Short bowel syndrome is an important clinical problem with high morbidity and mortality. Intestinal adapatation after massive small bowel resection includes cellular hyperplasia and increased nutrient transport but many patients require parenteral nutritional (TPN) support due to malabsorption. The applicant's preliminary data indicate that combinations of a modified enteral diet, L-glutamine, and recombinant growth hormone (GH) can improve nutrient absorption and reduce requirements for TPN. The individual contributions of these factors have not been defined. Other factors, which might be important in gut adaption after massive small bowel resection, include the brush border di-/tripeptide transporter PepT1, glucagon-like peptide-2 (GLP-2), insulin-like growth factor-1 (IGF-1), intestinal trefoil factor, and keratinocyte growth factor (KGF). The applicant hypothesizes that improved intestinal adaption will occur in response to specific dietary substrates and recombinant growth factors, and that the improved adapation will be mediated by an increase in mucosal glutathione (GSH) redox status and local expression of growth-related peptides. The investigator's Specific Aims are to: (1) determine potential mechanisms of human gut adaptation in the context of a randomized, double-blind clinical trial of diet modification, with or without recombinant GH treatment; (2) investigate whether dietary substrates for mucosal glutathione synthesis improve the efficacy of GH, KGF, GLP-2 as agents to enhance adaptive intestinal mucosal growth and function in rat short bowel syndrome; (3) evaluate gut mucosal GSH and expression of intestinal trefoil factor as critical mechanisms of both endogenous and diet/growth factor-stimulated intestinal adaptation in rodent models.
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