Novel Treatments for Intestinal Failure Explored in Neonatal Piglets with Short Bowel Syndrome: Focusing on the Microbiome, Sepsis and Trophic Factors

• Author / Creator

  Pauline, Mirielle L

• Short bowel syndrome (SBS) is the leading cause of intestinal failure (IF) in infants, and occurs when there is a significant loss of intestine due to acquired or congenital reasons, leading to infants being unable to absorb sufficient nutrients for survival and growth. SBS traditionally had a mortality rate of 25-50%, with infants dying from complications of parenteral nutrition (PN). Over the last 25 years, this has drastically changed due to multidisciplinary IF teams, changes in PN, home parenteral nutrition (HPN) and antibacterial locks. In order for these infants to survive, the remnant bowel needs to undergo a compensatory process termed adaptation, with structural and functional changes of the intestine to improve nutrient absorption. For the risks associated with PN to be eliminated, children need to undergo adaptation and achieve enteral autonomy. Glucagon-like peptide-2 (GLP-2) is produced by enteroendocrine L cells of the distal bowel and has been shown to stimulate intestinal adaptation. While GLP-2 analogues have helped SBS patients decrease PN volume, along with some patients achieve enteral autonomy, the mechanism by which GLP-2 exerts its intestinotrophic effects is still not fully understood. Insulin-like growth factor-1 (IGF-1) is one of the most abundant hormones in human milk and colostrum, and importantly the placenta secretes IGF-1 and levels increase in the infant at birth. IGF-1 is expressed primarily in the subepithelial myofibroblasts close to the GLP-2 receptors, and IGF-1 receptors are found in the epithelial crypt cells that are the drivers of villus lengthening and adaptation. Every time a child with SBS becomes septic, this negatively impacts their enteral tolerance and therefore their gut adaptation. Sepsis in SBS children comes from central line associated bloodstream infections (CLABSI), both from line contamination and potentially gut bacterial translocation. Many patients with SBS suffer from dysbiosis as a result of prematurity, prolonged hospitalization, recurrent antibiotics and altered intestinal anatomy. Probiotics have been suggested as a way to modify the microbiome in SBS but there have been few studies to date with mixed results. CLABSI risk is modulated with the use of antibacterial locks. In these studies, we investigate novel treatment approaches to promote adaptation, and hence autonomy from PN, with probiotics and trophic factors, along with strategies to reduce CLABSI and maintaining catheter patency while on PN, including with a novel locking solution. Studies were undertaken in a surgical animal model of SBS, with a 75% small bowel resection, with a jejunocolic anastomosis (JC). Piglets had a jugular venous catheter inserted for total PN (TPN) and a gastric tube for enteral nutrition (EN). Piglets were maintained in laboratory for 7-14 days. Structural adaptation was measured via bowel length, mucosal and intestinal weight and histopathology. Functional adaptation was measured via fat absorption and Üssing chamber. Trophic factor signalling was assessed using relative gene expression of tight junction proteins, trophic factors and their associated receptors. The microbiome structure was determined via PCR, while the microbiome function was determined via short chain fatty acid (SCFA) analysis by gas chromatography. Our results demonstrated the benefits for catheter patency and reduced CLABSI with the use of a novel locking solution. We identified potential benefits of using probiotics in SBS, both for adaptation and modulating dysbiosis. We confirmed the benefits of GLP-2 analogues for intestinal adaptation, but highlighted this is particularly when longer acting analogues are used and is not augmented by the use of IGF-1. These studies of novel treatments in piglets demonstrate the importance of translational research in developing and testing new approaches for SBS. Moving forward, these studies will provide important preclinical data for strategies of modulating dysbiosis, CLABSI and adaptation for infants and children with SBS.

• Subjects / Keywords

  • Short Bowel Syndrome
  • Microbiome
  • Probiotics
  • Trophic Factors

• Graduation date

  Spring 2024

• Type of Item

  Thesis

• Degree

  Doctor of Philosophy

• DOI

  https://doi.org/10.7939/r3-danb-9s58

• License

  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.