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Up to 20% of people worldwide develop gastrointestinal symptoms following a meal(1), leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H-1-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders. In mice, oral tolerance to food antigens can break down after enteric infection, and this leads to food-induced pain resembling irritable bowel syndrome in humans.

Post-infectious irritable bowel syndrome (PI-IBS) is a common gastrointestinal disorder characterized by persistent abdominal pain despite recovery from acute gastroenteritis. The underlying mechanisms are unclear, although long-term changes in neuronal function, and low grade inflammation of the bowel have been hypothesized. We investigated the presence and mechanism of neuronal sensitization in a unique cohort of individuals who developed PI-IBS following exposure to contaminated drinking water 7 years ago. We provide direct evidence of ongoing sensitization of neuronal signaling in the bowel of patients with PI-IBS. These changes occur in the absence of any detectable tissue inflammation, and instead appear to be driven by pro-nociceptive changes in the gut micro-environment. This is evidenced by the activation of murine colonic afferents, and sensitization responses to capsaicin in dorsal root ganglia (DRGs) following application of supernatants generated from tissue biopsy of patients with PI-IBS. We demonstrate that neuronal signaling within the bowel of PI-IBS patients is sensitized 2 years after the initial infection has resolved. This sensitization appears to be mediated by a persistent pro-nociceptive change in the gut micro-environment, that has the capacity to stimulate visceral afferents and facilitate neuronal TRPV1 signaling. ispartof: Scientific Reports vol:7 issue:1 pages:13606- ispartof: location:England status: published

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.

To the Editor: We thank Keszthelyi and Masclee (1) for their interest in our study and are pleased to note that they agree with our conclusion that transient receptor potential vanilloid 1 (TRPV1) may be an important player in the visceral hypersensitivity of irritable bowel syndrome (IBS) patients (2). The authors comment on the potential role of neuropeptides such as substance P, calictonine-gene-related peptide, and neurokinin A and regret that we did not measure these mediators to obtain a more mechanistic insight into the differential nociceptive responses observed in our study (2). The reasoning is that TRPV1 activation will lead to the release of these neuropeptides from nociceptive nerve fibers and presumably may further activate or sensitize TRPV1. Although this may theoretically be correct, no increase in mucosal substance P levels in IBS compared with healthy controls was measured by Keszthelyi et al. (3) in their recent study, making it less likely that substance P may be involved. To what extent CGRP or neurokinin A may sensitize or upregulate TRPV1 expression is definitely an interesting hypothesis to be further evaluated. We, however, hypothesized that the observed increased pain response to rectal application of capsaicin in the absence of increased expression of TRPV1 would result from TRPV1 sensitization by mast cell mediators rather than by neuropeptides. This hypothesis was based on the abundant evidence in the literature supporting a role for mast cells in IBS, and on our recent clinical study showing clinical improvement following treatment with the mast cell stabilizer and histamine 1 receptor antagonist ketotifen (4). To test this hypothesis, we pewrformed live calcium imaging recordings of submucosal neurons in rectal biopsies, and demonstrated that TRPV1 is sensitized in IBS patients compared with healthy controls, a finding that was mimicked by histamine and reversed by the histamine 1 receptor antagonist pyrilamine. Similar findings were obtained using murine dorsal root ganglia neurons, indicating that histamine, most likely released by mast cells, sensitizes TRPV1 through histamine 1 receptors (5). This was further corroborated by our recent proof-of-concept clinical trial showing improved global symptom relief and reduced abdominal pain in IBS patients during a 12-week treatment with the histamine 1 receptor antagonist ebastine (6). So, although neuropeptides released from afferent nerve fibers may potentially be involved in the sensitization of TRPV1, our recent evidence would rather indicate that mast cell mediators, in particular histamine, may be more likely.

and cortisol responses to stimulation with CRH and ACTH: 1) differ between IBS patients and healthy controls (HCs), 2) are affected by sex and EALs, 3) are associated with GR mRNA expression. Methods: Male and female Rome III+ IBS patients and HCs underwent CRH (1μg/kg ovine) and ACTH (250μg) stimulation tests with serial plasma ACTH and cortisol levels measured. GR mRNA levels were measured from peripheral blood mononuclear cells using real-time PCR. Presence of EALs