Background: Fistulae represent a critical clinical complication in Crohn's disease (CD) patients. Up to 50% of CD patients are affected during disease course from fistulas and about one third of patients suffer from recurring fistulae formation. Since medical treatment options often fail, surgical approaches are often needed, however frequently also not successful.
Methods: The fifth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of fistulas in patients with CD. The aim of subgroup II was to obtain a better understanding of the pathophysiological mechanisms underlying the formation of CD fistulas and to identify future topics in fistula research that might support the development of novel therapeutic approaches.
Results: Current knowledge suggests that CD fistulas develop as a result of a process called epithelial-to-mesenchymal transition (EMT), probably in areas with chronic ongoing inflammation. During EMT, differentiated and resident intestinal epithelial cells (IEC) become dedifferentiated and acquire a mesenchymal phenotype. I particular, IEC downregulate epithelial markers, such as E-cadherin and upregulate the expression of mesenchymal markers, such as vimentin or alpha-SMA. Furthermore, fistula-associated cells acquire markers associated with cell invasiveness what then contributes to the development of invasive fistula tracts. Emerging evidence suggests that a specific immune cell and cytokine profile can be detected around CD fistulas, in examples high expression levels of tumour necrosis factor (TNF), interleukin (IL)-13 and transforming growth factor beta (TGF-beta) what seems to promote onset of EMT and cell invasiveness. Notably, also genetic factors as well as the intestinal microbiota might be involved in fistula development. A major drawback in investigating fistula pathogenesis and in the development of novel fistula therapies is the absence of a suitable animal model.
Conclusions: Current knowledge about fistula pathogenesis is still poor. Future research needs to be directed towards the generation of an in vivo model to allow fistula research in real-life circumstances. The aim would be to identify the driving forces for fistula development, fistula progression and, ideally, fistula closure in vivo. This might critically support the development of new and more effective therapeutic strategies for the treatment of patients suffering from CD fistula.