The Farnesoid X Receptor Agonist Tropifexor Prevents Liver Damage in Parenteral Nutrition‐fed Neonatal Piglets

Abstract

Objectives: Intestinal failure-associated liver disease (IFALD) is a lifethreatening complication for patients with intestinal failure who receive long-term parenteral nutrition (PN). We evaluated the effects of the farnesoid X receptor agonist tropifexor on a neonatal piglet model of IFALD fed with PN. Methods: The piglets received PN and tropifexor for 14 days, then levels of liver enzymes, bile acid metabolism, inflammation, and intestinal barrier markers were assessed using quantitative real-time PCR. Fibroblast growth factor (FGF) 19 serum levels were determined using enzyme-linked immunosorbent assays. Bile acids were determined in liver, serum, and intestinal contents, and the microbiome was sequenced in different intestinal segments.Results: The PN model was established in newborn piglets. The levels of serum liver enzymes, pro-inflammatory factors, and oxidative stress increased in the livers of piglets fed with PN, but not in those fed with PN and tropifexor. Tropifexor stimulated FGF19 expression in ileal epithelial cells, increased portal FGF19 levels, then inhibited cholesterol 7a-hydroxylase expression in the liver. Tropifexor increased the relative abundance of bacteria associated with bile salt hydrolase and 7adehydrogenation in the contents of ileum and altered the composition of bile acids in serum, liver, and intestinal contents. Tropifexor also inhibited intestinal inflammation, alleviated intestinal mucosal atrophy, and improved the intestinal barrier. Conclusions: Tropifexor might prevent liver damage in neonatal piglets receiving PN by altering the composition of intestinal microbiota and bile acids. Tropifexor also alleviates intestinal inflammation and preserves the intestinal barrier.

Lactobacillus plantarum supplementation alleviates liver and intestinal injury in parenteral nutrition‐fed piglets

“…**P < 0.01. CA, cholic acid; CDCA, chenodeoxycholic acid; HCA, hyocholic acid; HDCA, hyodeoxycholic acid; LCA, lithocholic acid; ns, not significant; UDCA, ursodeoxycholic acid Consistently, we found LP administration increased the expression levels of intestinal FGF19 and hepatic SHP to reduce the protein expression of CYP7A1, resulting in the reduction of BAs synthesis.Previous study found the FXR agonist tropifexor increased the expression levels of antioxidative genes (GCLM and SOD1) to reduce oxidative stress in the liver of PN-fed piglets 14. Consistently, LP administration increased the expression of GCLM and SOD1, suggesting that LP may reduce oxidative stress in the liver of F I G U R E 4 Lactobacillus plantarum CGMCC 1258 (LP) alters the metabolism of bile acids (BAs) in piglets.…”

“…33 Previous studies found the FXR agonist tropifexor alleviated intestinal injury. 14,18 Furthermore, LP administration facilitated the gut health of suckling piglets by improving the intestinal morphology and intestinal barrier function and microflora. 34 Consistently, we found LP administration alleviated intestinal injury, ameliorated intestinal inflammation, and promoted the expression of genes related to the intestinal barrier in the PN piglets.…”

“…The piglet's PN model was established as previously described. 13,14 Briefly, a sterile polyurethane catheter (BTPU-040; Instech) was inserted in the PN piglets' right jugular vein. Postoperatively, piglets were provided with the "all-in-one" PN solution daily containing 243.83 ml/kg fluid and 197.7 kcal/kg energy as previously described (Supporting Information: Table S1).…”

“…Postoperatively, piglets were provided with the "all-in-one" PN solution daily containing 243.83 ml/kg fluid and 197.7 kcal/kg energy as previously described (Supporting Information: Table S1). 13,14…”

“…The gut microbial communities were amplified and sequenced using the 16S rRNA gene amplicon sequencing as described previously. 13,14,18 Briefly, total microbial genomic DNA samples from the samples of luminal contents were extracted using the DNeasy Power Soil Kit (QIAGEN, Inc) following the manufacturer's instructions. The bacterial 16S rRNA gene V4-V5 region was amplified using the forward primer 515F (5′-GTGCCAGCMGCCGCGGTAA-3′) and the reverse primer 907R (5′-CCGTCAATTCMTTTRAGTTT-3′).…”