Development and validation of an ambulatory piglet model for short bowel syndrome with ileo-colonic anastomosis
Authors: Manithody Chandrashekhara , Denton Christine , Price Amber , Blomenkamp Keith , Patel Yogi , Welu Adam , Glbert Ester , Madnawat Himani , Jain Sonali , Villalona Gustavo A , Jain Ajay K 
Published: April 2020

Extensive bowel resection results in short bowel syndrome. Absence of the ileocecal valve and length of remaining bowel are important prognostic factors. Such patients require total parenteral nutrition for survival, which has significant side effects, thus understanding mechanisms driving total parenteral nutrition-associated complications in short bowel syndrome is a major research focus. We hypothesized that we could develop an ambulatory total parenteral nutrition-short bowel syndrome piglet model recapitulating human short bowel syndrome for advanced research. Fourteen neonatal pigs received duodenal, jugular catheters, and a jacket with a miniaturized pump. Animals were randomly allocated to enteral nutrition ( n = 5), total parenteral nutrition only ( n = 5) or total parenteral nutrition with 75% small bowel, ileocecal valve resection, and ileo-colonic anastomosis ( n = 4). Blood, liver, and gut were analyzed. Animals underwent successful bowel resection and anastomosis. Increased bilirubin was noted in short bowel syndrome and total parenteral nutrition. Mean conjugated bilirubin (mg/dL)±SE was 0.036 ± 0.004 for enteral nutrition ( P = 0.03), 1.29 ± 0.613 for total parenteral nutrition ( P = 0.01), and 3.89 ± 0.51 for short bowel syndrome ( P = 0.000064). Linear gut density was reduced in short bowel syndrome and total parenteral nutrition vs. enteral nutrition. The mean linear gut density (g/cm)±SE for distal gut was 0.30 ± 0.02 for enteral nutrition ( P = 0.0005); 0.16 ± 0.01 for total parenteral nutrition ( P = 0.01), and 0.11 ± 0.008 for short bowel syndrome ( P = 0.0001). We noted gut adaptation in short bowel syndrome ( P = 0.015) with significant reduction in gut FXR, gut FGF19, and enhanced hepatic CyP7A1 expression in short bowel syndrome and total parenteral nutrition ( P < 0.05). We successfully created an ambulatory total parenteral nutrition-short bowel syndrome model with distal small bowel and ileocecal valve resection recapitulating human short bowel syndrome. Our model validated total parenteral nutrition-related hyperbilirubinemia and gut changes, as noted in human short bowel syndrome. This model holds great potential for future innovative research and clinical applications. Impact statement Short bowel syndrome is associated with significant comorbidities and mortality. This study is important as unlike current systems, it provides a validated piglet model which mirrors anatomical, histological, and serological characteristics observed in human SBS. This model can be used to advance knowledge into mechanistic pathways and therapeutic modalities to improve outcomes for SBS patients. This study is novel in that in addition to significant reduction in the remnant bowel and noted liver disease, we also developed a method to emulate ileocecal valve resection and described gut adaptive responses which has important clinical implications in humans.