Author
STOLL, BARBARA - Children'S Nutrition Research Center (CNRC) | |
JIANG, YANJUN - Children'S Nutrition Research Center (CNRC) | |
FANG, ZHENGFENG - Sichuan Agricultural University | |
WANG, HONGTAO - Children'S Nutrition Research Center (CNRC) | |
GUTHRIE, GREG - Children'S Nutrition Research Center (CNRC) | |
BURRIN, DOUGLAS - Doug |
Submitted to: Meeting Abstract
Publication Type: Abstract Only Publication Acceptance Date: 4/22/2015 Publication Date: 5/6/2015 Citation: Stoll, B., Jiang, Y., Fang, Z., Wang, H., Guthrie, G., Burrin, D.G. 2015. Enteral obeticholic acid prevents PNALD and promotes intestinal growth in TPN fed neonatal piglets [abstract]. Proceedings of the 48th Annual Meeting of the European Society for Paediatric Gastroenterology, Hepatology and Nutrition, May 6-9, 2015, Amsterdam, The Netherlands, 60(Suppl. 1):64. Interpretive Summary: Technical Abstract: Total parenteral nutrition (PN) is a vital support for neonatal infants with congenital or acquired gastrointestinal (GI) disorders and requiring small bowel resection. An adverse outcome associated with prolonged PN use is parenteral nutrition associated liver disease (PNALD). We previously showed that enteral chenodeoxycholic acid (CDCA) treatment reduced PNALD and induced intestinal mucosal growth. We hypothesized that the protective CDCA effects were mediated by dual activation of FXR-mediated induction of intestinal fibroblast growth factor 19 (FGF19) and TGR5 receptor-mediated glucagon-like peptide 2 release. The aim of the current study was to compare the physiological effects of obeticholic acid (OCA)(selective FXR agonist) vs CDCA (dual FXR and TGR5 agonist) on hepatic bile acid homeostasis and intestine growth in PN-fed piglets. Term, newborn piglets were assigned to receive complete TPN (PN), PN plus enteral CDCA (30 mg/kg), or PN plus enteral OCA (0.5, 5, 15 mg/kg) daily for 19 d. Endpoints of PNALD, bile acid homeostasis, intestinal growth and crypt cell proliferation (in vivo BrdU labeling) were measured. Compared to control PN pigs, treatment with OCA5 and OCA15, but not CDCA, reduced serum PNALD markers (bilirubin, GGT, total bile acid, triglyceride, and VLDL). Gallbladder bile content was increased in CDCA and OCA15 vs PN. Compared to PN, hepatic expression of CYP7A1 protein was suppressed, whereas bile salt export pump (BSEP) mRNA was increased by OCA5 and OCA15, but not CDCA. Liver mass was higher in CDCA compared to PN and all OCA groups. However, both CDCA and OCA dose-dependently increased intestinal mass, villus height, and crypt cell BrdU-labeling indices. Also, CDCA, OCA5 and OCA15 increased ileal expression of FXR-target genes (FGF19, intestinal fatty acid binding protein (IBABP), and organic solute transporter (OSTalpha). We conclude that enteral OCA is more effective than CDCA in prevention of PNALD. Both bile acids induced intestinal trophic effects but OCA has greater potency than CDCA. |