Mechanisms of intestinal failure in post-surgical inflammatory bowel disease

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DESCRIPTION (provided by applicant): Crohn's disease is a major cause of bowel resection. Recurrent inflammation, fibrostenotic disease and obstruction in small intestine frequently lead to repeat surgeries, increasing the risk of intestinal failure or short bowel syndrome. Current therapies do not effectively prevent post-surgical inflammation or fibrosis. A major goal of this research is to develop a new animal model of post- surgical inflammation and fibrosis after ileo-cecal resection (ICR), a common surgical intervention in CD. Interleukin-10 (IL-10) null mice given ICR or sham transection under conventional (CONV) or germ free (GF) conditions will be used to test a hypothesis that bacteria independent factors released by tissue damage during surgery can initiate post-surgical fibrosis and inflammation in susceptible hosts, but commensal microflora are required to sustain chronic post-surgical disease. Adaptive growth of remnant small intestine or colon protects against intestinal failure after bowel resection, but little is known about the effects of bacteria or active IBD on intestinal adaptation. Proposed studies will test the hypothesis that commensal microflora or active IBD impact on early ICR-induced expansion of stem cells or long-term adaptive growth of intestine. Specific aims are as follows: Aim #1: will analyze post-surgical inflammation and fibrosis in CONV IL-10 null or WT mice after ICR or sham transection, and establish if post-surgical small bowel disease in IL-10 null mice progresses to stenosis, obstruction or intestinal failure. These studies will also test if tissue damage associated pattern signals (DAMPS) or receptor for advanced glycosylation end products (RAGE) correlate with initiation or perpetuation of post-surgical inflammation or fibrosis. Aim #2 will analyze responses to ICR in germ free (GF) IL-10 null and WT mice to define if bacteria-independent factors can initiate or sustain post-surgical inflammation or fibrosis in susceptible IL-10 null mice, and if this correlates with up-regulation of DAMPS or RAGE. Aim#3 will analyze crypt stem cells and long-term adaptive growth in the intestine of GF and CONV WT or IL-10 null mice after ICR, to define the role of commensal microflora or active IBD in adaptive growth responses to bowel resection. Animal models and information derived from these exploratory studies will provide the basis for more extensive future experiments to define new mechanisms or causative factors underlying recurrent inflammation and fibrosis after surgery for CD, and test new preventative or therapeutic interventions aimed at reducing the risk of intestinal failure.Multiple surgeries for Crohn's disease can cause intestinal failure and the devastating condition of short bowel syndrome, leading to temporary or long-term requirement for intravenous feeding. Fibrostenosing disease and obstruction are common causes of intestinal failure yet there are no therapies to prevent these complications. This research will develop new animal models that will permit better understanding of mechanisms that lead to intestinal failure, and testing of new therapies that may prevent a condition that compromises quality of life and poses a major burden in health care costs.