Background: There is growing evidence that liver graft ischemia-reperfusion (I/R) is a risk factor for hepatocellular carcinoma (HCC) recurrence after liver transplantation, but the involved mechanisms are unclear. Here, we tested the hypothesis that mesenteric congestion due to portal blood flow interruption induces endotoxin-mediated Toll-Like Receptor 4 (TLR4) engagement, resulting in elevated liver cancer burden. We also assessed the role of remote ischemic preconditioning (RIPC) in this context.

Methods: C57Bl/6j mice were exposed to standardized models of liver I/R injury and RIPC, by occluding hepatic and femoral blood vessels. HCC was induced by injecting RIL-175 cells in the portal vein. We further evaluated the impact of the gut-liver axis (LPS-TLR4 pathway) in this context, by studying mice with enhanced (LPS infusion) or defective (TLR4^-/- knockout mice, gut sterilization, TLR4 antagonist) TLR4 responses.

Results: Portal triad clamping provokes upstream mesenteric venous engorgement, increased bacterial translocation, resulting in aggravated tumor burden. RIPC prevented this mechanism by preserving intestinal integrity and reducing bacterial translocation, thereby mitigating HCC recurrence. These observations are linked to the LPS-TLR4 pathway, as testified by the high and low tumor burden displayed by mice with enhanced, or defective, TLR4 response, respectively.Conclusion: Modulation of the gut-liver axis and of the LPS-TLR4 response by RIPC, gut-sterilization and TLR4 antagonism represent potential therapeutic targets to prevent ischemia-reperfusion lesions, and to alleviate HCC recurrence after liver transplantation.

CITATION INFORMATION: Orci L, Lacotte S, Delaune V, Oldani G, Slits F, Rossetti C, Rubbia-Brandt L, Morel P, Toso C. Effects of the Gut-Liver Axis on Ischemia-Mediated Hepatocellular Carcinoma Recurrence in the Mouse Liver. Am J Transplant. 2017;17 (suppl 3).

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