The Role of the Hepcidin-Ferroportin-Axis in Crohn’s Perianal Fistula

Abstract Background and aims Crohn’s perianal fistula (CPF) is a severe phenotype of Crohn’s disease (CD) associated with significant morbidity and reduction in quality of life. CPF is characterized by fistula formation with prolonged periods of active pus drainage through the external opening. The underlying etiology remains poorly understood. There is increasing evidence that the process of epithelial to mesenchymal transition (EMT) is a crucial process in the pathogenesis of CPF. However, the drivers of EMT during fistula formation and progression are still not fully understood. EMT is well known for its role in cancer metastasis, with recent studies highlighting the importance of iron regulation in this process. Ferroportin (FPN), a major iron exporter, and intracellular iron levels have been linked to EMT, with reduced FPN expression leading to increased intracellular iron and enhanced EMT in cancer cells. Hepcidin, the master regulator of iron metabolism, controls iron homeostasis by downregulating FPN, hereby affecting iron release into the circulation. The main aim of this research proposal is to investigate the role of hepcidin-ferroportin signalling in the pathogenesis of CPF. Methods Two different approaches will be combined to understand the role of FPN in CPF: (a) cell culture experiments in epithelial cells to understand the role of FPN in EMT in vitro and (b) patient samples to investigate the role of hepcidin-FPN signalling in vivo. Anticipated impact We hypothesize that a decrease in FPN will drive EMT in epithelial cells in vitro, resulting in loss of epithelial defining properties including polarity and epithelial-specific cell contacts. In vivo, we anticipate that ferroportin expression will be reduced in cells lining the fistula tract compared to tissue samples from idiopathic fistulas. As the hepcidin-FPN axis is amenable to pharmacological manipulation, understanding the role of the hepcidin-FPN signalling in the regulation of EMT may enable the development of effective therapies for CPF.