Pathophysiology of fistula formation in Crohn's disease

Abstract

Fistulae represent an important complication in patient suffering from Crohn's disease (CD). Cumulative inci-dence 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 mesen-chymal 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 fibrob-lasts, 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 media-tors like TNF and interleukin-13 further induce their own expression in an autocrine manner and enhance expres-sion of molecules associated with cell invasiveness ag-gravating the process. Additionally, pathogen-associated molecular patterns also seem to play a role for induction of EMT and fistula development. Though current knowl-edge suggests a number of therapeutic options, new and more effective therapeutic approaches are urgently needed for patients suffering from CD-associated fistu-lae. A better understanding of the pathophysiology of fistula formation, however, is a prerequisite for the de-velopment of more efficacious medical anti-fistula treat-ments. 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-mesen-chymal 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 me-diators like TNF and IL-13 induce their own expression and expression of molecules associated with cell inva-siveness. A better understanding of the pathophysiol-ogy of fistula formation is a prerequisite for developing more efficacious medical anti-fistula treatments. August 15, 2014|Volume 5|Issue 3| WJGP|www.wjgnet.com 205 WJGP 5 th Anniversary Special Issues (6): Crohn's disease Scharl M et al . Crohn's disease fistula Scharl M, Rogler G. Pathophysiology of fistula formation in Crohn's disease. World J Gastrointest Pathophysiol 2014; 5(3): 205-212 Available from: