Pathogenesis of CD fistula. (a) Normal condition persisting in the gut. (b) In CD, the intestinal lesions can be triggered by multiple factors such as inflammatory cells reacting to microbiota or intestinal pathogens. The inflammatory infiltrate includes T-cells, B-cells, and macrophages which produce TNFα. Fibroblasts, staying underneath, produce TGF-β and IL-13. These cytokines trigger EMT and tissue remodeling. (c) During EMT, intestinal epithelial cells (IECs) lose their adhesion properties, downregulating β-catenin and E-cadherin proteins. IECs start migrating underneath in order to repair the lesion and become transitional cells (TCs). (d) TCs produce IL-13 which induces other cells to undergo EMT, penetrating deeper in lower layers. The process is facilitated by the production of metalloproteinases (MMPs) which degrade the extracellular matrix. Image adapted from Panes et al. [15] and drawn with BioRender.com (accessed on 23 November 2021).