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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]
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“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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Cited by
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Ford, A. C., Sperber, A. D., Corsetti, M., & Camilleri, M. (2020) · The Lancet · doi:10.1016/s0140-6736(20)31548-8 · Cited by 818
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Self-citation
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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