Development and validation of an ambulatory piglet model for short bowel syndrome with ileo-colonic anastomosis

Abstract

<jats:p> 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 &lt; 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. </jats:p><jats:sec><jats:title>Impact statement</jats:title><jats:p> 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. </jats:p></jats:sec>

Impaired Gut–Systemic Signaling Drives Total Parenteral Nutrition-Associated Injury

“…When nutritional needs are entirely met via such intravenous therapy, the process is referred to as TPN. Such therapy remains an essential modality of nutrition delivery throughout the world for neonatal, pediatric, and adult patients [30]. Its use has grown exponentially over the past few decades.…”

“…In this study, we used a novel ambulatory piglet TPN model. We utilized this model to study human physiology because of the extensive homology of the liver and gastrointestinal tract of the pig [30,59] to humans in both form and function [59][60][61][62]. This model is therefore, highly relevant to human pediatric and adult TPN injury [1,8,63].…”

“…Serum bilirubin and changes in villous to crypt (V/C) ratio, which are hallmarks for TPN-associated liver and gut injury, were used as surrogates for initial sample size calculation. In consultation with our university statistician, for our calculations, we used historical data of 5-10-fold changes in serum bilirubin [1,18,30,31], as well as a 2-3 fold reduction in the V/C ratio [1,22,29] with TPN to model the sample size calculation. From our previous work [1,7,8,20,21,32], we predicted that the actual effects across variables would be larger, thus reasonably obtainable with eight animals per group.…”

Beyond lipids: Novel mechanisms for parenteral nutrition–associated liver disease

“…Recent research has facilitated the development of a working understanding of the importance of the gut with respect to its role in liver injury, and the term IFALD is often used instead of PNALD. IFALD presents itself as a 19,20 spectrum ranging from relatively minor liver dysfunction, such as mildly elevated serum liver enzymes, to progressive cholestasis and eventual liver fibrosis/cirrhosis 16,21,22 . IFALD also includes intrahepatic bile acid (BA) accumulation, steatosis, inflammation, glucose intolerance, and dyslipidemia.…”

“…The primary treatment for IFALD is the elimination of PN and the establishment of EN 16,38 . However, for children and infants who cannot be tapered from PN because of insufficient bowel function or length, alternative strategies could be used.…”