In 1998, preterm infants comprised 11.6 percent of births in the U.S., the highest reported incidence since 1976. Due to significant advances in neonatal care, mortality among premature infants has declined over the past decade. However, with the survival of these premature infants, clinicians have entered an era where intervention strategies for serious complications of prematurity are needed. Necrotizing enterocolitis is the most common surgical emergency among premature infants, which requires removal of the necrotic intestine and often leaves the infant with inadequate intestinal surface area for digestion and absorption of nutrients. These infants typically receive their nutritional requirements intravenously through a therapy known as total parenteral nutrition (TPN). However, medical treatments aimed at increasing the structure and function of the remaining small intestine could allow these children to consume nutrients orally and eliminate their long-term reliance on TPN. The long-range goal of this research is to optimize the quality of life for children with short-bowel syndrome. The objective of this application is to understand how the introduction of intravenous short-chain fatty acids (SCFAs), nutrients known to be trophic to the small intestine, impact small intestinal structure and function. It is our central hypothesis that the addition of SCFAs to TPN will prepare the residual small intestine for proper digestion and absorption of orally consumed nutrients by increasing the abundance of nutrient transporters within the small intestine. We further hypothesize that the regulatory mechanism whereby SCFAs exert these effects is by upregulating an important intestinal peptide, glucagon-like peptide-2. To test these hypotheses, we will pursue the following four specific aims: (1) determine the structural and functional enhancements of the remaining small intestine following SCFA administration; (2) determine the effects of SCFAs on enterocyte-associated functional proteins; (3) determine the cellular and molecular alterations underlying acute responses to SCFAs, and; (4) examine the mechanism regulating the observed SCFA adaptations. The rationale that underlies the proposed research is that, if the molecular alterations and regulatory mechanisms underlying short-chain fatty acid regeneration in intestinal structure and function become known, it will be possible to optimize the nutritional support of children with short-bowel syndrome and reduce their long-term dependence on TPN.