Location: Houston, Texas2010 Annual Report
1a. Objectives (from AD-416)
Objective 1: Establish a model using caesarean-delivered animal model to investigate the impact of prematurity on the gastrointestinal and metabolic response to perinatal nutrition. Subobjective 1A: Quantify the effect of chronic parenteral nutrition in the first 2 weeks after birth on the short-term (3 months) and long-term (12 months) development of body composition and glucose homeostasis in models delivered preterm and at term. Subobjective 1B: Quantify whether manipulation of dietary macronutrients and supplementation with bioactive food ingredients fed to premature animal models prevents the onset of mucosal inflammation and gastrointestinal disease, specifically necrotizing enterocolitis. Objective 2: Compare the impact of continuous versus intermittent bolus delivery of nutrients provided enterally or parenterally on protein synthesis and accretion in neonatal animal models and identify the intracellular signaling mechanism involved. Subobjective 2A: Compare the short-term effects of enteral or parenteral amino acids provided in a continuous vs. intermittent bolus delivery pattern. Subobjective 2B: Compare the short-term effects of an enteral or parenteral complete diet provided in a continuous vs. intermittent bolus delivery pattern. Subobjective 2C: Compare the long-term effects of an enteral or parenteral complete diet provided in a continuous vs. intermittent bolus delivery pattern.
1b. Approach (from AD-416)
The goal of our research is to determine how key nutrients, bioactive ingredients, and the pattern of nutrient delivery affects nutrient metabolism, body composition and incidence of disease in early postnatal life. Children's Nutrition Research Center researchers will use multiple experimental approaches involving innovative neonatal animal models to specifically examine the effects of prematurity, parenteral nutrition, and intermittent bolus feeding versus continuous feeding on glucose and protein metabolism. Main endpoints of metabolism will include measurements of glucose tolerance and insulin sensitivity using hyperinsulinemic, euglycemic clamps. The metabolic fate of amino acids and glucose will be measured using oxidation and incorporation of stable isotopic tracers into end-products such as CO2 and protein. Our research team will also examine whether specific carbohydrates and treatment with the bioactive gut peptide, glucagon-like peptide-2, can prevent the onset of necrotizing enterocolitis using a novel premature animal model. We will quantify endpoints of gastrointestinal function, such as blood flow and nutrient absorption, as well as disease based on measures of proinflammatory cytokine expression and gut microbiota communities. This research will provide novel information that will be directly useful to optimize the nutritional management of low birth weight infants and reduce the risk of early postnatal diseases.
3. Progress Report
We are completing studies designed to test whether pretreatment with glucagon-like peptide 2 (GLP-2) reduces inflammation and Necrotizing enterocolitis (NEC) in premature piglets. NEC is a devastating intestinal disease that occurs in premature infants and is associated with reduced blood flow and increased inflammation. We hypothesized that pretreatment with GLP-2 could prevent the onset of NEC in premature piglets. We completed the animal experiments in which we treated premature piglets during the TPN phase and enteral formula feeding phase. Our results showed that GLP-2 treatment stimulated intestinal growth in the premature piglet. In addition, we found that GLP-2 delayed the onset of NEC, but did not prevent or reduce the incidence of the disease. These findings were presented at the Society for Pediatric Research Meeting in Vancouver, Canada, in May 2010. We are continuing with the laboratory analysis of the samples from this study. We are also considering extending the GLP-2 treatment period to test whether this might improve the chances that it will prevent NEC. These studies may eventually lead to a preventative treatment of NEC in premature infants. We are completing studies to examine the effects of continuous parenteral amino acid infusion on protein synthesis in newborns to identify optimum nutrition support regimens to increase growth of premature infants. We previously showed that the stimulation of muscle growth in newborn piglets by feeding is facilitated by the rise in amino acids and insulin after feeding. We completed and published (in the journal Amino Acids) a study that compared how amino acids and insulin separately increase protein synthesis in different tissues of newborn pigs. We showed that both amino acids and insulin increased protein synthesis in a variety of different types of muscles. To examine whether the effect of feeding in the newborn is driven by all amino acids or a single amino acid, we examined the response to leucine, an essential amino acid that is enriched in whey protein. We previously showed that leucine rapidly stimulates protein synthesis, but this response is not sustained. We completed and published (Journal of Nutrition) a study to address the effect of prolonged parenteral leucine infusion on protein synthesis in neonatal pigs. The results showed that prolonged intravenous infusion of leucine activates key signals in muscle cells that control growth. We are currently examining the effects of complete enteral diets provided in an intermittent bolus delivery pattern on protein synthesis. We examined the time course of changes in protein synthesis in newborn muscle after a meal, and our results showed that food consumption rapidly increases skeletal muscle protein synthesis by enhancing cellular development for growth, and this increase is sustained for 2 hours but returns to baseline by 4 hours after a meal. The ADODR monitors activities for the project by routine site visits, and review of major purchases of supplies/equipment, use of SCA funds for foreign travel, and submission of grant applications by investigators funded through the SCA.
1. Improving preterm infant nutrition by getting a grasp on NEC. Necrotizing enterocolitis (NEC) is a serious intestinal disease in premature infants, and there is an urgent need to develop nutritional approaches to prevent NEC. Researchers at the Children's Nutrition Research Center, Houston, Texas, have completed studies testing if the type of dietary carbohydrate, either polycose (an easily digestible source of carbohydrate calories) or lactose-based formula, used in infant formulas induces NEC. Our results showed that the incidence and severity of NEC was higher in preterm animal models fed a formula containing polycose and such findings highlight the potential risk associated with poor digestion of polycose in infant formula. These results have the potential impact of modifying the design of human infant formulas since considerable evidence shows that human milk is protective against NEC and contains mainly lactose, whereas many formulas fed to preterm infants contain substantial amounts of polycose along with lactose.