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Title: Rapid postnatal upregulation of intestinal FXR-FGF19 signalling in premature pigs

item SMITH, VICTORIA - California Polytechnic State University
item JIANG, YANJUN - Children'S Nutrition Research Center (CNRC)
item THYMANN, THOMAS - University Of Copenhagen
item SANGILD, PER - University Of Copenhagen
item MAJ, MAGDALENA - California Polytechnic State University
item MANJARIN, RODRIGO - California Polytechnic State University
item Burrin, Douglas - Doug

Submitted to: Journal of Pediatric Gastroenterology and Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/8/2020
Publication Date: 1/27/2020
Citation: Smith, V., Jiang, Y., Thymann, T., Sangild, P., Maj, M., Manjarin, R., Burrin, D.G. 2020. Rapid postnatal upregulation of intestinal FXR-FGF19 signalling in premature pigs. Journal of Pediatric Gastroenterology and Nutrition.

Interpretive Summary: Premature birth is a worldwide problem and leads to growth failure and neurodevelopmental delay in children. The underlying reason for poor growth in premature infants is poorly understood. Previous research suggests that premature infants have lower secretion of bile from the liver and this may limit the digestion of dietary fat needed for growth. Fibroblast growth factor 19 (FGF19) is an important gut hormone that is secreted into the blood after feeding and this secretion is triggered by the presence of bile in the gut. We used neonatal pigs as a model for human infants to test whether the secretion of FGF19 into the blood is different between premature and term pigs. We found that plasma FGF19 concentrations are significantly lower in preterm versus term newborn pigs, but levels increase rapidly with enteral feeding after birth and were similar in both group at 5 days of age. We also showed that the gut expression of genes involved in sensing of bile and secretion of FGF19 were low at birth and upregulated in the first month, but decreased after the first month of age. Our results suggest that lower FGF19 secretion may be a factor in growth failure in premature infants. Further studies are needed to test whether FGF19 functions as a growth hormone in neonates.

Technical Abstract: Bile acid (BA) homeostasis is regulated by intestinal cellular signaling involving the farnesoid X receptor (FXR) and fibroblast growth factor 19 (FGF19) secretion. Using preterm and term pigs as a model, we examined postnatal changes in expression of the FXR-FGF19 axis that is poorly characterized in human infants. Pigs delivered by cesarean-section at 10 d preterm and near full term (115 d gestation) were fitted with orogastric and umbilical arterial catheters. Pigs were fed combined parenteral nutrition and minimal enteral nutrition for 5 d, followed by milk formula until 26 d. Plasma and tissue samples were collected at d 0, 5, 11, and 26. Plasma FGF19 concentration and liver and distal intestinal gene expression of FGF19 and other FXR target genes were quantified. Plasma FGF19 levels were lower in preterm vs. term newborn pigs (P<0.05), increased markedly by 5 d, especially in preterm pigs, and decreased in both groups until d 26. Likewise, intestinal FXR and FGF19 expression was lower (P=0.05) in premature vs term newborn pigs and decreased (P=0.05) between d 5 and 26. Hepatic expression of cholesterol 7a-hydroxylase (CYP7A1) was inversely correlated with plasma FGF19 in both groups. We conclude that the activity of FXR-FGF19 axis is lower in preterm than in term newborn pigs but increases transiently and then declines by the first month of age. We also provide supportive evidence of negative feedback between plasma FGF19 and hepatic CYP7A1 expression.