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Histamine Receptor H1–Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome
Open accessAbstract
Background & aims Histamine sensitizes the nociceptor transient reporter potential channel V1 (TRPV1) and has been shown to contribute to visceral hypersensitivity in animals. We investigated the role of TRPV1 in irritable bowel syndrome (IBS) and evaluated if an antagonist of histamine receptor H1 (HRH1) could reduce symptoms of patients in a randomized placebo-controlled trial.Methods By using live calcium imaging, we compared activation of submucosal neurons by the TRPV1 agonist capsaicin in rectal biopsy specimens collected from 9 patients with IBS (ROME 3 criteria) and 15 healthy subjects. The sensitization of TRPV1 by histamine, its metabolite imidazole acetaldehyde, and supernatants from biopsy specimens was assessed by calcium imaging of mouse dorsal root ganglion neurons. We then performed a double-blind trial of patients with IBS (mean age, 31 y; range, 18-65 y; 34 female). After a 2-week run-in period, subjects were assigned randomly to groups given either the HRH1 antagonist ebastine (20 mg/day; n = 28) or placebo (n = 27) for 12 weeks. Rectal biopsy specimens were collected, barostat studies were performed, and symptoms were assessed (using the validated gastrointestinal symptom rating scale) before and after the 12-week period. Patients were followed up for an additional 2 weeks. Abdominal pain, symptom relief, and health-related quality of life were assessed on a weekly basis. The primary end point of the study was the effect of ebastine on the symptom score evoked by rectal distension.Results TRPV1 responses of submucosal neurons from patients with IBS were potentiated compared with those of healthy volunteers. Moreover, TRPV1 responses of submucosal neurons from healthy volunteers could be potentiated by their pre-incubation with histamine; this effect was blocked by the HRH1 antagonist pyrilamine. Supernatants from rectal biopsy specimens from patients with IBS, but not from the healthy volunteers, sensitized TRPV1 in mouse nociceptive dorsal root ganglion neurons via HRH1; this effect could be reproduced by histamine and imidazole acetaldehyde. Compared with subjects given placebo, those given ebastine had reduced visceral hypersensitivity, increased symptom relief (ebastine 46% vs placebo 13%; P = .024), and reduced abdominal pain scores (ebastine 39 ± 23 vs placebo 62 ± 22; P = .0004).Conclusions In studies of rectal biopsy specimens from patients, we found that HRH1-mediated sensitization of TRPV1 is involved in IBS. Ebastine, an antagonist of HRH1, reduced visceral hypersensitivity, symptoms, and abdominal pain in patients with IBS. Inhibitors of this pathway might be developed as a new treatment approach for IBS. ClinicalTrials.gov no: NCT01144832.
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“in a small RCT in 45 patients the histamine 1 receptor antagonist ebastine led to significant improvements in both abdominal pain and global symptoms.290”
From British Society of Gastroenterology guidelines on the management of irritable bowel syndrome (2021) · cites this paper as [290]
Experimental — accuracy not yet measuredIn the citing paper
“These mediators may alter nociceptive pathways in IBS115 or increase intestinal permeability116.”
From The gut Microbiome in adult and pediatric functional gastrointestinal disorders (2019) · cites this paper as [115]
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“The TRPV1 channel contributes to chronic allergic inflammation in animals, such as that seen in irritable bowel syndrome and asthma (99-101).”
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BackgroundIrritable bowel syndrome – controversies in diagnosis and management
Duncanson, K., Tikhe, D., Williams, G. M., & Talley, N. J. (2023) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2023.2223975 · Cited by 21
“Diet in diagnosis and management ● Evidence-based low FODMAP diet, challenges, and reintroduction [41] ● Dietitian-first model using low FODMAP diet and challenges as part of diagnostic process [41] ● Determined by biomarkers, microbiome, metabolome ● Options include low FODMAP diet and challenges [41], modified FODMA…”
BackgroundMethodThe role of the gut microbiome in disorders of gut–brain interaction
Gawey, B. J., Mars, R. A. T., & Kashyap, P. (2024) · FEBS Journal · doi:10.1111/febs.17200 · Cited by 30
“Other studies have shown that antagonism of H1R decreases VH and abdominal pain in stressed rats and patients with IBS [117,118].”
Glioplasticity in irritable bowel syndrome
Lilli, N. L., Quénéhervé, L., Haddara, S., Brochard, C., Aubert, P., Rolli‐Derkinderen, M., Durand, T., Naveilhan, P., Hardouin, J.-B., GIORGIO, R. D., et al. (2017) · Neurogastroenterology & Motility · doi:10.1111/nmo.13232 · Cited by 21
Pain in irritable bowel syndrome: Does anything really help?
BouSaba, J., Sannaa, W., & Camilleri, M. (2021) · Neurogastroenterology & Motility · doi:10.1111/nmo.14305 · Cited by 21
Toward an effective peripheral visceral analgesic: responding to the national opioid crisis
Camilleri, M. (2018) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00013.2018 · Cited by 20
“Additional studies have assessed TRPV1 activity in subtypes of IBS and demonstrated TRPV1 upregulation and sensitization of submucosal neurons from rectal biopsies in IBS patients with visceral hypersensitivity (67, 72).”
BackgroundFungal feelings in the irritable bowel syndrome: the intestinal mycobiome and abdominal pain
van Thiel, I. A. M., de Jonge, W., & van den Wijngaard, R. M. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2168992 · Cited by 20
“Next to mast cell derived histamine that triggers visceral hypersensitivity via the histamine1-receptor in the maternal separation model and patients, tryptase was implicated in IBS pathophysiology by others as well.(26,33,40) This serine protease is released during mast cell degranulation.”
BackgroundTian, S., Zhang, H., Chen, S., Wu, P.-N., & Chen, M. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1175057 · Cited by 16
“, 2006), and TRPV1’s role in visceral hypersensitivity in IBS (Wouters et al., 2016).”
BackgroundTherapeutic Potential of Palmitoylethanolamide in Gastrointestinal Disorders
Branković, M., Gmizić, T., Dukić, M., Zdravkovic, M. D., Daskalovic, B., Mrda, D., Nikolić, N., Brajković, M., Gojgić, M., Lalatović, J., et al. (2024) · Antioxidants · doi:10.3390/antiox13050600 · Cited by 19
“This was not the only study that failed to elucidate the exact mechanism of action because IBS is a multifactorial disease, so a single mechanism is not enough to cover its complexity [102–105].”
Extrinsic Sensory Afferent Nerves Innervating the Gastrointestinal Tract in Health and Disease
Harrington, A. M., Castro, J., Erickson, A., Grundy, L., & Brierley, S. M. (2018) · Elsevier eBooks · doi:10.1016/b978-0-12-809954-4.00017-7 · Cited by 22
Human visceral nociception: findings from translational studies in human tissue
Hockley, J. R. F., Smith, E. S. J., & Bulmer, D. C. (2018) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00398.2017 · Cited by 20
“Abdominal pain is a symptom common to organic [e.g., inflammatory bowel disease (IBD)] and functional [e.g., irritable bowel syndrome (IBS)] gastrointestinal (GI) diseases (61, 75).”
BackgroundInfluentialSelf-citationGrundy, L., Caldwell, A., Garcia‐Caraballo, S., Grundy, D., Spencer, N. J., Dong, X., Castro, J., Harrington, A. M., & Brierley, S. M. (2021) · Journal of Neuroscience · doi:10.1523/jneurosci.0033-21.2021 · Cited by 20
Genetic and phenotypic diversity of fecal Candida albicans strains in irritable bowel syndrome
van Thiel, I. A. M., Stavrou, A. A., de Jong, A. W., Theelen, B., Davids, M., Hakvoort, T. B. M., Admiraal, I., Weert, I., Hesselink, M., Vu, D., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-09436-x · Cited by 20
Interoceptive Processing in Functional Gastrointestinal Disorders
Karaivazoglou, K., Aggeletopoulou, I., & Triantos, C. K. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25147633 · Cited by 17
“In IBS, there is an increased expression of the transient receptor potential channel subfamily V member 1 (TRPV1) and member 3 (TRPV3) genes, and TRPV1 mRNA has been associated with increased visceral hypersensitivity [14,21,40,41].”
BackgroundDucarmon, Q. R., Hoogerwerf, M.-A., Janse, J. J., Geelen, A. R., Koopman, J. P. R., Zwittink, R. D., Goeman, J. J., Kuijper, E. J., & Roestenberg, M. (2020) · Gut Microbes · doi:10.1080/19490976.2020.1840764 · Cited by 17
Laatikainen, R., Salmenkari, H., Sibakov, T., Vapaatalo, H., & Turpeinen, A. M. (2020) · Nutrients · doi:10.3390/nu12072140 · Cited by 17
An Update on the Assessment and Management of Pediatric Abdominal Pain
Friesen, C. A., Colombo, J. M., Deacy, A. D., & Schurman, J. V. (2021) · Pediatric Health Medicine and Therapeutics · doi:10.2147/phmt.s287719 · Cited by 21
Belgian consensus on irritable bowel syndrome
Kindt, S., Louis, H., Schepper, H. U. D., Arts, J., Caenepeel, P., Looze, D. A. D., Gerkens, A., Holvoet, T., Latour, P., Mahler, T., et al. (2022) · Acta gastro-enterologica belgica · doi:10.51821/85.2.10100 · Cited by 21
Irritable bowel syndrome: When food is a pain in the gut
Hussein, H., Remoortel, S. V., & Boeckxstaens, G. E. (2024) · Immunological Reviews · doi:10.1111/imr.13374 · Cited by 16
“9,10 Histamine was able to sensitize TRPV1, TRPV4, and TRPA1 expressed by DRG neurons via the histamine 1 receptor (H 1 R).”
InfluentialSelf-citationAguilera‐Lizarraga, J., López-López, C., Jaramillo-Polanco, J., Florens, M. V., Yu, Y., Tsang, Q. K., Chakraborty, A., Gand, S. D., Pia, F., Quan, R., et al. (2025) · Gastroenterology · doi:10.1053/j.gastro.2025.01.246 · Cited by 21
Self-citationGut Non-Bacterial Microbiota: Emerging Link to Irritable Bowel Syndrome
Liu, A., Gao, W., Zhu, Y., Hou, X., & Chu, H. (2022) · Toxins · doi:10.3390/toxins14090596 · Cited by 18
“The released histamine causes abdominal pain by intensifying nociceptor transient reporter potential channel V1 (TRPV1) responses of patients’ submucosal neurons, and the antagonist of histamine receptor H1 significantly improves the symptoms and quality of life of the patients [82,83].”
BackgroundLi, Y., Li, J., & Dai, C. (2024) · mBio · doi:10.1128/mbio.01533-24 · Cited by 23
“Recently, both clinical and animal experiments have shown that TRPV1 is involved in the pathogenesis of VH (20–22).”
BackgroundQuan, R., Decraecker, L., Appeltans, I., Cuende‐Estévez, M., Remoortel, S. V., Aguilera‐Lizarraga, J., Wang, Z., Hicks, G. A., Wykosky, J., McLean, P. G., et al. (2024) · The American Journal of Gastroenterology · doi:10.14309/ajg.0000000000003042 · Cited by 16
“Histamine derived from mast cells has been shown by us and others to act as a nociceptive mediator in the gut through H 1 R binding on a ff erent neurons (17,19).”
Self-citationCorsetti, M., & Whorwell, P. (2017) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2017.1298442 · Cited by 16
Irritable Bowel Syndrome: Manipulating the Endocannabinoid System as First-Line Treatment
Brugnatelli, V., Turco, F., Freo, U., & Zanette, G. (2020) · Frontiers in Neuroscience · doi:10.3389/fnins.2020.00371 · Cited by 16
“It is also evident that both an IBS-diet (Wouters et al., 2016) and a stress-relief practice are required to boost the beneficial effects of any of the agents suggested.”
BackgroundPPARγ: A turning point for irritable bowel syndrome treatment
Roudsari, N. M., Lashgari, N., Zandi, N., Pazoki, B., Momtaz, S., Sahebkar, A., & Abdolghaffari, A. H. (2020) · Life Sciences · doi:10.1016/j.lfs.2020.118103 · Cited by 16
The Emerging Role of Mast Cells in Irritable Bowel Syndrome.
Boeckxstaens, G. E. (2018) · Europe PMC (PubMed Central) · Cited by 16
Self-citationThe relationship between gut microbiota and proteolytic activity in irritable bowel syndrome
Hou, J., Wang, X., Li, Y., Su, S., Wang, Y., & Wang, B. (2021) · Microbial Pathogenesis · doi:10.1016/j.micpath.2021.104995 · Cited by 18
The Endocannabinoid System: Implications in Gastrointestinal Physiology and Pathology
Caruso, E. A., Nunzio, V. D., Tutino, V., & Notarnicola, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031306 · Cited by 15
“However, further research is needed to refine treatment protocols and explore their full therapeutic potential.”
Yao, Q., Zhang, W., Wang, Y., Shi, L., Zhao, Y., Liang, J., Zhao, Y. P., Kang, J., Zheng, X., Guo, R., et al. (2025) · Nutrients · doi:10.3390/nu17101670 · Cited by 16
“Additionally, TRPV1 has been shown to be activated by histamine, resulting in heightened visceral sensitivity [52].”
Polyphenols from Olive-Mill Wastewater and Biological Activity: Focus on Irritable Bowel Syndrome
Curci, F., Corbo, F., Clodoveo, M. L., Salvagno, L., Rosato, A., Corazza, I., Budriesi, R., Micucci, M., & Mattioli, L. (2022) · Nutrients · doi:10.3390/nu14061264 · Cited by 15
“H1-histaminergic receptor blockers are used to reduce visceral hypersensitivity and symptoms in IBS [50].”
BackgroundInhibition of Serine Proteases as a Novel Therapeutic Strategy for Abdominal Pain in IBS
Decraecker, L., Boeckxstaens, G. E., & Denadai‐Souza, A. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.880422 · Cited by 15
“, 2009) although others reported no increase in mast cell count (Cenac et al., 2007; Wouters et al., 2016).”
BackgroundSelf-citationMechanotransduction in the urothelium: ATP signalling and mechanoreceptors
Li, X., Hu, J., Yin, P., Liu, L.-M., & Chen, Y. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e19427 · Cited by 15
Lin, Y., Jia, Q., Sun, W., Fu, J., Lv, Y., Hou, Y., Wang, C., & Han, S. (2019) · Talanta · doi:10.1016/j.talanta.2019.120539 · Cited by 15
Han, Y., Peng, X.-M., Zhang, H.-X., Chen, S., & Zhang, L.-Y. (2021) · Evidence-based Complementary and Alternative Medicine · doi:10.1155/2021/1975228 · Cited by 14
“Activation of TRPV1 on sensory neurons results in depolarization of neuronal cell membrane, directly or indirectly triggering afferent nerve endings to release sensory neuropeptides such as SP and CGRP and inducing VH [37, 38].”
BackgroundLu, Q., Yang, Y., Zhang, H., Chen, C., Zhao, J., Yang, Z., Yi, F., Li, L., Feng, H., Zhu, J., et al. (2021) · Drug Design Development and Therapy · doi:10.2147/dddt.s329507 · Cited by 14
“receptors, leading to increased intracellular PKA and PKC levels.(52,64) Gαi-coupled G protein-coupled recep-”
BackgroundNew Pathways, New Targets: Visceral Hypersensitivity Pathogenesis in Irritable Bowel Syndrome
Barshop, K., & Staller, K. D. (2016) · Clinical and Translational Gastroenterology · doi:10.1038/ctg.2016.12 · Cited by 13
“With two recent clinical trials failing to demonstrate improvement of IBS symptoms with the anti-inflammatory agent mesalazine,(8,9) Wouters et al.(6) argue against inflammation as a potential”
BackgroundInfluentialDiet–microbial cross–talk underlying increased visceral perception
Palma, G. D., Reed, D. E., & Berčík, P. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2166780 · Cited by 13
“The H1R antagonist ebastine also decreased abdominal pain scores and improved global symptom relief in a small clinical study of IBS patients.(30) Additionally, the H1R antagonist and mast cell stabilizer ketotifen has also been shown to improve visceral hypersensitivity in patients with IBS.”
BackgroundASIA (Shoenfeld's syndrome) due to hysteroscopic Essure sterilization
Chauhan, U., Cassidy, B., & Tervaert, J. W. C. (2021) · Autoimmunity Reviews · doi:10.1016/j.autrev.2021.102979 · Cited by 14
Fang, X., Fan, W., Drossman, D. D., Han, S., & Ke, M. (2022) · World Journal of Gastroenterology · doi:10.3748/wjg.v28.i33.4861 · Cited by 13
Update on treatment of abdominal pain in irritable bowel syndrome: A narrative review
Camilleri, M., & Dilmaghani, S. (2023) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2023.108400 · Cited by 13
Volumetric analysis of small bowel motility in an unselected cohort of patients with Crohn’s disease
Dreja, J., Ekberg, O., Leander, P., Månsson, S., & Ohlsson, B. (2020) · Neurogastroenterology & Motility · doi:10.1111/nmo.13909 · Cited by 13
“Satisfaction with bowel habits (mm) 10 (7-20) 50 (22-76) <.”
Pruritogenic mechanisms and gut sensation: putting the “irritant” into irritable bowel syndrome
Brizuela, M., Castro, J., Harrington, A. M., & Brierley, S. M. (2021) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00331.2020 · Cited by 12
The Duodenal Microenvironment in Functional Dyspepsia
Huyghe, P., Ceulemans, M., Keita, Å. V., Söderholm, J. D., Depoortere, I., Tack, J. F., Wauters, L. I., & Vanuytsel, T. (2025) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm24176 · Cited by 14
Metadata
- Authors
- Wouters, M. M., Balemans, D., Van Wanrooy, S., Dooley, J., Cibert-Goton, V., Alpizar, Y. A., Valdez-Morales, E. E., Nasser, Y., Van Veldhoven, P. P., Vanbrabant, W., Van der Merwe, S., Mols, R., Ghesquière, B., Cirillo, C., Kortekaas, I., Carmeliet, P., Peetermans, W. E., Vermeire, S., Rutgeerts, P., Augustijns, P., Hellings, P. W., Belmans, A., Vanner, S., Bulmer, D. C., Talavera, K., Vanden Berghe, P., Liston, A., & Boeckxstaens, G. E.
- Affiliations
- Universitair Ziekenhuis Leuven (BE)
- VIB-KU Leuven Center for Microbiology (BE)
- KU Leuven (BE)
- Queen's University (CA)
- Amsterdam UMC Location University of Amsterdam (NL)
- Queen Mary University of London (GB)
- Corresponding author
- Boeckxstaens, Guy E.
- ORCID
- Wouters, Mira M.
- Dooley, James
- Alpizar, Yeranddy A.
- Nasser, Yasmin
- Mols, Raf
- Ghesquière, Bart
- Cirillo, Carla
- Kortekaas, Inge
- Carmeliet, Peter
- Peetermans, Willy E.
- Vermeire, Séverine
- Augustijns, Patrick
- Hellings, Peter W.
- Belmans, Ann
- Vanner, Stephen
- Bulmer, David C.
- Talavera, Karel
- Liston, Adrian
- Boeckxstaens, Guy E.
- Venue
- Gastroenterology
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 150
- Issue
- 4
- Pages
- 875-887.e9
- ISSN
- 0016-5085 (ISSN-L)
- OpenAlex
- W2203163745
- Cited by
- 372
- References
- 46
- Citations by year
- 2026: 22 · 2025: 33 · 2024: 42 · 2023: 39 · 2022: 32 · 2021: 49 · 2020: 39 · 2019: 24 · 2018: 38 · 2017: 37 · 2016: 15
- FWCI
- 41.60
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Gastroenterology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Lirias (submittedVersion)
- Queen Mary Research Online (Queen Mary University of London) (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Funders
- Bowel and Cancer Research (1119105)
- Canadian Association of Gastroenterology
- KU Leuven (GOA 14.011)
- Crohn's and Colitis Canada
- Vlaamse regering
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Neuroscience › Sensory Systems › Ion Channels and Receptors
- Health Sciences › Medicine › Physiology (medical) › Pain Mechanisms and Treatments
- Keywords
- irritable bowel syndrome, TRPV1, visceral hypersensitivity, ebastine, mepyramine, capsaicin, submucosal neurons, dorsal root ganglion neurons, rectal distension, abdominal pain, histamine sensitization, health-related quality of life, gastrointestinal symptoms, barostat, calcium imaging
- MeSH terms
- Adolescent, Adult, Aged, Analgesics, Belgium, Biopsy, Butyrophenones, Double-Blind Method, Female, Gastrointestinal Agents, Histamine H1 Antagonists, Humans, Male, Middle Aged, Neurons, Pain Measurement, Piperidines, Quality of Life, Surveys and Questionnaires, Receptors, Histamine H1, Rectum, Remission Induction, Time Factors, Abdominal Pain, Treatment Outcome, Pain Threshold, Calcium Signaling, Receptor Cross-Talk, Irritable Bowel Syndrome, TRPV Cation Channels, Young Adult
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