Results of the Fifth Scientific Workshop of the ECCO (II): Pathophysiology of Perianal Fistulizing Disease

Abstract

The fifth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of fistulas to the disease course of patients with Crohn's disease (CD). The objectives were to reach a better understanding of the pathophysiological mechanisms underlying the formation of CD fistulas; to identify future topics in fistula research that could provide insights into pathogenesis; to develop novel therapeutic approaches; and to review current therapeutic strategies (with clarification of existing approaches to prevention, diagnosis and treatment). The results of the workshop are presented in two separate manuscripts. This manuscript describes current state-of-the-art knowledge about fistula pathogenesis, including the roles of epithelial-to-mesenchymal transition and cytokine matrix remodelling enzymes, and highlights the common association between fistulas and stenosis in CD. The review also considers the possible roles that genetic predisposition and intestinal microbiota play in fistula development. Finally, it proposes future directions and needs for fistula research that might substantially increase our understanding of this complex condition and help unravel novel therapeutic strategies and specific targets for treatment. Overall, it aims to highlight unanswered questions in fistula research and to provide a framework for future research work.

Keywords: Crohn’s disease; Inflammatory bowel disease; cytokines; epithelial-to-mesenchymal transition; fibrosis; fistula; genetic predisposition; intestinal microbiota; mouse models.

Figure 1.

Pathogenesis of Crohn’s disease-associated fistulae. Due to an epithelial barrier defect, several pathogen-associated molecular patterns (PAMPs), such as muramyl dipeptide (MDP), are able to enter the gut mucosa. Both the process of wound repair (1) and the inflammatory response caused by PAMPs (2) induce the event of epithelial-to-mesenchymal transition (EMT). First, increased expression of TNF is initiated (3), resulting in up-regulation of TGF-β production. This triggers a signalling cascade of molecules associated with cell invasiveness, such as β6-integrin (4). The enhanced activity of matrix metalloproteinases (MMPs) and the up-regulation of protein expression favour the transformation of intestinal epithelial cells (IECs) towards invasive myofibroblast forms, which results in fistula formation (5).