Location: Children's Nutrition Research CenterTitle: Enteral obeticholic acid promotes intestinal growth in total parenteral nutrition fed neonatal pigs
|JIANG, YANJUN - Children'S Nutrition Research Center (CNRC)|
|FANG, ZHENGFENG - Sichuan University|
|STOLL, BARBARA - Children'S Nutrition Research Center (CNRC)|
|GUTHRIE, GREGORY - Children'S Nutrition Research Center (CNRC)|
|HOLST, JENS - University Of Copenhagen|
|HARTMANN, BOLETTE - University Of Copenhagen|
|Burrin, Douglas - Doug|
Submitted to: Hepatology
Publication Type: Abstract Only
Publication Acceptance Date: 8/1/2015
Publication Date: 11/13/2015
Citation: Jiang, Y., Fang, Z., Stoll, B., Guthrie, G.J., Holst, J., Hartmann, B., Burrin, D.G. 2015. Enteral obeticholic acid promotes intestinal growth in total parenteral nutrition fed neonatal pigs [abstract]. Hepatology. Paper No. 1689. 62(1)Suppl:1032A.
Technical Abstract: Intestinal atrophy is an adverse outcome associated with prolonged total parenteral nutrition (PN) partly due to disruption of normal enterohepatic circulation of bile acids. Previously we showed that enteral treatment with chenodeoxycholic acid (CDCA), a dual agonist for the nuclear receptor, farnesoid X receptor (FXR) and G protein-coupled receptor TGR-5, induced intestinal mucosal growth in a parenteral nutrition associated liver disease (PNALD) piglet model. We hypothesized that the intestinal trophic CDCA effects were mainly mediated by TGR5 receptor-mediated glucagon-like peptide 2 (GLP-2) released from enteroendocrine cells. However, CDCA may also exert trophic effects via FXR signaling in intestine. The aim of the current study was to compare the physiological effects of a selective and potent FXR agonist, obeticholic acid (OCA) vs CDCA on intestinal growth in TPN-fed pigs. Term, newborn pigs were assigned to receive complete TPN (PN), PN + enteral CDCA (30 mg/kg), or PN + enteral OCA (0.5, 5, 15 mg/kg) daily for 19 d. The daily parenteral lipid was Intralipid given at 10 g/kg. Intestinal growth and crypt cell proliferation (in vivo BrdU labeling) were measured. We found that both CDCA and OCA treatments significantly increased small intestinal weight, compared to PN pigs, but OCA15 was higher than CDCA (146% vs. 118%). The OCA-induced increase in jejunal and ileal weight was dose-dependent, yet the trophic effects of OCA and CDCA were greater in the ileum than jejunum. Ileal villus height and crypt depth were increased by OCA and CDCA. The percentage of BrdU positive crypt cells in PN, CDCA, OCA0.5, OCA5 and OCA15 groups were 31%, 40%, 40%, 46% and 46% respectively, suggesting OCA and CDCA increased crypt cell proliferation. Portal plasma GLP-1 and -2 concentrations were significantly increased in pigs treated with CDCA, but not OCA, compared to PN pigs suggesting differential intestinal activation of TGR5 signaling. OCA, but not CDCA, treatment dose-dependently increased ileal transcriptional expression of FXR target genes, small heterodimer partner (SHP), ileal lipid binding protein (ILBP), and fibroblast growth factor 19 (FGF19). The expression of fibroblast growth factor receptor 4 (FGFR4) and beta-Klotho mRNA were relative abundant in ileal tissue in all groups. We conclude that the intestinal trophic effects of OCA are greater than CDCA in TPN-fed pigs. The trophic effects of CDCA appear to occur via TGR5-mediated GLP-2 secretion rather than FXR signaling. We show novel evidence that OCA exerts trophic effects in the neonatal intestine and this appears to act mainly via FXR-dependent mechanisms.