PP071 - DEVELOPMENTAL DIVERGENCE IN LIVER INJURY IN SHORT BOWEL SYNDROME: DISTINCT NEONATAL CHOLESTATIC AND ADULT STEATOTIC PHENOTYPES

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PP071

DEVELOPMENTAL DIVERGENCE IN LIVER INJURY IN SHORT BOWEL SYNDROME: DISTINCT NEONATAL CHOLESTATIC AND ADULT STEATOTIC PHENOTYPES

A. Verma1, A. Andrews1, B. Schenberg1, J. Wray1, J. Samanta1, H. Khan1, M. Balaji1, K. Puri1, A. Subbarao1, L. Thirumangalakudi1, F. Medina1, C. Manithody1, A. Jain1,*

1Department of Pediatrics, Saint Louis University School of Medicine, Saint Louis, United States

 

Rationale: Short bowel syndrome (SBS) leads to intestinal failure associated liver disease (IFALD), yet hepatic injury patterns vary across developmental stages. Neonates exhibit prominent cholestasis, whereas mechanisms underlying adult SBS associated liver injury remain poorly defined. We hypothesized that developmental stage governs distinct gut liver signaling responses, resulting in divergent hepatic phenotypes.

Methods: Adult C57BL/6J mice (n=10, 8–12 weeks) underwent sham surgery or graded small bowel resection (30%, 50%, 75%) with primary anastomosis. Survival, weight change, liver biochemistry, histology, and gene expression were assessed.

 

Results: SBS reduced survival (median 14 days, range 7–16) without correlation to resection length (p=0.9321) and did not differ significantly from sham (11.5 vs 15 days, p=0.103). SBS mice lost weight (−2.7 g, p=0.002), while sham animals gained weight (0.63 g). Liver injury was characterized by elevations in AST (1903 vs 87.25 IU/L, p=0.03) and ALT (256.5 vs 29.4 IU/L, p<0.001), with minimal cholestatic changes as GGT (p=0.2) and bilirubin remained unchanged. Histology demonstrated prominent hepatic steatosis on H&E and oil red O staining, Figure 1. Mechanistically, hepatic FXR expression increased (2.27 fold, p<0.001), intestinal FGF15 decreased (p=0.01), and CYP7A1 was markedly upregulated (p<0.001), indicating disruption of enterohepatic feedback signaling. Intestinal FXR showed a non significant increase (p=0.24), while FGFR4 was unchanged.

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Conclusion: In contrast to neonatal IFALD characterized by cholestatic injury, the adult murine system demonstrates a predominantly steatotic and hepatocellular injury phenotype with minimal cholestasis. These findings reveal a critical developmental divergence in IFALD pathobiology and emphasize the importance of age specific mechanisms in studying SBS and targeting gut liver signaling pathways.

Disclosure of Interest: None declared