Original ResearchFull Report: Clinical—Alimentary TractHistamine Receptor H1–Mediated Sensitization of TRPV1 Mediates Visceral Hypersensitivity and Symptoms in Patients With Irritable Bowel Syndrome
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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.
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Authors share co-first authorship.