Mechanisms of Adaptation in Human Short Bowel Syndrome

Short bowel syndrome (SBS) is a condition that occurs after massive surgical removal of sections of the small bowel required to treat conditions such as Crohn's disease, lack of adequate blood flow to the intestine, trauma, twisting of the bowel and other disorders. Patients with SBS develop severe diarrhea, weight loss, loss of nutrients in the stool, malnutrition, dehydration and deficiency of specific nutrients. SBS is thus a major cause of intestinal failure in adults and children. SBS has a high rate of death and medical complications and patients experience enormous health care-related costs and decreased quality of life. Patients with SBS often require intravenous feeding \[known as parenteral nutrition (PN)\] due to chronic malabsorption and malnutrition and also commonly develop infections from intestinal bacteria, suggesting abnormalities in the intestinal "barrier" to bacteria present in the intestine. In animal models of SBS, increased growth of the intestinal lining (mucosa) and improved nutrient absorption occur over time (intestinal adaptation). Although SBS patients commonly exhibit decreased diet-induced diarrhea within the first 2 years after intestinal surgery, very little is known about how the intestinal mucosa adapts in patients with SBS. The proposed pilot study will be the first comprehensive study of serial changes in gut mucosal structure and function in the early period (2-30 months) of SBS in humans. Our Specific Aims are designed to determine: 1) whether the residual small bowel and colonic mucosa in SBS patients exhibits adaptive growth, with concomitantly improved nutrient absorption and gut barrier function; 2) The underlying mechanisms of early gut adaptation in human SBS, by evaluating changes in mucosal cell growth and production of key molecules that are responsible for nutrient transport/absorption and gut barrier function; and 3) The utility of plasma citrulline concentrations and serum flagellin antibody titers as markers for human intestinal absorptive capacity and gut barrier function, respectively. Our research will provide important and new information on the natural history and underlying causes of early intestinal adaptation in man. This information will be valuable in the design of future therapeutic studies in patients with SBS that hold promise for improving the rehabilitation of these individuals.