like symptoms see a physician, the actual prevalence may be much higher. IBS impairs the quality of life in patients to a similar degree as in patients with inflammatory bowel diseases3 and the impairment is proportional to the severity of the symptoms experienced by the patient.4

IBS is a heterogeneous entity with etiology comprising of multiple factors such as inflammation, neuroimmune interactions,5 gut microbiota,6 environmental pollution,7 and abnormal gut-brain axis.8 This heterogeneity has a significant impact on treatment. As the disease profile may vary between the patients, the treatment should be personally tailored with regard to predominant symptoms and disease characteristics. It is particularly crucial due to the plethora of drugs available on the market nowadays.9 However, despite the number of drugs available the treatments are not fully satisfactory in all patients. Also, the symptoms eventually relapse.

A large portion of both established and investigated treatment options include drugs based on serotonin (5-hydroxytryptamine, 5-HT). Indeed, 5-HT plays an important role in the gut by affecting motility and secretion.10 Moreover, it was recently found that alterations in 5-HT metabolism may be implicated in visceral hypersensitivity, which is an important feature of IBS.11 Interestingly, in a study performed by Cremon et al12 the lamina propria mast cell (MC) count positively correlates with the increase in spontaneous 5-HT release in patients with IBS. While serotonin has already proven to be implicated in the pathogenesis of IBS, histamine is emerging as an important biogenic amine in this disease. Although the pathophysiological role of histamine in IBS is not entirely clear, there is evidence that supports the use of agents targeting the histamine receptors (HRs) as a potential therapeutic option in these patients. In this review, the role of histamine and HRs in IBS is critically appraised. Moreover, the possible use of anti-histamine therapeutics is discussed.

Overview of Histamine and Histamine Receptors in the Gastrointestinal Tract

Histamine (2-[4-imidazolyl]-ethylamine) is a short-acting endogenous amine, which is widely distributed in the human body.13 Histamine is synthesized by the enzyme histidine decarboxylase in all human tissues, but is particularly abundant in the skin, lungs, and GI tract.14

Histamine is produced mainly by MCs and, to a lesser extent, by basophils, gastric enterochromaffin-like cells, and histaminergic neurons.15,16 However, platelets, dendritic cells (DCs), T cells, and even microbes can also express histidine decarboxylase following a stimulation by cytokines, including IL-1, IL-3, IL-12, IL-18, granulocyte-macrophage colony-stimulating factor, macrophage colony-stimulating factor, and TNF-α.13,17,18 Only MCs and basophils are capable of storing large quantities of histamine. Other cell types such as DCs and lymphocytes do not store histamine intracellularly but the synthesis is followed by an immediate secretion.

Histamine is involved in several physiological functions, including cell proliferation and differentiation, hematopoiesis, regeneration, and the regulation of innate and adaptive immune systems.19 Histamine exerts its biological actions by binding to 4 subtypes of HRs, which are named chronologically in order of their discovery: H1R-H4R. These 4 binding sites belong to the rhodopsin-like family of G protein-coupled receptors, which are differentially expressed in numerous cell types. Although all 4 HRs are expressed in the human body, the intestines seem to be devoid of H3Rs.20 The expression pattern of HRs does not change anatomically along the intestine.

In the GI tract, histamine is believed to impact at least 3 major functions: modulation of GI motility, enhancement of gastric acid production, and alteration of mucosal ion secretion.2123 H1Rs are involved in mediating sensorineural signaling and vascular dilatation.24 Activation of H1R is known to regulate food and water intake and diurnal feeding rhythm.25 Stimulation of H2R results in degranulation of MCs, synthesis of antibodies, production of T helper (Th) 1 cytokines, and T-cell proliferation.16,26 H4R plays a significant role in nociception, autoimmune disorders, colon cancer, and allergy.2729 Clear interpretation of histamine involvement in regulation of GI motility is currently lacking. However, the evidence indicates that overproduction of histamine by MCs may be responsible for diarrhea caused by increased neuronal secretomotor function.30 Another hypothesis assumes that in constipated patients histamine induces altered enteric neuron function as a result of an excessive segmental contractile colonic motor activity.31 However, the pathological relevance of increased histamine levels in diseases, such as IBS, is not yet fully elucidated.

Table 1 describes the localization and role of specific HRs in the GI tract. Localization of HRs in the intestinal wall is depicted in Figure.

Irritable Bowel Syndrome and Histamine

The summary on animal and human studies with MCs and HRs as targets is shown in Table 2.3241

The etiology and the pathophysiology are only partly understood, with some evidence suggesting that intestinal infections, and dysfunctional mucosal immune responses may play a role in the development of IBS and its symptoms.

Patients with IBS frequently experience post-prandial worsening of their symptoms. Moreover, a vast majority of IBS patients feel that distinct foods play pivotal role in triggering their symptoms. In a recent study,42 58% of patients with IBS experienced GI symptoms from histamine-releasing food items such as milk, wine or beer, and foods rich in biogenic amines (wine, beer, and cheese). Interestingly, the use of spherical carbon adsorbents, known for adsorbing molecules (for instance histamine) from the gut lumen has been proven to be beneficial in some patients.41

High levels of histamine were found in supernatants from IBS colonic samples.43 Application of this supernatant to rat submucous neurons resulted in increased neuronal activity. Furthermore, positive correlation between histamine levels in the supernatant and the degree of activation was stated.44 The neuronal response of submucous neurons to the artificially designed cocktail, which is a combination of mucosal and immune mediators mimicking nerve activating components found in colonic biopsy supernatants and serum of IBS-patients, was lower in mucosal IBS biopsies compared to healthy controls.45 This effect appears in IBS most likely due to the desensitization to mediators, which is caused by the chronic contact of the gut wall with the mediators found in the gut lumen. Additionally, histamine induced murine jejunal afferent firing and excited primary sensory neurons.46,47 According to the study of Barbara et al,43 the pronociceptive effect of histamine appears to be mediated, at least partly, by H1R expressed on sensory afferents. In contrast, Guarino et al48 found that supernatants from patients with IBS impair contractility of isolated human colonic smooth muscles and the phenomenon is histamine-independent. The effect was significantly reversible by apocynin, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, suggesting the intracellular oxidative stress damage to be the main cause of this contractility impairment.

The expression of H1R and H2R in the intestinal tissue samples of IBS patients is upregulated.20 Moreover, it has been reported that H1R activation results in proinflammatory effects such as IFN production and Th1 cell proliferation, while H2R activation appears to suppress inflammation.19,49,50 Activation of H2R by histamine suppresses IL-12 production by monocytes,51 IFN-γ production by macrophages,52 TNF-α secretion by MCs,53 and IL-12 release by immature DCs.54 In vivo studies showed that histamine suppresses both Th1- and Th2-type responses by H2R.55 It is noteworthy that in colonic biopsies of IBS patients or patients with food allergy, no alterations in H4R mRNA levels were reported.20 However, involvement of the H4R in visceral sensory signaling and GI contractility has been documented56; yet, more studies are needed to fully elucidate the contribution of H4R in IBS.

There is a large body of evidence suggesting that MCs are an important factor in the pathophysiology of IBS.39 IBS patients have an increased number of MCs, which contain granules rich in mediators such as histamine, tryptase, and nerve growth factors that can activate and sensitize enteric nerves, and modulate the integrity of the epithelial barrier.57,58 An increased number of mucosal MCs has been observed in biopsy samples from the rectum,59 rectosigmoid,60 descending colon,43 ascending colon,59 cecum,61 terminal ileum,59 jejunum,62 and duodenum63 of patients with IBS. Also, the level of activation and intensity of MCs degranulation is increased. Activated MCs spontaneously secreting higher amounts of histamine in close proximity to colonic nerves correlated with severity and frequency of abdominal pain in IBS patients.31 According to the study of Cremon et al64 it is possible that the number of functionally active MCs is more important in IBS, rather than the absolute number of cells. The recent review by Zhang et al65 profoundly embraces all aspects of MCs in IBS.

Possible Application of Anti-histamine Drugs in Irritable Bowel Syndrome

Abdominal pain, often described as discomfort, is believed to be linked to visceral hypersensitivity which seems to be multifactorial.66,67 MCs and histamine seem to contribute majorly to visceral hypersensitivity. A study on H1R knockout mice showed that they are more prone to visceral pain, measured by abdominal stretching after intraperitoneal injection of either acetic acid or MgSO4 than their wild type littermates.68 A study in the rat model of IBS induced by acetic acid revealed a higher degranulation rate of MCs in the colon from rats with IBS-like symptoms. Moreover, pretreatment with a MC stabilizer, doxantrazole, decreased visceral sensory response to rectal distention in these rats.69 Finally, histamine was shown to activate enteric neurons through H1 and H2 receptors.70,71

MCs with their stored enzymes are important players in dysregulated brain-gut axis. Thus, targeting MCs or HRs arises as a potent treatment option for selected patients with IBS. A few clinical studies have addressed this hypothesis. Klooker et al38 attempted to translate the research on the use of MC stabilizers in IBS from animals33 to humans. The randomized double-blinded controlled trial showed that ketotifen increased tolerance to abdominal discomfort in patients with IBS with visceral hypersensitivity, improved symptoms and the quality of life. However, no effect on the number of MCs, release of tryptase and histamine from rectal biopsies could be demonstrated. Since ketotifen is a H1 receptor antagonist, an MC stabilizer, a phosphodiesterase inhibitor and a functional leukotriene inhibitor, it was not completely evident which of its features was responsible for the anti-IBS effects. Therefore, MC stabilization and H1R blockade could be further explored as potential new treatments for IBS.

A recent study showed that by blocking H1R with ebastine, a second generation H1R antagonist, attenuation of visceral hypersensitivity and other IBS symptoms could be achieved.39 Interestingly, the transient receptor potential vanilloid 1 (TRPV1) was found to be implicated in the process; either histamine alone or the supernatant from rectal biopsies from patients with IBS sensitize TRPV1 channels. Upon activation by stimuli such as noxious heat, acidosis or endovanilloids, TRPV1 becomes non-selectively permeable for ions. It is most likely that sensitization lowers the threshold for channel activation possibly leading to activation by the normal body temperature. The involvement of TRPV1 in IBS has been investigated before. Akbar et al60 discovered increased sensory fibers which express TRPV1 channel in patients with IBS. Also, the results from animal studies suggested the contribution of TRPV1 in visceral hypersensitivity.72,73 However, TRPV1 is distinctive, involved in both physiological and pathophysiological actions in the human body, such as maintaining proper lower urinary tract function.74 Thus, prior to the discovery of a crosstalk between MCs and TRPV1, it was unreasonable to talk about the TRPV1 as a stand-alone therapeutic target. Now, as the connection between the two became apparent, it is easier to indicate plausible therapeutic agents.

The aforementioned HR antagonists are without doubt a part of that group with ebastine in the lead. Ebastine is a second-generation H1R antagonist free of any significant influence on the central nervous system as it does not penetrate the blood-brain barrier.75 The occurrence rate of the most common adverse events such as drowsiness, headache and dry mouth is comparable to placebos. Ebastine showed a satisfactory utility in abating the symptoms of allergic rhinitis and chronic idiopathic urticaria.75 Smaller studies also indicate its possible use in cold urticaria, atopic asthma, mosquito bites, and the common cold (with pseudoephedrine).7679 Additional advantages include the once-daily administration, pharmacokinetics independent of food intake, and availability of a novel formulation––fast dissolving tablet––which does not require the aid of a drink. Currently, there is an ongoing multicenter trial assessing the efficacy of ebastine in patients with IBS (ClinicalTrials.gov Identifier: NCT01908465).

Conclusions and Future Perspectives

The following questions remain unanswered: should we focus more on histamine receptors in IBS? The answer cannot come as a simple binary result but requires further elaboration. We already use MCs as a target, though in a rather indirect way. McIntosh et al80 recently reported that diets low in fermentable oligosaccharides, disaccharides, mono-saccharides, and polyols (FODMAPs) changes the metabolome, significantly reducing histamine levels in the urine. Consequently, by administering the diet low in FODMAPs we could modulate the histamine levels in patients with IBS thus altering the symptoms. Although histamine is not the only mediator found to be implicated in the pathogenesis of IBS, it is evident that this biogenic amine is pathologically of great importance.

In conclusion, HR antagonists are definitely worth being considered as potential therapeutic agents in treating IBS, especially the second generation agents which lack activity in the central nervous system, but display a considerably safe profile. Larger studies on ebastine will reveal the efficacy of H1R antagonists in patients with IBS. For other HR compounds like ketotifen, famotidine, ranitidine, and AST-120, there is already evidence from clinical trials in patients with IBS that suggest that their use may be beneficial. However, until the mechanisms of action of these compounds are elucidated the possibility of using HRs-targeting agents remains speculative.

Figures
Fig. 1. Localization of histamine receptors in the intestinal wall.
Tables

Localization and Role of Specific Histamine Receptors in the Gastrointestinal Tract

Receptors Localization Role
H1 Enterocytes, connective tissue cells, immune cells, blood vessels, myocytes, and myenteric plexus Regulation of diurnal feeding rhythm, mediation of sensorineural signaling, control of vascular dilatation and permeability, impact on gastrointestinal contractility and motility, and modulation of visceral pain
H2 Enterocytes, immune cells, myocytes, and myenteric plexus Immunomodulatory properties and control of gastrointestinal contractility and motility
H3 Not found in the human gastrointestinal tract
H4 Lamina propria mononuclear cells and intestinal mast cells, leukocytes in mucosal and submucosal blood vessels, and enterocytes in the apical end of intestinal glands Immunomodulatory properties, impact on gastrointestinal contractility and motility, and modulation of visceral pain

Animal and Human Studies Focusing on Histamine Receptors and Mast Cells as a Potential Target in Irritable Bowel Syndrome Treatment

Compound Mechanism of action Dose Species Effect References
Animal studies
 Disodium cromoglycate MCs stabilizer 25 and 50 mg/kg, ip Rat Inhibition of visceral hypersensitivity during colorectal distension in stress-sensitive rats Carroll et al,32 2013
 Doxantrazole MCs stabilizer 2 mg/kg, ip Rat Suppression of stress- and corticotropin releasing factor-induced rectal hyperalgesia to rectal distension Gué et al,33 1997
 Ebastine H1R antagonist 0.1 and 1 mg/kg administered 3 times, ip in 24 hr Rat Reversed post stress visceral hypersensitivity at the dose 1 mg/kg Stanisor et al,34 2013
 Fexofenadine H1R antagonist
MCs stabilizer
1.8 and 18 mg/kg administered 3 times, ip in 24 hr Rat Reversed post stress visceral hypersensitivity Stanisor et al,34 2013
 Ketotifen H1R antagonist and MCs stabilizer 10 mg/kg/day, po in drinking water Rat Prevention of hypermotility and mucosal MC hyperplasia Serna et al,35 2006
Human studies
 Disodium cromoglycate MCs stabilizer 1500 mg/day for 8 wk Human Improvement of symptoms Stefanini et al,36 1992
 Disodium cromoglycate MCs stabilizer 1500 mg/day for 1 mo Human Improvement of symptoms Stefanini et al,37 1995
 Ketotifen MCs stabilizer and H1R antagonist 2 mg bid for 2 wk, 4 mg bid for 4 wk and 6 mg bid for another 4 wk Human Increased tolerance to discomfort in patients with IBS with visceral hypersensitivity, reduced IBS symptoms and improved health-related quality of life Klooker et al,38 2010
 Ebastine H1R antagonist 20 mg/day for 12 wk Human Reduced visceral hypersensitivity and abdominal pain, increased symptom relief in patients with IBS Wouters et al,39 2016
 Famotidine H2R antagonist 20 mg bid Human Improvement of symptoms Dave and Rubin,40 1999
 Ranitidine H2R antagonist 150 mg/kg bid Human Improvement of symptoms Dave and Rubin,40 1999
 AST-120 (spherical carbon adsorbent) Adsorption of low molecular substances (including histamine and serotonin among others) 2 g or placebo 3 times/day for 8 wk, placebo for 2 wk, and 2 g of drug for 8 wk Human Improvement in bloating and stool consistency Tack et al,41 2011

MCs, mast cells; ip, intraperitoneally; H1R, histamine H1 receptor; H2R, histamine H2 receptor; po, per os; bid, twice daily; IBS, irritable bowel syndrome.


References
  1. Lovell, RM, and Ford, AC (2012). Global Prevalence of and Risk Factors for Irritable Bowel Syndrome: A Meta-analysis. Clin Gastroenterol Hepatol. 10, Array-721.
    Pubmed CrossRef
  2. Bai, T, Xia, J, and Jiang, Y (2017). Comparison of the Rome IV and Rome III criteria for IBS diagnosis: a cross-sectional survey. J Gastroenterol Hepatol. 32, 1018-1025.
    CrossRef
  3. Pace, F, Molteni, P, and Bollani, S (2003). Inflammatory bowel disease versus irritable bowel syndrome: a hospital-based, case-control study of disease impact on quality of life. Scand J Gastroenterol. 38, 1031-1038.
    Pubmed CrossRef
  4. Monnikes, H (2011). Quality of life in patients with irritable bowel syndrome. J Clin Gastroenterol. 45, S98-S101.
    Pubmed CrossRef
  5. Ohman, L, and Simrén, M (2010). Pathogenesis of IBS: role of inflammation, immunity and neuroimmune interactions. Nat Rev Gastroenterol Hepatol. 7, 163-173.
    Pubmed CrossRef
  6. Distrutti, E, Monaldi, L, Ricci, P, and Fiorucci, S (2016). Gut microbiota role in irritable bowel syndrome: new therapeutic strategies. World J Gastroenterol. 22, 2219-2241.
    Pubmed KoreaMed
  7. Marynowski, M, Likońska, A, Zatorski, H, and Fichna, J (2015). Role of environmental pollution in irritable bowel syndrome. World J Gastroenterol. 21, 11371-11378.
    Pubmed KoreaMed CrossRef
  8. Fichna, J, and Storr, MA (2012). Brain-gut interactions in IBS. Front Pharmacol. 3, 127.
    Pubmed KoreaMed CrossRef
  9. Mosińska, P, Salaga, M, and Fichna, J (2016). Novel investigational drugs for constipation-predominant irritable bowel syndrome: a review. Expert Opin Investig Drugs. 25, 275-286.
    CrossRef
  10. Gershon, MD (2004). Review article: serotonin receptors and transporters--roles in normal and abnormal gastrointestinal motility. Aliment Pharmacol Ther. 20, 3-14.
    CrossRef
  11. Keszthelyi, D, Troost, FJ, and Jonkers, DM (2015). Visceral hypersensitivity in irritable bowel syndrome: evidence for involvement of serotonin metabolism--a preliminary study. Neurogastroenterol Motil. 27, 1127-1137.
    Pubmed CrossRef
  12. Cremon, C, Carini, G, and Wang, B (2011). Intestinal serotonin release, sensory neuron activation, and abdominal pain in irritable bowel syndrome. Am J Gastroenterol. 106, 1290-1298.
    Pubmed CrossRef
  13. Jutel, M, Akdis, M, and Akdis, CA (2009). Histamine, histamine receptors and their role in immune pathology. Clin Exp Allergy. 39, 1786-1800.
    CrossRef
  14. Wouters, MM (2014). Histamine antagonism and postinflammatory visceral hypersensitivity. Gut. 63, 1836-1837.
    Pubmed CrossRef
  15. Akdis, CA, and Blaser, K (2003). Histamine in the immune regulation of allergic inflammation. J Allergy Clin Immunol. 112, 15-22.
    Pubmed CrossRef
  16. Jutel, M, Watanabe, T, Akdis, M, Blaser, K, and Akdis, CA (2002). Immune regulation by histamine. Curr Opin Immunol. 14, 735-740.
    Pubmed CrossRef
  17. Dy, M, and Schneider, E (2004). Histamine-cytokine connection in immunity and hematopoiesis. Cytokine Growth Factor Rev. 15, 393-410.
    Pubmed CrossRef
  18. Schneider, E, Rolli-Derkinderen, M, Arock, M, and Dy, M (2002). Trends in histamine research: new functions during immune responses and hematopoiesis. Trends Immunol. 23, 255-263.
    Pubmed CrossRef
  19. Smolinska, S, Jutel, M, Crameri, R, and O’Mahony, L (2014). Histamine and gut mucosal immune regulation. Allergy. 69, 273-281.
    CrossRef
  20. Sander, LE, Lorentz, A, and Sellge, G (2006). Selective expression of histamine receptors H1R, H2R, and H4R, but not H3R, in the human intestinal tract. Gut. 55, 498-504.
    CrossRef
  21. Tanaka, S, Hamada, K, and Yamada, N (2002). Gastric acid secretion in L-histidine decarboxylase-deficient mice. Gastroenterology. 122, 145-155.
    Pubmed CrossRef
  22. Fargeas, MJ, Fioramonti, J, and Bueno, L (1989). Involvement of different receptors in the central and peripheral effects of histamine on intestinal motility in the rat. J Pharm Pharmacol. 41, 534-540.
    Pubmed CrossRef
  23. Keely, SJ, Stack, WA, O’Donoghue, DP, and Baird, AW (1995). Regulation of ion transport by histamine in human colon. Eur J Pharmacol. 279, 203-209.
    Pubmed CrossRef
  24. Togias, A (2003). H1-receptors: localization and role in airway physiology and in immune functions. J Allergy Clin Immunol. 112, S60-S68.
    Pubmed CrossRef
  25. Masaki, T, and Yoshimatsu, H (2006). The hypothalamic H1 receptor: a novel therapeutic target for disrupting diurnal feeding rhythm and obesity. Trends Pharmacol Sci. 27, 279-284.
    Pubmed CrossRef
  26. Meiler, F, Zumkehr, J, Klunker, S, Rückert, B, Akdis, CA, and Akdis, M (2008). In vivo switch to IL-10-secreting T regulatory cells in high dose allergen exposure. J Exp Med. 205, 2887-2898.
    Pubmed KoreaMed CrossRef
  27. Thurmond, RL, Desai, PJ, and Dunford, PJ (2004). A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther. 309, 404-413.
    Pubmed CrossRef
  28. Varga, C, Horvath, K, Berko, A, Thurmond, RL, Dunford, PJ, and Whittle, BJ (2005). Inhibitory effects of histamine H4 receptor antagonists on experimental colitis in the rat. Eur J Pharmacol. 522, 130-138.
    Pubmed CrossRef
  29. Cianchi, F, Cortesini, C, and Schiavone, N (2005). The role of cyclooxygenase-2 in mediating the effects of histamine on cell proliferation and vascular endothelial growth factor production in colorectal cancer. Clin Cancer Res. 11, 6807-6815.
    Pubmed CrossRef
  30. Wood, JD (2002). Neuropathophysiology of irritable bowel syndrome. J Clin Gastroenterol. 35, S11-S22.
    Pubmed CrossRef
  31. Barbara, G, Stanghellini, V, and De Giorgio, R (2004). Activated mast cells in proximity to colonic nerves correlate with abdominal pain in irritable bowel syndrome. Gastroenterology. 126, 693-702.
    Pubmed CrossRef
  32. Carroll, SY, O’Mahony, SM, Grenham, S, Cryan, JF, and Hyland, NP (2013). Disodium cromoglycate reverses colonic visceral hypersensitivity and influences colonic ion transport in a stress-sensitive rat strain. PLoS One. 8, e84718.
    Pubmed KoreaMed CrossRef
  33. Gué, M, Del Rio-Lacheze, C, Eutamene, H, Théodorou, V, Fioramonti, J, and Buéno, L (1997). Stress-induced visceral hypersensitivity to rectal distension in rats: role of CRF and mast cells. Neurogastroenterol Motil. 9, 271-279.
    CrossRef
  34. Stanisor, OI, van Diest, SA, and Yu, Z (2013). Stress-induced visceral hypersensitivity in maternally separated rats can be reversed by peripherally restricted histamine-1-receptor antagonists. PLoS One. 8, e66884.
    Pubmed KoreaMed CrossRef
  35. Serna, H, Porras, M, and Vergara, P (2006). Mast cell stabilizer ketotifen [4-(1-Methyl-4-piperidylidene)-4H-benzo[4,5]cyclohepta[1,2-b]thiophen-10(9H)-one Fumarate] prevents mucosal mast cell hyperplasia and intestinal dysmotility in experimental Trichinella spiralis inflammation in the rat. J Pharmacol Exp Ther. 319, 1104-1111.
    Pubmed CrossRef
  36. Stefanini, GF, Prati, E, and Albini, MC (1992). Oral disodium cromoglycate treatment on irritable bowel syndrome: an open study on 101 subjects with diarrheic type. Am J Gastroenterol. 87, 55-57.
    Pubmed
  37. Stefanini, GF, Saggioro, A, and Alvisi, V (1995). Oral cromolyn sodium in comparison with elimination diet in the irritable bowel syndrome, diarrheic type. Multicenter study of 428 patients. Scand J Gastroenterol. 30, 535-541.
    Pubmed CrossRef
  38. Klooker, TK, Braak, B, and Koopman, KE (2010). The mast cell stabiliser ketotifen decreases visceral hypersensitivity and improves intestinal symptoms in patients with irritable bowel syndrome. Gut. 59, 1213-1221.
    Pubmed CrossRef
  39. Wouters, MM, Balemans, D, and Van Wanrooy, S (2016). Histamine receptor H1-mediated sensitization of TRPV1 mediates visceral hypersensitivity and symptoms in patients with irritable bowel syndrome. Gastroenterology. 150, 875-887.
    Pubmed CrossRef
  40. Dave, B, and Rubin, W (1999). Inhibition of gastric secretion relieves diarrhea and postprandial urgency associated with irritable bowel syndrome or functional diarrhea. Dig Dis Sci. 44, 1893-1898.
    Pubmed CrossRef
  41. Tack, JF, Miner, PB, Fischer, L, and Harris, MS (2011). Randomised clinical trial: the safety and efficacy of AST-120 in non-constipating irritable bowel syndrome - a double-blind, placebo-controlled study. Aliment Pharmacol Ther. 34, 868-877.
    Pubmed CrossRef
  42. Böhn, L, Störsrud, S, Törnblom, H, Bengtsson, U, and Simrén, M (2013). Self-reported food-related gastrointestinal symptoms in IBS are common and associated with more severe symptoms and reduced quality of life. Am J Gastroenterol. 108, 634-641.
    Pubmed CrossRef
  43. Barbara, G, Wang, B, and Stanghellini, V (2007). Mast cell-dependent excitation of visceral-nociceptive sensory neurons in irritable bowel syndrome. Gastroenterology. 132, 26-37.
    Pubmed CrossRef
  44. Buhner, S, and Schemann, M (2012). Mast cell-nerve axis with a focus on the human gut. Biochim Biophys Acta. 1822, 85-92.
    CrossRef
  45. Ostertag, D, Buhner, S, and Michel, K (2015). Reduced responses of submucous neurons from irritable bowel syndrome patients to a cocktail containing histamine, serotonin, TNFα, and tryptase (IBS-cocktail). Front Neurosci. 9, 465.
    CrossRef
  46. Kreis, ME, Haupt, W, Kirkup, AJ, and Grundy, D (1998). Histamine sensitivity of mesenteric afferent nerves in the rat jejunum. Am J Physiol. 275, G675-G680.
    Pubmed
  47. Brunsden, AM, and Grundy, D (1999). Sensitization of visceral afferents to bradykinin in rat jejunum in vitro. J Physiol. 521, 517-527.
    Pubmed KoreaMed CrossRef
  48. Guarino, MP, Barbara, G, and Cicenia, A (2017). Supernatants of irritable bowel syndrome mucosal biopsies impair human colonic smooth muscle contractility. Neurogastroenterol Motil. 29, e12928.
    CrossRef
  49. O’Mahony, L, Akdis, M, and Akdis, CA (2011). Regulation of the immune response and inflammation by histamine and histamine receptors. J Allergy Clin Immunol. 128, 1153-1162.
    CrossRef
  50. Frei, R, Ferstl, R, and Konieczna, P (2013). Histamine receptor 2 modifies dendritic cell responses to microbial ligands. J Allergy Clin Immunol. 132, 194-204.
    Pubmed CrossRef
  51. Elenkov, IJ, Webster, E, Papanicolaou, DA, Fleisher, TA, Chrousos, GP, and Wilder, RL (1998). Histamine potently suppresses human IL-12 and stimulates IL-10 production via H2 receptors. J Immunol. 161, 2586-2593.
    Pubmed
  52. Horváth, BV, Szalai, C, and Mándi, Y (1999). Histamine and histamine-receptor antagonists modify gene expression and biosynthesis of interferon gamma in peripheral human blood mononuclear cells and in CD19-depleted cell subsets. Immunol Lett. 70, 95-99.
    Pubmed CrossRef
  53. Bissonnette, EY (1996). Histamine inhibits tumor necrosis factor alpha release by mast cells through H2 and H3 receptors. Am J Respir Cell Mol Biol. 14, 620-626.
    Pubmed CrossRef
  54. Mazzoni, A, Young, HA, Spitzer, JH, Visintin, A, and Segal, DM (2001). Histamine regulates cytokine production in maturing dendritic cells, resulting in altered T cell polarization. J Clin Invest. 108, 1865-1873.
    Pubmed KoreaMed CrossRef
  55. Jutel, M, Watanabe, T, and Klunker, S (2001). Histamine regulates T-cell and antibody responses by differential expression of H1 and H2 receptors. Nature. 413, 420-425.
    Pubmed CrossRef
  56. Deiteren, A, De Man, JG, Pelckmans, PA, and De Winter, BY (2015). Histamine H4 receptors in the gastrointestinal tract. Br J Pharmacol. 172, 1165-1178.
    KoreaMed CrossRef
  57. van Wanrooij, SJ, Wouters, MM, and Van Oudenhove, L (2014). Sensitivity testing in irritable bowel syndrome with rectal capsaicin stimulations: role of TRPV1 upregulation and sensitization in visceral hypersensitivity?. Am J Gastroenterol. 109, 99-109.
    CrossRef
  58. Piche, T, Barbara, G, and Aubert, P (2009). Impaired intestinal barrier integrity in the colon of patients with irritable bowel syndrome: involvement of soluble mediators. Gut. 58, 196-201.
    CrossRef
  59. Park, JH, Rhee, PL, and Kim, HS (2006). Mucosal mast cell counts correlate with visceral hypersensitivity in patients with diarrhea predominant irritable bowel syndrome. J Gastroenterol Hepatol. 21, 71-78.
    Pubmed CrossRef
  60. Akbar, A, Yiangou, Y, Facer, P, Walters, JR, Anand, P, and Ghosh, S (2008). Increased capsaicin receptor TRPV1-expressing sensory fibres in irritable bowel syndrome and their correlation with abdominal pain. Gut. 57, 923-929.
    Pubmed KoreaMed CrossRef
  61. Vivinus-Nébot, M, Dainese, R, and Anty, R (2012). Combination of allergic factors can worsen diarrheic irritable bowel syndrome: role of barrier defects and mast cells. Am J Gastroenterol. 107, 75-81.
    CrossRef
  62. Guilarte, M, Santos, J, and de Torres, I (2007). Diarrhoea-predominant IBS patients show mast cell activation and hyperplasia in the jejunum. Gut. 56, 203-209.
    CrossRef
  63. Schemann, M, and Camilleri, M (2013). Functions and imaging of mast cell and neural axis of the gut. Gastroenterology. 144, 698-704.
    Pubmed KoreaMed CrossRef
  64. Cremon, C, Gargano, L, and Morselli-Labate, AM (2009). Mucosal immune activation in irritable bowel syndrome: gender-dependence and association with digestive symptoms. Am J Gastroenterol. 104, 392-400.
    Pubmed CrossRef
  65. Zhang, L, Song, J, and Hou, X (2016). Mast cells and irritable bowel syndrome: from the bench to the bedside. J Neurogastroenterol Motil. 22, 181-192.
    Pubmed KoreaMed CrossRef
  66. Deiteren, A, de Wit, A, van der Linden, L, De Man, JG, Pelckmans, PA, and De Winter, BY (2016). Irritable bowel syndrome and visceral hypersensitivity : risk factors and pathophysiological mechanisms. Acta Gastroenterol Belg. 79, 29-38.
    Pubmed
  67. De Winter, BY, Deiteren, A, and De Man, JG (2016). Novel nervous system mechanisms in visceral pain. Neurogastroenterol Motil. 28, 309-315.
    Pubmed CrossRef
  68. Mobarakeh, JI, Sakurada, S, and Katsuyama, S (2000). Role of histamine H1 receptor in pain perception: a study of the receptor gene knockout mice. Eur J Pharmacol. 391, 81-89.
    Pubmed CrossRef
  69. La, JH, Kim, TW, Sung, TS, Kim, HJ, Kim, JY, and Yang, IS (2004). Role of mucosal mast cells in visceral hypersensitivity in a rat model of irritable bowel syndrome. J Vet Sci. 5, 319-324.
    Pubmed
  70. Fu, LW, Pan, HL, and Longhurst, JC (1997). Endogenous histamine stimulates ischemically sensitive abdominal visceral afferents through H1 receptors. Am J Physiol. 273, H2726-H2737.
  71. Liu, S, Hu, HZ, and Gao, N (2003). Neuroimmune interactions in guinea pig stomach and small intestine. Am J Physiol Gastrointest Liver Physiol. 284, G154-G164.
    CrossRef
  72. Winston, J, Shenoy, M, Medley, D, Naniwadekar, A, and Pasricha, PJ (2007). The vanilloid receptor initiates and maintains colonic hypersensitivity induced by neonatal colon irritation in rats. Gastroenterology. 132, 615-627.
    Pubmed CrossRef
  73. van den Wijngaard, RM, Klooker, TK, and Welting, O (2009). Essential role for TRPV1 in stress-induced (mast cell-dependent) colonic hypersensitivity in maternally separated rats. Neurogastroenterol Motil. 21, 1107-e94.
    Pubmed CrossRef
  74. Pingle, SC, Matta, JA, and Ahern, GP (2007). Capsaicin receptor: TRPV1 a promiscuous TRP channel. Transient receptor potential (TRP) channels. Berlin Heidelberg: Springer, pp. 155-171
    CrossRef
  75. Sastre, J (2008). Ebastine in allergic rhinitis and chronic idiopathic urticaria. Allergy. 63, 1-20.
    Pubmed CrossRef
  76. Magerl, M, Schmolke, J, Siebenhaar, F, Zuberbier, T, Metz, M, and Maurer, M (2007). Acquired cold urticaria symptoms can be safely prevented by ebastine. Allergy. 62, 1465-1468.
    Pubmed CrossRef
  77. Wood-Baker, R, and Holgate, ST (1990). Dose-response relationship of the H1-histamine antagonist, ebastine, against histamine and methacholine-induced bronchoconstriction in patients with asthma. Agents Actions. 30, 284-286.
    Pubmed CrossRef
  78. Karppinen, A, Petman, L, Jekunen, A, Kautiainen, H, Vaalasti, A, and Reunala, T (2000). Treatment of mosquito bites with ebastine: a field trial. Acta Derm Venereol. 80, 114-116.
    Pubmed
  79. Robert, M, Llorens, M, García, E, Luria, X, and Common Cold Collaborative Group (2004). Efficacy and tolerability of ebastine 10 mg plus pseudoephedrine 120 mg in the symptomatic relief of the common cold. Eur J Intern Med. 15, 242-247.
    Pubmed CrossRef
  80. McIntosh, K, Reed, DE, and Schneider, T (2017). FODMAPs alter symptoms and the metabolome of patients with IBS: a randomised controlled trial. Gut. 66, 1241-1251.
    CrossRef


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