Cellular and molecular mechanisms in the pathogenesis of irritable bowel syndrome

Sammanfattning: Irritable bowel syndrome (IBS) is part of the functional bowel disorder spectrum with no single accepted theory of its development and no biological marker for diagnosis. Today the diagnosis is defined by the ROME criteria, but this is not always correlated to the diagnosis the clinician gives. It has been difficult to find a single biomarker for IBS due to many reasons. One is the heterogeneity of IBS since it may include conditions that really are not IBS. Some conditions, that have been a part of IBS spectrum, have now its own disease entity, for example, enteric dysmotility or bile acid diarrhea. Another reason for difficulty in finding biomarkers is the morphometry method used to analyze mucosal cells. Most studies have focused on counting cells per high-power field, and this could be difficult if the mucosa that is chosen has an uneven stretch or if there is a highpower field without presence of mucosa. We therefore wanted to investigate if the method of counting cells per region of interest would be a more objective and applicable method in identifying patients with IBS. The general aim of this project was to identify cellular and molecular markers in patients with IBS. Another aim was to find histopathological changes that could explain the etiology of IBS. The cells that have been analyzed are mast cells and enteroendocrine cells. We have also analyzed the expression of human betadefensin 2. In study I, we analyzed enteroendocrine cells expressing serotonin and chromogranin A in jejunum of patients with IBS and healthy volunteers. We analyzed the morphometry with two different methods, one analyzing per highpower field, and one analyzing per mm2 . There was no difference in the number of EEC between patients and healthy volunteers, but the conclusion from the study was that counting per mm2 is a more objective method for morphometry. In study II, the colonic mucosa was stained for human beta-defensin 2 (HBD2) and patients with IBS had lower expression of HBD2 compared to patients with inflammatory bowel disease and healthy volunteers, that might indicate that HBD2 have role in the pathogenesis of IBS. In study III, mast cells expressing tryptase and CD117 in jejunum of patients with IBS were analyzed and compared to healthy volunteers. There were a lower number of tryptase positive cells in patients with IBS-D compared to healthy volunteers and a decrease of intraepithelial CD117 mast cells in patients with IBS compared to healthy controls, latest a novel finding. In conclusion, mast cells might have a role in the pathogenesis of IBS and that more focus should be on the intraepithelial mast cells in future studies.