O1091: Disruption of Enterohepatic Circulation Ameliorates Small Bowel Resection Associated Hepatic Injury

Background: Massive small bowel resection (SBR) is associated with liver injury and fibrosis. Efforts to elucidate the driving force behind hepatic injury have identified multiple factors, including the generation of toxic bile acid metabolites. Since the major site of bile acid resorption is the ileum, the purpose of this study was to determine the effect of proximal (jejunal) versus distal (ileocecal) resection on bile acid metabolism and liver injury.

Methods: Sham, 50% proximal, and 50% distal SBR were carried out in C57BL/6 mice. Tissues were harvest at both 2 and 10-week postoperative timepoints. Adaptation was histologically confirmed for all subjects. Proliferation was measured via Ki67 staining (n = 4 sham and 5 for other groups). PCR assays were performed to characterize differences in enterohepatic bile acid signaling, hepatic oxidative stress, and homeostatic cellular pathways (n = 7-20 per group). The bile acid pool was also characterized in each group (n = 7-12 per group). Western blot was utilized to assess cellular adaptive changes. Data was analyzed via student’s t-test or 1-way ANOVA to assess adequate postoperative adaptation. Normality was assessed for each dataset and a non-parametric test was used where appropriate. A p-value of 0.05 was used as the threshold for statistical significance.

Results: When compared with 50% proximal SBR, mice that underwent distal resection exhibited less hepatic oxidative stress as verified by lower levels of tumor necrosis factor-α (p < 0.0001), nicotinamide adenine dinucleotide phosphate oxidase (p < 0.0001), and glutathione synthetase (p < 0.05).Figure 1 Distal SBR mice had a healthier bile acid profile with increased de novo bile acid synthesis (increased cholesterol 7α hydroxylase expression; p < 0.0001), lower levels of insoluble bile acids (cholic acid, taurodeoxycholic acid, and taurolithocholic acid), and higher levels of soluble bile acids (tauroursodeoxycholic acid) compared to other groups.Figure 2 Colonic bile acid excretion and subsequent fibroblast growth factor 15 signaling was also upregulated after distal SBR. Conversely, these responses were uncoordinated in the proximal SBR group, and post-resection hepatic injury persisted.

Conclusion: Ileocecal resection interrupts the of delivery of hepatotoxic substances to the liver by physically disrupting the enterohepatic circulation. This hepatoprotective milieu is further propagated by stimulating healthy bile acid metabolism. These findings challenge the notion that preservation of the ileocecal region is beneficial in patients with short gut syndrome.