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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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“Thus, we exposed naive TRPexpressing DRG neurons to the nociceptive mediators present in the colon.(39) TRPV1 responses to 100 nmol/L capsaicin stimulation were significantly increased in naive colonic DRGs incubated with colonic supernatant derived from postinflammatory DSS mice compared with controls (area under the…”
MethodSelf-citationCeuleers, H., Spaendonk, H. V., Hanning, N., Heirbaut, J., Lambeir, A., Joossens, J., Augustyns, K., Man, J. G. D., Meester, I. D., & Winter, B. Y. D. (2016) · World Journal of Gastroenterology · doi:10.3748/wjg.v22.i47.10275 · Cited by 63
Balemans, D., Aguilera‐Lizarraga, J., Florens, M. V., Jain, P., Denadai‐Souza, A., Viola, M. F., Alpizar, Y. A., der Merwe, V., Berghe, P. V., Talavera, K., et al. (2019) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00116.2018 · Cited by 63
“Moreover, increased neuronal excitability of DRG neurons in response to IBS supernatant has been repeatedly reported (8, 13, 22, 38, 44).”
BackgroundMethodInfluentialSelf-citationGrundy, L., Caldwell, A., Garcia‐Caraballo, S., Erickson, A., Schober, G., Castro, J., Harrington, A. M., & Brierley, S. M. (2019) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00435.2019 · Cited by 62
Gut-innervating TRPV1+ Neurons Drive Chronic Visceral Pain via Microglial P2Y12 Receptor
Defaye, M., Abdullah, N. S., Iftinca, M., Hassan, A., Agosti, F., Zhang, Z., Cuménal, M., Zamponi, G. W., & Altier, C. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.12.012 · Cited by 60
“Enhanced microglia reactivity contributes to persistent pain in several preclinical pain models, including peripheral and spinal injury, peripheral inflammation, bone cancer pain, and colitis.7–11 During active colitis, activated microglia produce a large panel of proinflammatory mediators including interleukin-6 (IL-…”
BackgroundInfluentialEvidence for long-term sensitization of the bowel in patients with post-infectious-IBS
Balemans, D., Mondelaers, S. U., Cibert-Goton, V., Stakenborg, N., Aguilera-Lizarraga, J., Dooley, J., Liston, A., Bulmer, D. C., Vanden Berghe, P., Boeckxstaens, G. E., et al. (2017) · Scientific Reports · doi:10.1038/s41598-017-12618-7 · Cited by 60
Self-citationIs there a causal link between psychological disorders and functional gastrointestinal disorders?
Koloski, N. A., Holtmann, G., & Talley, N. J. (2020) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2020.1801414 · Cited by 68
Tervaert, J. W. C. (2018) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2019.01.003 · Cited by 61
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Self-citationKeshteli, A. H., Madsen, K. L., Mandal, R., Boeckxstaens, G. E., Berčík, P., Palma, G. D., Reed, D. E., Wishart, D. S., Vanner, S. J., & Dieleman, L. A. (2019) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.15141 · Cited by 56
“It has recently been reported that visceral hypersensitivity, symptoms and abdominal pain in IBS patients were reduced following administration of a histamine receptor H1 antagonist.(50) In addition, improvement in IBS severity following a low FODMAP diet was associated with reduction of urinary histamine.”
BackgroundSelf-citationDuodenal inflammation: an emerging target for functional dyspepsia?
Wauters, L. I., Burns, G. L., Ceulemans, M., Walker, M. M., Vanuytsel, T., Keely, S., & Talley, N. J. (2020) · Expert Opinion on Therapeutic Targets · doi:10.1080/14728222.2020.1752181 · Cited by 56
“The H1receptor antagonist and mast cell-stabilizer ketotifen also improved visceral hypersensitivity, symptoms, and quality of life in IBS patients [77] and similar effects were reported with ebastine via reduction of H1-mediated sensitization of the transient receptor potential vanilloid receptor type 1 (TRPV1) [50].”
BackgroundInfluentialPhenotyping of subjects for large scale studies on patients with IBS
Boeckxstaens, G. E., Drug, V. L., Dumitrascu, D. L., Farmer, A. D., Hammer, J., Hausken, T., Niesler, B., Pohl, D., Pojskić, L., Polster, A. V., et al. (2016) · Neurogastroenterology & Motility · doi:10.1111/nmo.12886 · Cited by 59
Self-citationNakato, R., Manabe, N., Shimizu, S., Hanayama, K., Shiotani, A., Hata, J., & Haruma, K. (2017) · Digestion · doi:10.1159/000463382 · Cited by 54
Intestinal neuro-immune interactions: focus on macrophages, mast cells and innate lymphoid cells
Stakenborg, N., Viola, M. F., & Boeckxstaens, G. E. (2019) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2019.11.020 · Cited by 55
Self-citationTargeting Histamine Receptors in Irritable Bowel Syndrome: A Critical Appraisal
Fabisiak, A., Włodarczyk, J., Fabisiak, N., Storr, M., & Fichna, J. (2017) · Journal of Neurogastroenterology and Motility · doi:10.5056/jnm16203 · Cited by 54
“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 t…”
BackgroundInfluentialKamphuis, J. B. J., Guiard, B. P., Leveque, M., Olier, M., Jouanin, I., Yvon, S., Tondereau, V., Rivière, P., Guéraud, F., Chevolleau, S., et al. (2019) · Gastroenterology · doi:10.1053/j.gastro.2019.10.037 · Cited by 53
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“gov identifier: NCT01144832), whose results were published in 2016 [87].”
BackgroundEx vivo study of human visceral nociceptors
McGuire, C., Boundouki, G., Hockley, J. R. F., Reed, D. E., Cibert‐Goton, V., Peiris, M., Kung, V., Broad, J., Aziz, Q., Chan, C. T., et al. (2016) · Gut · doi:10.1136/gutjnl-2016-311629 · Cited by 51
Self-citationLiu, J., Dai, Q., Qu, T., Ma, J., Lv, C., Wang, H., & Yu, Y. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106440 · Cited by 53
“VHS, a key pathophysiological mechanism underlying abdominal pain in IBS patients, can be induced by either upregulation or sensitization of hypersensitivity channels in IBS patients and VHS animal models (Anavi-Goffer and Coutts, 2003; Wouters et al., 2016a).”
BackgroundPharmacotherapy for Irritable Bowel Syndrome
Camilleri, M., & Ford, A. C. (2017) · Journal of Clinical Medicine · doi:10.3390/jcm6110101 · Cited by 53
“Histamine sensitizes TRPV1 on neurons from murine dorsal root ganglia and on human submucosal neurons in rectal biopsies via activation of H1 receptors [62].”
BackgroundThe gut–brain axis and pain signalling mechanisms in the gastrointestinal tract
Meerschaert, K. A., & Chiu, I. M. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-01017-9 · Cited by 57
“Mast cells can degranulate and release a range of factors, including histamine and tryptase, which have been shown to activate nociceptive neurons through histamine receptors (HRs) and protease-activated receptors (PARs), leading to increased visceral hypersensitivity 105–108 .”
Regulation of plasma histamine levels by the mast cell clock and its modulation by stress
Nakamura, Y., Ishimaru, K., Shibata, S., & Nakao, A. (2017) · Scientific Reports · doi:10.1038/srep39934 · Cited by 46
“Potentiation (sensitization) of cellular responses by histamine has been reported in patients with irritable bowel syndrome, in which pre-exposure of sensory neurons from the colon to histamine increases TRPV4-mediated intracellular signaling, thereby increasing visceral hypersensitivity 43 .”
Brunkwall, L., Ericson, U., Nilsson, P. M., Orho‐Melander, M., & Ohlsson, B. (2020) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.15104 · Cited by 46
Biomarkers as a diagnostic tool for irritable bowel syndrome: where are we?
Camilleri, M., Halawi, H., & Oduyebo, I. (2017) · Expert Review of Gastroenterology & Hepatology · doi:10.1080/17474124.2017.1288096 · Cited by 45
“However, it may conceivably help select patients with persistent evidence of visceral hypersensitivity who could benefit from targeted therapy with visceral analgesia, as shown with the histamine H1 receptor antagonist, ebastine, which has effects on the TRPV1 pain pathways [89].”
BackgroundBeckers, A. B., Weerts, Z. Z. R. M., Helyes, Z., Masclee, A., & Keszthelyi, D. (2017) · Alimentary Pharmacology & Therapeutics · doi:10.1111/apt.14294 · Cited by 45
“Moreover, Wouters et al demonstrated an increased Ca response and increased number of responding neurons to capsaicin in histamine pre-treated biopsy specimens of healthy volunteers.(34) Immunostaining showed co-expression of histamine receptor H1 (HRH1) and TRPV1 on submucosal neurons in both IBS patients and healthy…”
BackgroundExisting and Emerging Therapies for Managing Constipation and Diarrhea
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“[35,36] In a 12-week, double-blind, placebo-controlled study, the HRH1 receptor antagonist ebastine (20mg once daily) reduced visceral hypersensitivity, and improved symptoms, including abdominal pain, versus placebo.[35] (Table 1).”
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“Histamine and other mediators produced by MCs were found to be increased in the guts of patients affected by IBS, where they play a key role in visceral sensitivity [59], owing to their ability to directly enhance neuron excitability [53,54,60,61].”
Probiotics in Irritable Bowel Syndrome: A Review of Their Therapeutic Role
Kumar, L. S., Pugalenthi, L. S., Ahmad, M., Reddy, S., Barkhane, Z., & Elmadi, J. (2022) · Cureus · doi:10.7759/cureus.24240 · Cited by 59
“, histamine H1 receptor agonist (ebastine) reduced overall IBS symptoms, abdominal pain, and visceral hypersensitivity [41].”
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Ion channels, ion channel receptors, and visceral hypersensitivity in irritable bowel syndrome
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The Role of Diet in the Treatment of Irritable Bowel Syndrome
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Intestinal Permeability in Disorders of Gut–Brain Interaction: From Bench to Bedside
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Neural control of gut homeostasis
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Self-citationMultiple chemical sensitivity: It's time to catch up to the science
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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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