Tissue-specific mechanisms of bile acid homeostasis and activation of FXR-FGF19 signaling in preterm and term neonatal pigs

The tissue-specific molecular mechanisms involved in perinatal liver and intestinal farnesoid X receptor (FXR)-fibroblast growth factor 19 (FGF19) signaling are poorly defined. Our aim was to establish how gestational age and feeding status affect bile acid synthesis pathway, bile acid pool size, ileal response to bile acid stimulation, genes involved in bile acid-FXR-FGF19 signaling and plasma FGF19 in neonatal pigs. Term (n = 23) and preterm (n = 33) pigs were born via cesarean section at 100% and 90% gestation, respectively. Plasma FGF19, hepatic bile acid and oxysterol profiles, and FXR target gene expression were assessed in pigs at birth and after a bolus feed on day 3 of life. Pig ileal tissue explants were used to measure signaling response to bile acids. Preterm pigs had smaller, more hydrophobic bile acid pools, lower plasma FGF19, and blunted FXR-mediated ileal response to bile acid stimulation than term pigs. GATA binding protein 4 (GATA-4) expression was higher in jejunum than ileum and was higher in preterm than term pig ileum. Hepatic oxysterol analysis suggested dominance of the alternative pathway of bile acid synthesis in neonates, regardless of gestational age and persists in preterm pigs after feeding on day 3. These results highlight the tissue-specific molecular basis for the immature enterohepatic bile acid signaling via FXR-FGF19 in preterm pigs and may have implications for disturbances of bile acid homeostasis and metabolism in preterm infants. NEW & NOTEWORTHY Our results show that the lower hepatic bile acid synthesis and ileum FXR-FGF19 pathway responsiveness to bile acids contribute to low-circulating FGF19 in preterm compared with term neonatal pigs. The molecular mechanism explaining immature or low-ileum FXR-FGF19 signaling may be linked to developmental patterning effects of GATA-4.

Automated summary

The molecular mechanisms and tissue-specific differences in FXR-FGF19 signaling pathway in perinatal pigs were studied, indicating that preterm pigs have smaller, hydrophobic bile acid pools, lower plasma FGF19 levels, and blunted ileal response to bile acids compared to term pigs. It was also found that GATA-4 expression in the jejunum and ileum differed between preterm and term pigs, suggesting developmental patterning effects. These results may have implications for disturbances in bile acid homeostasis and metabolism in preterm infants.