Nutritional Regulation of Neonatal Gut and Liver Health and Disease

My laboratory has several basic and translational projects designed to establish how nutritional support, enteral versus parenteral, effects gut and liver function and susceptibility to disease in early development. We have used the neonatal piglet to established unique models of parenteral nutrition-associated liver disease (PNALD), necrotizing enterocolitis (NEC) and short-bowel syndrome (SBS) to address clinically-relevant problems in pediatric gastroenterology.

Current projects in the laboratory seek to identify the cellular and molecular mechanism that lead to PNALD and metabolic dysfunction associated with prematurity and neonatal parenteral nutrition (PN) support. Our recent studies show that chronic PN induces hepatic steatosis, cholestasis and insulin resistance in term and premature neonatal piglets. We are currently exploring how specific nutrients in commercial lipid emulsions alter the susceptibility to PNALD. We are exploring how nutrients affect interorgan and local cellular signaling pathways involved in hepatic lipid metabolism and bile acid homeostasis. We are also testing whether the adverse metabolic phenotype induced by PN is programmed and persists beyond the neonatal period and predisposes to adolescent fatty liver disease and type 2 diabetes.

Studies also are aimed at establishing the cellular and physiological functions of glucagon-like peptide 2 (GLP-2), an FDA-approved gut hormone currently in clinical trial for treatment of adult short-bowel syndrome. Past studies in TPN-fed piglets were first to show the trophic and vasoactive actions of GLP-2 in the neonatal gut. We identified the cellular co-localization of the GLP-2 receptor in enteric neurons with neurotransmitters. Current studies are aimed at establishing unique enterally-mediated signaling mechanisms that trigger enteroendocrine cell GLP-2 secretion and GLP-2 receptor function. We are also testing the efficacy of GLP-2 administration for prevention of NEC and treatment of SBS in premature piglet models.

We take an integrative experimental approach dictated by the research question to address relevant functions at the whole animal, tissue, cellular or molecular level. We use sophisticated metabolic, cell biological and molecular approaches, such as stable isotope metabolomics, laser-capture microdissection, gene microarray, and confocal microscopic imaging to identify the cellular localization of specific signals involved in the metabolism, proliferation and survival of relevant cell types, including mucosal epithelial cells and hepatocytes.