Gastroenterology

Gastroenterology

Volume 150, Issue 4, April 2016, Pages 875-887.e9
Gastroenterology

Original Research
Full Report: Clinical—Alimentary Tract
Histamine Receptor H1–Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome

https://doi.org/10.1053/j.gastro.2015.12.034Get rights and content

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.

Section snippets

Materials and Methods

For detailed descriptions of the methodology used, please see the Supplementary Material. All co-authors had access to the study data and reviewed and approved the final manuscript.

Sensitization of TRPV1 in Neurons of IBS Patients

To evaluate TRPV1 sensitization in IBS, the intracellular calcium (Ca2+) response of submucosal neurons24 to capsaicin was studied in rectal biopsy specimens of IBS patients (n = 9) and HVs (n = 12). Exposure to capsaicin (0.1 and 1 nmol/L) induced significantly higher Ca2+ responses (Figure 1A and B) and activated more neurons in biopsy specimens of IBS patients compared with HVs (Figure 1B). TRPV1 mRNA levels, however, were similar in IBS and HVs,12 indicating sensitization of TRPV1 on IBS

Discussion

In the present study, we provide evidence in IBS patients for sensitization of TRPV1 in the rectal submucosal plexus, an effect mediated by histamine and/or its metabolite imidazole acetaldehyde. We obtained similar results in the context of pain signaling in murine nociceptive DRG neurons, where histamine, imidazole acetaldehyde, and IBS biopsy supernatants sensitized TRPV1 via HRH1. The significance of this mechanism in IBS was confirmed further in a proof-of-principle clinical trial

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    Conflicts of interest The authors disclose no conflicts.

    Funding Funded by a government grant (Odysseus program, G-0905-07) of the Research Foundation-Flanders and by a KU Leuven University Grant (Global Opportunities for Associations GOA 14.011) (G.E.B.); by a Research Foundation-Flanders postdoctoral fellowship (1248513N to M.M.W. and 12C2113N to C.C.); by a Research Foundation-Flanders PhD fellowship (1127415N to D.B.); by a KU Leuven postdoctoral fellowship (Y.A.A.); by Bowel and Cancer Research (UK charity number 1119105 to V.C.G.); and Séverine Vermeire is a senior clinical investigator of Research Foundation-Flanders . Also funded by a Research Foundation-Flanders research grant G-0699-10N (G.E.B. and M.M.W.), G-0501-10 (P.V.d.B.), and by a grant from Research Fund KU Leuven (GOA 14.011 to K.T.) and an European Research Counsil (ERC) Start Grant IMMUNO (A.L.). funded by the Canadian Institutes of Health Research (S.Va.); supported by a joint fellowship from the Canadian Association of Gastroenterology, the Canadian Institutes of Health Research, and Crohn’s and Colitis Canada (Y.N.); supported by a National Council of Science and Technology (CONACyT) grant: 203341 fellowship (E.E.V.M.); and funded by a KU Leuven University grant (PF-TRPLe to K.T.).

    Author names in bold designate shared co-first authors.

    Authors share co-first authorship.

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