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

Gopalakrishnan, Shreya

Crohn’s disease (CD), characterized by chronic intestinal inflammation, is believed to arise in genetically susceptible hosts through dysregulated host-environmental responses. Others and we recently discovered a monogenic form of CD caused by mutations in the gene encoding X-linked inhibitor of apoptosis protein (XIAP) and have described XIAP mutations in approximately 4% of male children with early-onset Crohn’s disease (CD). To provide insights into the pathways that link XIAP mutations to CD, we investigated the role of XIAP in intestinal homeostasis and inflammation through the study of mice with deletion of Xiap. We discovered that in the absence of XIAP, microbiota-induced TNF release leads to apoptotic loss of antimicrobial peptide (AMP) producing cells called Paneth cells (PC), which is associated with decreased PC-AMP production and impaired control of the intestinal microbiota. These alterations are insufficient to elicit spontaneous intestinal inflammation in the presence of a pathogen-free microbiota but provide susceptibility to microbial and chemical triggers of intestinal inflammation. As such, exposure to the bacterial pathobiont Helicobacter hepaticus leads to the development of granulomatous ileitis in the Xiap-/- but not in wild type mice. Non-necrotizing granulomas are a hallmark of CD, suggesting a potential relevance of our findings in mice to the pathogenesis of human CD. Moreover, administration of dextran sulfate sodium was also associated with increased severity of colitis in Xiap-/- mice when compared to the wild type mice. Together, these findings demonstrate how genetic defects associated with CD can provide susceptibility to environmentally-induced chronic intestinal inflammation and raise the question of whether targeting the microbiota can be efficacious in the treatment and prevention of intestinal inflammation in patients harboring XIAP mutations.

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Gopalakrishnan, Shreya: X-linked inhibitor of apoptosis protein in intestinal homeostasis and the pathogenesis of inflammatory bowel disease. 2018.

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