Pathogenesis of Perianal Fistulizing Crohn's Disease: Current knowledge, gaps in understanding and future research directions.

Fistulizing perianal involvement is a common presentation of Crohn's disease. Perianal Crohn's disease dramatically impairs patients' social and sexual life and its management remains a critical challenge in field of inflammatory bowel disease. No medical therapy is specifically designed for the treatment of perianal Crohn's disease, largely due to the poorly understood pathophysiology. Limited evidence from pre-clinical and clinical studies suggest that the initiation, progression, and maintenance of Crohn's disease-associated perianal fistulas involves complex interactions between host, microbial, and environmental factors. This review intends to discuss the possible roles of genetic predisposition, mucosal immunity, and gut microbiome in perianal Crohn's disease, and considers how epithelial-to-mesenchymal transition may contribute to the pathogenesis. It also summarizes recent advances on the development of animal models and new therapies for perianal Crohn's disease. In the end, we discussed future directions in basic, translational, and clinical research that may dramatically improve our understanding of perianal Crohn's disease and open avenues for novel therapeutic strategies with a multidisciplinary approach. Overall, this review aims to identify current gaps in perianal fistulizing Crohn's disease and explore future research priorities for this debilitating condition.