NUTRIENT MODULATION OF GENE EXPRESSION IN GUT ADAPTATION

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Impairment of intestinal absorptive function is a major cause of morbidity and impaired quality of life, which lead to increased health care costs. This problem, which often results from loss of functional intestinal surface area, occurs in such clinical situations as inflammatory bowel disease, intestinal resection secondary to vascular disease, trauma or congenital and neonatal disorders, and chronic disorders such as AIDS enteropathy. Currently the only option for many of these patients is lifelong dependence on parenteral nutrition. Although small intestinal transplantation may soon become an alternative for selected patients, strategies designed to increase the absorptive function of intestinal grafts are needed. Following loss of small bowel surface area, the intestine undergoes an adaptive response characterized by crypt cell hyperplasia, villus lengthening, and increased absorptive function. Although lumenal nutrients are required for adaptation to occur, little is known about the underlying molecular and cellular mechanisms. Several experimental observations indicate that retinoids may be important nutrient regulators of intestinal cell proliferation and differentiation in the normal and adapting gut. The ultimate goal of this project is to design rational nutritional and pharmacological regimens to maximize adaptation in the setting of reduced functional intestinal surface area. The hypotheses of this proposal are: 1. Retinoids and other nutrients can directly modulate the intestinal adaptive response to loss of functional bowel surface area. 2. These nutrients, through both local and systemic mechanisms, exert these effects by altering the genetic program of the intestinal epithelial cells located in the crypt and on the villus. 3. Identification of the genomic effects of nutrients on the adapting intestine will facilitate the optimization of clinical regimens designed to maximize the intestinal adaptive response to disease and resection. To test these hypotheses, the specific aims of this proposal are: l. To evaluate the ability of retinoids to augment the intestinal adaptive response. This will be assessed by examining the morphometric response (villus height, crypt depth, and crypt cell production and enterocyte migration rates) and the pattern of expression of a cohort of rat genes cloned on the basis of their induction in the adapting ileal remnant following 70% intestinal resection. 2. To identify intestinal genes specifically regulated by retinoic acid in the normal and adapting remnant intestine following 70% resection-and in the human intestinal Caco-2 cell line.