A Role for Gut Luminal Histamine and Proteases in Irritable Bowel Syndrome

Abstract

Introduction: Irritable bowel syndrome (IBS) is one of the most prevalent disorders of gut-brain interaction, characterized by chronic reoccurring abdominal pain in the absence of structural or biochemical abnormalities 1–3. The cause for this abdominal pain remains incompletely understood, however, a role for luminal mediators has been suggested. Histamine and proteases are two of the most well-researched mediators, with evidence showing that both induce visceral hypersensitivity individually 4 5. A notable gap in the literature exists, however, regarding the combined effects of these luminal mediators. I hypothesize that a synergistic relationship might exist between histamine and proteases. Methods: Extracellular recordings were performed, measuring action potentials from mechanosensitive extrinsic afferent nerves innervating the murine colon during colonic distensions to 60 mmHg. The response of afferent nerves to colonic distensions, as well as afferent nerve basal activity were measured. Perforated patch clamp experiments were also conducted, and rheobase was measured. Results: Histamine and trypsin significantly increased afferent basal activity and distension responses when applied directly to afferent nerve recording preparations, with female mice exhibiting greater distension responses. The histamine receptor antagonist cocktail, and the PAR2 antagonist GB83 inhibited a previously characterized increase in afferent nerve mechanosensitivity in the presence of fecal supernatant from IBS patents experiencing high levels of abdominal pain. Afferent basal activity was only inhibited when both the histamine antagonist cocktail and GB83 were applied together, prior to fecal supernatant application. Subthreshold concentrations of histamine and trypsin had no effect on afferent activity when applied individually. However, in combination these subthreshold concentrations significantly increased afferent mechanosensitivity and basal activity, as well as significantly reduced rheobase during patch clamp experiments. Conclusion: A synergistic relationship between histamine and proteases is suggested. Likely, this contributes to the severe abdominal pain experienced by patients with IBS, and the neuronal hypersensitivity in these patients. Further research into this relationship, and other luminal mediators, is warranted. Additionally, the heightened response of afferent nerves prompted by histamine and trypsin application in preparations from female mice may suggest that differences in neuronal responses to luminal mediators contribute to the increased severity of symptoms often reported in female patients.