Enteral bile acid treatment improves parenteral nutrition-related liver disease and intestinal mucosal atrophy in neonatal pigs

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.

New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs

“…We previously showed that TPN results in reduced circulating FGF19 concentrations in TPN-fed compared with enterally fed piglets ( 23 ). In the current study with preterm piglets, we also found a lower portal plasma FGF19 antagonism of hepatic FXR function.…”

Validating hyperbilirubinemia and gut mucosal atrophy with a novel ultramobile ambulatory total parenteral nutrition piglet model

“…In addition, although marked cholestasis was seen with TPN infusion, no difference in other markers of hepatic dysfunction, such as alanine aminotransferase, was seen. Previous studies using similar duration of TPN infusion have also failed to note such differences [21], and it is likely that longer duration of TPN infusion may be needed to elicit such changes. Lipid dysfunction and glucose intolerance as noted in adult TPN infusion would also need close assessment.…”

“…Emerging data suggest that enteral bile acids can improve TPN-associated pathologies [21]. Thus, an important anticipated use of our TPN animal model would be enteral drug testing.…”

“…Current technology has allowed human patients on TPN to use a portable, ambulatory, unobtrusive mobile pump as the method of delivery [20,21]. However, the only TPN infusion animal model identified and described in the current literature involves tethering of pigs to maintain catheters, which is costly, resource-intensive, stressful for animals, and significantly different from TPN delivery in humans (Supplementary Fig.…”

Determination of 7α-OH cholesterol by LC–MS/MS: Application in assessing the activity of CYP7A1 in cholestatic minipigs

“…According to the consensus, high cholesterol diets enlarge the size of liver bile acid pool; and the pool size is positively related to the degree of CYP7A1 inhibition [37, 38]. This phenomenon especially could be seen in the pre-term infants/minipigs [39–41], because of their immature livers functions to excrete the excess bile acids [1, 42]. …”