Fistulizing Crohn's Disease

Abstract

Fistulas still represent one of the most important complications in patients with Crohn's disease (CD). At least one third of CD patients suffer from fistulas during their disease course and amongst them longstanding remission of complex fistulas occurs only in about one third. So far, fistula pathogenesis is only partially understood. From a histopathological view, a fistula is a tube covered by flat epithelial cells. Current research suggests that the driving force for fistula development is epithelial-to-mesenchymal transition (EMT). Around the fistula, high levels of tumor necrosis factor (TNF), IL-13, and TGFβ can be detected and recent studies indicated an involvement of the intestinal microbiota. Fistula diagnosis requires clinical and surgical assessment, radiologic investigations, e.g., magnet resonance imaging and endoscopy. Routine medical treatment of fistulas includes antibiotics, immunosuppressives, and anti-TNF antibodies. There is no well-established role for calcineurin inhibitors in fistula treatment, corticosteroids appear to be even contra-productive. A promising novel approach might be the application of adipose tissue-derived or bone marrow-derived mesenchymal stem cells that have been studied recently. Due to insufficient efficacy of medical treatment and recurrence of fistulas, surgical interventions are frequently necessary. Further research is needed to better understand fistula pathogenesis aiming to develop novel treatment option for our patients.

Figure 1

Pathogenesis of Crohn’s disease-associated fistulae. Due to an epithelial barrier defect several pathogen-associated molecular patterns (PAMPs), like e.g., muramyl-dipeptide (MDP), as well as bacteria are able to enter the gut mucosa. The resulting inflammatory response induces the event of epithelial-to-mesenchymal transition (EMT). First, an increased expression of tumor necrosis factor (TNF) is initiated, resulting in an upregulation of TGF-β production. This triggers a signaling cascade of molecules associated with matrix remodeling, in particular enhanced activity of matrix metalloproteinases (MMPs) and cell invasiveness, such as β6-Integrin. These events favor the transformation of the intestinal epithelial cells (IECs) towards invasive myofibroblast like cells, what finally results in fistula formation.