The long-term goal of this research is to establish how parenteral nutrition (PN) regulates hepatic metabolic function and alters the risk of liver disease in infants. Many infants receive PN during hospitalization and this is associated with steatosis and cholestatic liver disease (PNALD). Our preliminary studies using our neonatal pig model of PN-induced liver disease showed that treatment with the selective FXR agonist, obeticholic acid (OCA), prevented PNALD. The protective action of OCA is associated with an induction of intestinal and hepatic FXR target genes marked by increased local FGF19 expression and circulating FGF19, increased hepatobiliary bile-salt export pump expression, and reversal of biliary ductopenia. We also show that the new generation parenteral lipid emulsion (SMOFlipid) induced marked changes in the gut microbiome that correlate with activation of FXR in the liver and intestine. The overall objective of this competitive renewal is to establish cellular and molecular mechanisms whereby parenteral nutrition lipid emulsions disrupt bile acid homeostasis and to also determine how liver and intestinal FXR-FGF19 signaling mediate these actions. Our central hypothesis is that activation of bile acid receptor function, especially FXR and FGF19 action in the intestine and liver is necessary to prevent PNALD. Aim 1: We will quantify bile acid homeostasis and biliary structure in TPN-fed piglets treated with either enteral OCA or recombinant porcine FGF19 to test whether FGF19 is sufficient to prevent PNALD. We will quantify how bile acids and FGF19 regulate the expression of bile acid synthesis and transport genes in hepatoctyes and FXR-FGF19 signaling and proliferation in cholangiocytes. Aim 2: We will use fecal microbiome transplant (FMT) from preterm piglets given different lipid emulsions that induce or prevent cholestasis to test whether the gut microbial community is sufficient to prevent TPN-induced cholestasis. We will test how FMT from different donors into newborn, preterm recipient pigs shapes the gut microbiome and metabolome and liver metabolome. We will perform metabolomic profiling of gut contents and liver tissue and test whether candidate metabolites modulate FXR signaling in pig enteroids and hepatocytes. These studies will test novel mechanisms to establish how restoration of normal FXR-FGF19 signaling affects hepatic metabolic function and disease in a clinically-relevant, neonatal animal model. These studies in premature pigs are translational and may lead to new therapeutic strategies to prevent pediatric liver disease.

R01DK094616

2013-09-18

2023-08-31