Related Experiment Video
Updated: Nov 12, 2025
Single-Anastomosis Duodeno-Ileal Bypass with Sleeve Gastrectomy Model in Mice
Published on: February 10, 2023
Liver injury after small bowel resection is prevented in obesity-resistant 129S1/SvImJ mice
Emily J Onufer1, Yong-Hyun Han2,3, Cathleen Courtney1
1Division of Pediatric Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, Missouri.
Abstract:
Intestinal failure-associated liver disease is a major morbidity associated with short bowel syndrome. We sought to determine if the obesity-resistant mouse strain (129S1/SvImJ) conferred protection from liver injury after small bowel resection (SBR). Using a parenteral nutrition-independent model of resection-associated liver injury, C57BL/6J and 129S1/SvImJ mice underwent a 50% proximal SBR or sham operation. At postoperative week 10, hepatic steatosis, fibrosis, and cholestasis were assessed. Hepatic and systemic inflammatory pathways were evaluated using oxidative markers and abundance of tissue macrophages. Potential mechanisms of endotoxin resistance were also explored. Serum lipid levels were elevated in all mouse lines. Hepatic triglyceride levels were no different between mouse strains, but there was an increased accumulation of free fatty acids in the C57BL/6J mice. Histological and serum markers of hepatic fibrosis, steatosis, and cholestasis were significantly elevated in resected C57BL/6J SBR mice as well as oxidative stress markers and macrophage recruitment in both the liver and visceral white fat in C57BL/6J mice compared with sham controls and the 129S1/SvImJ mouse line. Serum endotoxin levels were significantly elevated in C57BL/6J mice with significant elevation of hepatic TLR4 and reduction in PPARα expression levels. Despite high levels of serum lipids, 129S1/SvImJ mice did not develop liver inflammation, fibrosis, or cholestasis after SBR, unlike C57BL/6J mice. These data suggest that the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARα and TLR4 contribute to the liver injury seen in C57BL/6J mice with short bowel syndrome.NEW & NOTEWORTHY Unlike C57BL/6 mice, the 129S1/SvImJ strain is resistant to liver inflammation and injury after small bowel resection. These disparate outcomes are likely due to the accumulation of hepatic free fatty acids as well as increased endotoxin-driven inflammatory pathways through PPARα and TLR4 in C57BL/6 mice with short bowel syndrome.
Insights
The 129S1/SvImJ mouse strain resists liver injury after small bowel resection (SBR), unlike C57BL/6J mice. This protection is linked to reduced free fatty acid accumulation and endotoxin-driven inflammation pathways.
Area of Science:
- Gastroenterology and Hepatology
- Immunology
- Metabolic Diseases
Background:
- Intestinal failure-associated liver disease (IFALD) is a significant complication of short bowel syndrome (SBS).
- Mouse strain differences may influence susceptibility to IFALD following small bowel resection (SBR).
Purpose of the Study:
- To investigate if the obesity-resistant 129S1/SvImJ mouse strain is protected from liver injury after SBR compared to the C57BL/6J strain.
- To elucidate mechanisms underlying differential liver injury susceptibility in SBS.
Main Methods:
- Comparison of liver injury markers (steatosis, fibrosis, cholestasis) in C57BL/6J and 129S1/SvImJ mice 10 weeks post-50% SBR or sham operation.
- Assessment of hepatic and systemic inflammation, oxidative stress, tissue macrophage abundance, and endotoxin pathways (TLR4, PPARα).
Main Results:
- C57BL/6J mice showed significantly elevated hepatic fibrosis, steatosis, cholestasis, oxidative stress, and macrophage recruitment post-SBR.
- 129S1/SvImJ mice exhibited resistance to these liver pathologies despite elevated serum lipids.
- C57BL/6J mice had higher serum endotoxin, hepatic TLR4, and lower PPARα expression compared to 129S1/SvImJ mice.
Conclusions:
- Hepatic free fatty acid accumulation and enhanced endotoxin-driven inflammatory pathways (TLR4, PPARα) contribute to liver injury in C57BL/6J mice with SBS.
- The 129S1/SvImJ mouse strain demonstrates significant protection against SBR-induced liver injury, highlighting strain-specific mechanisms in IFALD pathogenesis.
