Massachusetts Chapter of the American College of Surgeons

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Next Generation RNA-Seq Implicates New Pathways in Pathogenesis of Intestinal Failure-Associated Liver Disease in a Preterm Piglet Model
Scott C. Fligor1,2, Savas T. Tsikis1,2, Thomas I. Hirsch2, Asish Jain3, Liang Sun3, Shira Rockowitz3, Amy Pan1, Kathleen M. Gura2,4, Mark Puder1,2
1Vascular Biology Program, Department of Surgery, Boston Children’s Hospital, Boston, MA, USA; 2Harvard Medical School, Boston, MA, USA; 3The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Boston, MA, USA; 4Department of Pharmacy and the Division of Gastroenterology and Nutrition, Boston Children's Hospital, Boston, MA, USA

Background: Intestinal failure-associated liver disease (IFALD) is the primary life-limiting complication of intestinal failure. Here, we describe a preterm piglet model of IFALD and perform the first transcriptomic investigation in a large animal model.
Methods: Yorkshire piglets were delivered five days preterm via c-section. Piglets received parenteral nutrition for 14 days (PN group) or were bottle fed with sow milk replacer (control group). RNA-Seq of liver tissue was performed on the Illumina Novaseq platform.
Results: PN piglets developed cholestasis (direct bilirubin 1.9 vs. 0.1 mg/dl, P=0.02), steatosis (liver triglycerides 45.6 vs. 15.2 mg/g tissue, P=0.02), and fibrosis (5/6 PN piglets had Ishak score of 3) consistent with IFALD. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis demonstrated the most significantly downregulated pathways were metabolic pathways, with retinol metabolism particularly downregulated. Among the most upregulated pathways were complement and coagulation cascades, NF-kappa B signaling pathway, TNF signaling pathway, and PI3K Akt signaling pathway. Gene Ontology (GO) biological process analysis demonstrated the top upregulated pathways were cell adhesion, biological adhesion, and inflammatory response.
Conclusion: This study is the first whole transcriptome investigation of IFALD in either a large animal model or humans. Retinol metabolism was highly downregulated and may represent a key underexplored pathway integral to IFALD development. Additionally, numerous inflammatory pathways were strongly upregulated, consistent with a central role of inflammation in IFALD pathogenesis.


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