X-linked inhibitor of apoptosis protein in intestinal homeostasis and the pathogenesis of inflammatory bowel disease

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Inflammatory bowel diseases (IBD) are a group of diseases that affect an estimated two million people in Europe and that are characterized by chronic intestinal inflammation and an increased risk of colorectal cancer. While the precise mechanisms of IBD pathogenesis are not known, it is believed that inflammation results from an exaggerated host immune response to environmental factors including the intestinal microbiota. Current treatment is therefore based on immunosuppression, targets final steps in immune pathways common to pathogenic and protective immunity, and is associated with susceptibility to infection and malignancy. Moreover, the efficacy of current treatment is limited and at any time half of people with IBD are not in remission.Recent studies suggest that a subset of IBD cases might be related to congenital or acquired immunodeficiency and that chronic inflammation in these patients may result from an inability to control microbial expansion and invasion at the intestinal mucosal surface thus explaining the lack of efficacy of immunosuppression in these patients.In studies aiming to identify the genetic contributions to early onset IBD, we have identified mutations in the X-linked inhibitor of apoptosis protein (XIAP), a gene associated with a primary immunodeficiency called X-linked lymphoproliferative syndrome. These results are in accordance with the concept of immune defects underyling intestinal inflammation in IBD. Using primary human cells from these patients, we could demonstrate a selective and severe defect in NOD2-dependent bacterial recognition. Moreover, Xiap-/- mice showed pronounced defects in the expression of NOD2- and Wnt-dependent antimicrobial peptides in Paneth cells. These results suggest that XIAP acts as a master regulator of two pathways central to intestinal homeostasis and control of the intestinal microbiota.Here, we propose to study the role of XIAP in the regulation of the intestinal microbiota and the pathogenesis of intestinal inflammation. Specifically, we propose to investigate (a) whether Xiap-/- mice exhibit impaired microbial control upon challenge in vitro and in vivo, (b) whether Xiapdeficiency in mice and humans is associated with alterations in the intestinal microbiota that might predispose to intestinal inflammation, (c) whether Xiap-deficiency in mice is associated with increased susceptibility to intestinal inflammation and (d) whether susceptibility to inflammation is dependent on the intestinal microbiota.Together, these studies will provide unique insight into the mechanisms that control intestinal homeostasis and will reveal whether primary immunodeficiency associated with defects in XIAPdependent microbial control contribute to the pathogenesis of intestinal inflammation. These studies have major implications for IBD and might force a reconsideration of the mechanisms underlying intestinal inflammation and the strategies required for efficacious targeting of inflammation in IBD.