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World J Gastrointest Pathophysiol. Aug 15, 2014; 5(3): 205-212
Published online Aug 15, 2014. doi: 10.4291/wjgp.v5.i3.205
Pathophysiology of fistula formation in Crohn's disease
Michael Scharl, Gerhard Rogler
Michael Scharl, Gerhard Rogler, Division of Gastroenterology and Hepatology, University Hospital Zürich, 8091 Zürich, Switzerland
Michael Scharl, Gerhard Rogler, Zurich Center for Integrative Human Physiology, University of Zürich, 8057 Zürich, Switzerland
Author contributions: Scharl M and Rogler G wrote and discussed the paper.
Supported by A grant from Fonds zur Förderung des akademischen Nachwuchses (FAN) of the Zürcher Universitätsverein (ZUNIV) to MS; by a research grant from the Swiss Philanthropy Foundation to MS and GR; by a research credit from the University of Zurich to MS; by research grants from the Swiss National Science Foundation (SNF) to MS, No. 314730-146204, GR, No. 310030-120312, and the Swiss IBD Cohort, No. 3347CO-108792; and by the Zurich Center for Integrative Human Physiology (ZIHP) of the University of Zurich
Correspondence to: Dr. Michael Scharl, MD, PhD, Division of Gastroenterology and Hepatology, University Hospital Zürich, Rämistrasse 100, 8091 Zürich, Switzerland. michael.scharl@usz.ch
Telephone: +41-44-2559519 Fax: +41-44-2559497
Received: December 9, 2013
Revised: April 4, 2014
Accepted: May 29, 2014
Published online: August 15, 2014
Processing time: 268 Days and 11.1 Hours
Abstract

Fistulae represent an important complication in patient suffering from Crohn’s disease (CD). Cumulative incidence of fistula formation in CD patients is 17%-50% and about one third of patients suffer from recurring fistulae formation. Medical treatment options often fail and also surgery frequently is not successful. Available data indicate that CD-associated fistulae originate from an epithelial defect that may be caused by ongoing inflammation. Having undergone epithelial to mesenchymal transition (EMT), intestinal epithelial cells (IEC) penetrate into deeper layers of the mucosa and the gut wall causing localized tissue damage formation of a tube like structure and finally a connection to other organs or the body surface. EMT of IEC may be initially aimed to improve wound repair mechanisms since “conventional” wound healing mechanisms, such as migration of fibroblasts, are impaired in CD patients. EMT also enhances activation of matrix remodelling enzymes such as matrix metalloproteinase (MMP)-3 and MMP-9 causing further tissue damage and inflammation. Finally, soluble mediators like TNF and interleukin-13 further induce their own expression in an autocrine manner and enhance expression of molecules associated with cell invasiveness aggravating the process. Additionally, pathogen-associated molecular patterns also seem to play a role for induction of EMT and fistula development. Though current knowledge suggests a number of therapeutic options, new and more effective therapeutic approaches are urgently needed for patients suffering from CD-associated fistulae. A better understanding of the pathophysiology of fistula formation, however, is a prerequisite for the development of more efficacious medical anti-fistula treatments.

Keywords: Crohn’s disease; Fistula; Tumor necrosis factor; Interleukin-13; Transforming growth factor; Epithelial to mesenchymal transition

Core tip: Fistulae represent an important complication in Crohn’s disease (CD) patients. CD-associated fistulae originate from an epithelial defect due to destructive inflammation. Having undergone epithelial-to-mesenchymal transition (EMT), intestinal epithelial cells (IEC) penetrate into deeper layers of the gut wall causing further tissue damage finally forming connections to other organs or the body surface. EMT of IEC results in activation of matrix remodelling enzymes. Soluble mediators like TNF and IL-13 induce their own expression and expression of molecules associated with cell invasiveness. A better understanding of the pathophysiology of fistula formation is a prerequisite for developing more efficacious medical anti-fistula treatments.