Cellular and molecular mechanisms in the pathogenesis of pouchitis: more than just the microbiota

Pouchitis, defined as inflammation of the ileal pouch, is the most common complication following restorative proctocolectomy for refractory ulcerative colitis. Antibiotics remain the first line of therapy for pouchitis, but the majority of patients develop subsequent episodes and some are refractory to antibiotic therapy. This highlights the need for more effective treatment options and points to a more complex pathophysiology beyond the role of th pouch microbiome, similar to what is seen in inflammatory bowel disease. In this review, we outline the putative mechanisms of pouchitis, including genetic predisposition, microbiome alterations, dysfunction of the intestinal barrier and the immune system and review the available animal models of pouchitis. In addition, we introduce the concept of pouchitis as a possible transmural disease and discuss the potential role of non-immune cells, including stromal cells, in perpetuating inflammation and intestinal barrier dysfunction. We discuss future directions, implications for novel therapies and propose novel multicellular disease models that can better capture the complexity of pouchitis pathogenesis.