Mechanisms of Neonatal Intestinal Failure-Associated Liver Disease: Exploring the Gut-Liver Axis

  • Author / Creator
    Lavallee, Celeste M
  • Neonates with intestinal failure (IF), who must rely on parenteral nutrition (PN) for growth and maintenance of health, are at risk for intestinal failure-associated liver disease (IFALD). In neonates, short bowel syndrome (SBS) as a result of intestinal resection is the most common cause of IF. SBS patients without a remnant ileum and ileocecal valve (ICV) are considered to have the worst prognosis. The inclusion of fish oil (FO) in the PN lipid emulsion has recently been used as both a prevention and treatment strategy for IFALD. However, the relationship between IFALD and intestinal anatomy in SBS has not been formally studied. Similarly, the molecular mechanisms that promote improvement of the disease with the use of FO-containing PN lipids are poorly understood. The overall objective of this thesis was to define the mechanisms by which remnant SBS anatomy and PN lipid composition impact the development of IFALD. Outcome measures included bile flow and biochemical indicators of liver disease, intestinal structure and permeability of the jejunum, bacterial translocation and characterization of the gut microbiota, bile acid identification and quantification, and gene expression of proteins involved in epithelial barrier function, the host immune response, and bile acid metabolism. To examine the effects of remnant anatomy on IFALD, we studied neonatal piglets that were randomized to a 75% intestinal resection including resection of the ileum and ICV (JC), 75% intestinal resection leaving intact ileum and ICV (JI), non-resected but PN-fed sham (Sham), or sow-fed control (SF); JC, JI and Sham piglets were 100% PN-fed for 14 days. As expected, PN-feeding resulted in cholestasis, as indicated by reduced bile flow and increase in markers of liver disease. However, we observed no differences between the PN-fed piglets, regardless of remnant anatomy. Further, in this neonatal model, we did not detect any differences between any of the groups, whether SF or PN-fed, in jejunal permeability as measured directly through permeability studies, or as indicated through the expression of tight junction proteins. Bacterial translocation to the lymph nodes was greater in SBS (JC and JI) piglets compared to SF, but not different between SBS and Sham groups. Overall, sepsis had a greater impact on the development of IFALD than did remnant anatomy. To determine whether PN lipid composition affects the gut microbiota and host immune responses, we compared PN-fed neonatal piglets given equivalent lipid doses of either a pure soybean oil (SO) or a mixed lipid (ML) containing FO for 14 days. We also studied a group of SF piglets. We characterized the gut microbiota with 16S rRNA gene sequencing, and we quantified the relative gene expression of tight junction proteins, mucins, antimicrobial peptides and inflammatory cytokines. Indeed, there were differences in the gut microbiota between all three groups. The microbiota of the ML group was more similar to that of the SF group than the SO group was to the SF group, indicating reduced disturbance with ML. Differences in gene expression relevant for epithelial barrier function (EBF) and the mucosal immune response were identified between SO and ML. Finally, to investigate the molecular mechanisms that contribute to IFALD and to determine the impact of FO in PN lipid, we measured the expression of genes involved in bile acid metabolism and transport and determined bile acid composition of excreted bile, in neonatal piglets that were either SF or PN-fed for 14 days with either SO, ML, or pure FO as the PN lipid. While bile acid excretion was reduced with PN, FO-containing PN lipid resulted in greater expression of bile acid transport genes, and greater excretion of hepatotoxic, hydrophobic bile acids.

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  • Degree
    Master of Science
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    This thesis is made available by the University of Alberta Libraries with permission of the copyright owner solely for non-commercial purposes. This thesis, or any portion thereof, may not otherwise be copied or reproduced without the written consent of the copyright owner, except to the extent permitted by Canadian copyright law.