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

Authors: VONDEROHE, CATILN - Children'S Nutrition Research Center (CNRC); GUTHRIE, GREG - Children'S Nutrition Research Center (CNRC); STOLL, BARBARA - Children'S Nutrition Research Center (CNRC); CHACKO, SHAJI - Children'S Nutrition Research Center (CNRC); Dawson, Harry; Burrin, Douglas - Doug

Submitted to: American Journal of Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/27/2021
Publication Date: 12/1/2021
Citation: Vonderohe, C., Guthrie, G., Stoll, B., Chacko, S., Dawson, H.D., Burrin, D.G. 2021. Tissue-specific mechanisms of bile acid homeostasis and activation of FXR-FGF19 signaling in preterm and term neonatal pigs. American Journal of Physiology. https://doi.org/10.1152/ajpgi.00274.2021.
DOI: https://doi.org/10.1152/ajpgi.00274.2021

Interpretive Summary: Thousands of premature babies are born in the United States every year, and these babies are at much higher risk of devastating heart, lung, gastrointestinal, and developmental diseases that may continue to affect them later in life. Preterm babies also grow more slowly than their term counterparts, tend to be unable to tolerate feeding, and do not properly digest what they eat. Bile acids are molecules secreted by the body to help the gut digest and absorb fat from the diet. Recent work has also shown that bile acids can act as important signaling molecules that allow the gut to communicate with the liver and the rest of the body. Bile acids work to increase the release of a hormone called fibroblast growth factor 19 (FGF19) that signals the liver to decrease the production of bile acids and may also signal the muscles to grow larger and store less fat. The goal of this project was to study the differences in bile acid signaling between preterm and term piglets (used as models for term and preterm babies) at birth, and after feeding on day 3 of life. We found that preterm pigs had a smaller amount of bile acids in their liver and gallbladder which resulted in lower levels of FGF19 in the blood compared to term pigs. Additionally, the intestinal tissue of preterm pigs was less responsive to bile acid signaling than tissue from term pigs. Lower FGF19 may explain why preterm piglets grow more slowly than their term counterparts, and is an interesting focus for more work in preterm infants.

Technical Abstract: The tissue specific molecular mechanisms involved in perinatal liver and intestinal FXR-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 was 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-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.