Ischemia-reperfusion injury (IRI) represents a major risk factor of graft dysfunction in liver transplantation (LT). We have reported a critical role of endoplasmic reticulum (ER) stress in the pathogenesis of liver IRI, whereas management strategy has not been established to date. A recent study has shown the beneficial impact of gut microbiota alteration on hepatic C/EBP homologous protein (CHOP) expression (ER stress marker). We aimed to determine the impact of antibiotics (Abx) pre-treatment on graft ER stress and IRI in clinically relevant murine LT model and LT patients. Livers from Balb/c mice with extended cold storage (18 hr in UW solution) were transplanted to allogenic C57BL/6 mice, followed by sampling at 6h after reperfusion. Pre-transplant Abx (amoxicillin) treatment to donor and recipient for 10 days mitigated IRI, evidenced by sAST/ALT levels, Suzuki's histology scores of hepatocellular damage and frequency of TUNEL+ cells (n=6/gr, p<0.05). Abx pre-treatment depressed hepatic CHOP expression, decreased Ly6G+/CD11b+ cells infiltration, and suppressed mRNA levels coding for MCP1/CXCL2/CXCL10/IL1β (p<0.05). Sixty human primary OLT recipients recruited under IRB protocol were classified into Abx treated (n=20; treated for ≥10 days) and control (n=40) groups. Liver biopsies collected at 2h post-reperfusion were screened for CHOP expression (Western blots). Pre-operatively, the Abx group was characterized as having a higher MELD score (median, Abx/control=38/28, p=0.0001) and longer hospital stay (27.5/1 days, p<0.0001). There was no difference between both groups in ischemia time or donor demographic parameters (i.e., age, gender, serum liver enzymes). The Abx group experienced longer post-operative ICU stay (19/8 days, p<0.001) and hospital stay (39/25 days, p<0.05), however notably, had significantly depressed CHOP expression in biopsy (1.13/1.57, p<0.05), lower AST level at POD1 (131/327 IU/L, p<0.01) and trended towards better post-LT survival (3-year, 88.1/82.9%). In conclusion, this translational study identified the therapeutic potential of pre-operative gut microbiota alteration on hepatic ER stress and liver graft protection against IRI. As emergence of drug-resistant bacteria discourages peri-operative overuse of antibiotic, seeking optimal antibiotic regimen or evaluating other microbiota manipulation strategies warrant further study.

CITATION INFORMATION: Ito T., Kaldas F., Nakamura K., Kageyama S., Aziz A., Busuttil R., Kupiec-Weglinski J. Preoperative Antibiotics Treatment Decreases Endoplasmic Reticulum Stress and Protects Liver Transplant from Ischemia-Reperfusion Injury Am J Transplant. 2017;17 (suppl 3).

« Back to 2018 American Transplant Congress