Title: Enteral bile acid treatment improves parenteral nutrition-related liver disease and intestinal mucosal atrophy in neonatal pigs Authors
|Jain, Ajay -|
|Stoll, Barbara -|
|Holst, Jens -|
|Moore, David -|
Submitted to: American Journal of Physiology - Gastrointestinal and Liver Physiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: November 9, 2011
Publication Date: November 17, 2011
Citation: Jain, A.K., Stoll, B., Burrin, D.G., Holst, J.J., Moore, D.D. 2011. Enteral bile acid treatment improves parenteral nutrition-related liver disease and intestinal mucosal atrophy in neonatal pigs. American Journal of Physiology - Gastrointestinal and Liver Physiology. 302(2):G218-G224. Interpretive Summary: Some infants develop liver disease after prolonged feeding with parenteral or intravenous nutrition (PN) due to an accumulation of fat and bile acids in the liver. Bile acids function as detergents and aid in intestinal fat digestion, but become toxic when they accumulate in the liver and spill over into the blood, leading to a potentially harmful condition known as PN-associated cholestasis, or PNALD. The cause of PNALD remains poorly understood, but is thought to be caused by a lack of stimulation of the intestine since there is no input of food into the gut during PN. The aim of this study was to first use our neonatal piglet model to test whether lack of intestinal stimulation associated with PN results in deficient secretion of a novel gut hormone, fibroblast growth factor 19 (FGF19). FGF19 acts to suppress bile acid accumulation in the liver. FGF19 secretion from the intestine is stimulated when bile acids bind to specific receptors, namely the farnesoid X receptor. Thus, we also tested whether infusing bile acids into the intestine would stimulate FGF19 secretion and prevent bile acid accumulation. Our results showed that PN does result in depressed circulating FGF19 levels and that replacement of bile acids into the intestine partially restored normal FGF19 secretion. More importantly, we found that the increased FGF19 associated with bile acid treatment prevents PNALD. Another unexpected finding was that the bile acid treatment also increased intestinal mucosal growth, thus reversing the negative impact of PN. This was associated with increased secretion of the intestinal growth hormone glucagon-like peptide 2. These findings may provide a new therapeutic approach for prevention of PNALD in infants.
Technical Abstract: Total parenteral nutrition (TPN) is essential for patients with impaired gut function but leads to parenteral nutrition-associated liver disease (PNALD). TPN disrupts the normal enterohepatic circulation of bile acids, and we hypothesized that it would decrease intestinal expression of the newly described metabolic hormone fibroblast growth factor-19 (FGF19) and also glucagon-like peptides-1 and -2 (GLP-1 and GLP-2). We tested the effects of restoring bile acids by treating a neonatal piglet PNALD model with chenodeoxycholic acid (CDCA). Neonatal pigs received enteral feeding (EN), TPN, or TPN CDCA for 14 days, and responses were assessed by serum markers, histology, and levels of key regulatory peptides. Cholestasis and steatosis were demonstrated in the TPN group relative to EN controls by elevated levels of serum total and direct bilirubin and also bile acids and liver triglyceride (TG) content. CDCA treatment improved direct bilirubin levels by almost fourfold compared with the TPN group and also normalized serum bile acids and liver TG. FGF19, GLP-1, and GLP-2 were decreased in plasma of the TPN group compared with the EN group but were all induced by CDCA treatment. Intestinal mucosal growth marked by weight and villus/crypt ratio was significantly reduced in the TPN group compared with the EN group, and CDCA treatment increased both parameters. These results suggest that decreased circulating FGF19 during TPN may contribute to PNALD. Moreover, we show that enteral CDCA not only resolves PNALD but acts as a potent intestinal trophic agent and secretagogue for GLP-2.