PMID- 29331341 OWN - NLM STAT- MEDLINE DCOM- 20190916 LR - 20190916 IS - 1600-0641 (Electronic) IS - 0168-8278 (Linking) VI - 68 IP - 5 DP - 2018 May TI - Effects of the gut-liver axis on ischaemia-mediated hepatocellular carcinoma recurrence in the mouse liver. PG - 978-985 LID - S0168-8278(18)30009-6 [pii] LID - 10.1016/j.jhep.2017.12.025 [doi] AB - BACKGROUND & AIMS: There is growing evidence that liver graft ischemia-reperfusion (I/R) is a risk factor for hepatocellular carcinoma (HCC) recurrence, but the mechanisms involved are unclear. Herein, we tested the hypothesis that mesenteric congestion resulting from 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, induced by occluding the hepatic and femoral blood vessels. HCC was induced by injecting RIL-175 cells into the portal vein. We further evaluated the impact of the gut-liver axis (lipopolysaccharide (LPS)-Tlr4 pathway) in this context by studying mice with enhanced (lipopolysaccharide infusion) or defective (Tlr4(-/-) mice, gut sterilization, and Tlr4 antagonist) Tlr4 responses. RESULTS: Portal triad clamping provoked upstream mesenteric venous engorgement and 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 were linked to the LPS-Tlr4 pathway, as supported by the high and low tumor burden displayed by mice with enhanced or defective Tlr4 responses, respectively. CONCLUSIONS: Modulation of the gut-liver axis and the LPS-Tlr4 response by RIPC, gut sterilization, and Tlr4 antagonism represents a potential therapeutic target to prevent I/R lesions, and to alleviate HCC recurrence after liver transplantation and resection. LAY SUMMARY: Cancer recurrence can occur after liver resection or liver transplantation for hepatocellular carcinoma (HCC). This study suggests that intestinal venous congestion, which often occurs during liver surgery, favors the translocation of gut-derived bacterial products in the portal vein, thereby facilitating cancer recurrence by enhancing the signaling of Toll-like receptor 4 in the liver. Using a mouse model of HCC recurrence, we show that strategies that (i) reduce bacterial translocation (by gut decontamination, or by protecting the intestine from venous ischemia damage) or (ii) inhibit Tlr4 signaling in the liver, could reduce cancer recurrence. CI - Copyright (c) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. FAU - Orci, Lorenzo A AU - Orci LA AD - Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. Electronic address: lorenzo.orci@hcuge.ch. FAU - Lacotte, Stephanie AU - Lacotte S AD - Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. FAU - Delaune, Vaihere AU - Delaune V AD - Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. FAU - Slits, Florence AU - Slits F AD - Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. FAU - Oldani, Graziano AU - Oldani G AD - Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. FAU - Lazarevic, Vladimir AU - Lazarevic V AD - Genomic Research Laboratory, Geneva University Hospitals, Geneva, University of Geneva, Switzerland. FAU - Rossetti, Carlo AU - Rossetti C AD - Dipartimento di Biotecnologie e Scienze della Vita, Universita degli Studi dell'Insubria, Varese, Italy. FAU - Rubbia-Brandt, Laura AU - Rubbia-Brandt L AD - Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland. FAU - Morel, Philippe AU - Morel P AD - Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. FAU - Toso, Christian AU - Toso C AD - Division of Abdominal and Transplantation Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland; Hepato-Pancreato-Biliary Centre, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180110 PL - Netherlands TA - J Hepatol JT - Journal of hepatology JID - 8503886 RN - 0 (Tlr4 protein, mouse) RN - 0 (Toll-Like Receptor 4) SB - IM MH - Animals MH - Intestines/blood supply/microbiology MH - Ischemic Preconditioning MH - Liver/*injuries/physiopathology MH - Liver Neoplasms, Experimental/*etiology MH - Liver Transplantation/*adverse effects MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Models, Biological MH - Neoplasm Recurrence, Local/etiology/prevention & control MH - Reperfusion Injury/*complications MH - Toll-Like Receptor 4/deficiency/physiology OTO - NOTNLM OT - Endotoxin OT - Gut-liver axis OT - Hepatocellular carcinoma OT - Ischemia-reperfusion OT - Liver surgery OT - Remote ischemic preconditioning OT - Toll-like receptor 4 EDAT- 2018/01/15 06:00 MHDA- 2019/09/17 06:00 CRDT- 2018/01/15 06:00 PHST- 2016/11/08 00:00 [received] PHST- 2017/12/06 00:00 [revised] PHST- 2017/12/22 00:00 [accepted] PHST- 2018/01/15 06:00 [pubmed] PHST- 2019/09/17 06:00 [medline] PHST- 2018/01/15 06:00 [entrez] AID - S0168-8278(18)30009-6 [pii] AID - 10.1016/j.jhep.2017.12.025 [doi] PST - ppublish SO - J Hepatol. 2018 May;68(5):978-985. doi: 10.1016/j.jhep.2017.12.025. Epub 2018 Jan 10.