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Citation Information: J Clin Invest. 2019;129(8):3420-3434. https://doi.org/10.1172/JCI127550.
Abstract
Although modifications of gut microbiota with antibiotics (Abx) influence mouse skin and cardiac allografts, its role in orthotopic liver transplantation (OLT) remains unknown. We aimed to determine whether and how recipient Abx pretreatment may affect hepatic ischemia-reperfusion injury (IRI) and OLT outcomes. Mice (C57BL/6) with or without Abx treatment (10 days) were transplanted with allogeneic (BALB/c) cold-stored (18 hours) livers, followed by liver and blood sampling (6 hours). We divided 264 human OLT recipients on the basis of duration of pre-OLT Abx treatment into control (Abx-free/Abx <10 days; n = 108) and Abx treatment (Abx ≥10days; n = 156) groups; OLT biopsy (Bx) samples were collected 2 hours after OLT (n = 52). Abx in mice mitigated IRI-stressed OLT (IRI-OLT), decreased CCAAT/enhancer-binding protein homologous protein (CHOP) (endoplasmic reticulum [ER] stress), enhanced LC3B (autophagy), and inhibited inflammation, whereas it increased serum prostaglandin E2 (PGE2) and hepatic PGE2 receptor 4 (EP4) expression. PGE2 increased EP4, suppressed CHOP, and induced autophagosome formation in hepatocyte cultures in an EP4-dependent manner. An EP4 antagonist restored CHOP, suppressed LC3B, and recreated IRI-OLT. Remarkably, human recipients of Abx treatment plus OLT (Abx-OLT), despite severe pretransplantation clinical acuity, had higher EP4 and LC3B levels but lower CHOP levels, which coincided with improved hepatocellular function (serum aspartate aminotransferase/serum aspartate aminotransferase [sALT/sAST]) and a decreased incidence of early allograft dysfunction (EAD). Multivariate analysis identified “Abx-free/Abx <10 days” as a predictive factor of EAD. This study documents the benefits of Abx pretreatment in liver transplant recipients, identifies ER stress and autophagy regulation by the PGE2/EP4 axis as a homeostatic underpinning, and points to the microbiome as a therapeutic target in OLT.
Authors
Kojiro Nakamura, Shoichi Kageyama, Takahiro Ito, Hirofumi Hirao, Kentaro Kadono, Antony Aziz, Kenneth J. Dery, Matthew J. Everly, Kojiro Taura, Shinji Uemoto, Douglas G. Farmer, Fady M. Kaldas, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski
Should antibiotics be regularly administered before liver transplantation?
Submitter: Francesco Paolo Russo | francescopaolo.russo@unipd.it
Authors: Francesco Paolo Russo and Alberto Ferrarese
Gastroenterology and Multivisceral Transplant Unit, Department of Surgery, Oncology and Gastroenterology, University Hospital Padua
Published July 9, 2020
We have read with great interest the paper by Nakamura et al. (1) on the role of antibiotic (ATB) in the setting of liver transplantation (LT). In their translational study, a large amount of data about the favorable role of pre-LT ATB administration on the short-term post-LT course has been provided, also in the clinical setting. One of the main findings was that extended (≥ 10 days) pre-LT ATB treatment seemed to significantly reduce the incidence of early allograft dysfunction (EAD), in accordance with what demonstrated on experimental models.
Some comments should be of interest, however. First, EAD is a clinical syndrome that often rises from mixed donors and recipients’ characteristics, the timing of surgery, and other poorly predictable features (2). Moreover, in the 52 LT recipients whose grafts were biopsied 2 hours after LT, baseline characteristics between cohorts (ATB vs. non-ATB treatment) were significantly different, in terms of severity of liver disease and probably indications to LT. Therefore, we can hypothesize that organ allocation was different among groups, making the risk of EAD very difficult to compare.
Second, the prevalence of EAD was similar between n. 24 and n. 28 LT recipients with and without prior ATB therapy (p = .38). However, when a larger retrospective cohort was analyzed (n. 108 vs. n. 156 patients with and without prior ATB therapy), the incidence of EAD was lower in the former group (p=.03). We can hypothesize that data could be influenced by the small sample size in the former case, or by the retrospective analysis and patients’ different baseline characteristics in the latter.
Third, the Authors chose amoxicillin as ATB class in the experimental model, but we did not know if LT recipients used the same ATB treatment prior to LT in the clinical setting. This information could be very important to assess if any type of treatment should be effective in reducing EAD, also because sickest patients might simultaneously receive more than one class of ATB in specific conditions (e.g., for the treatment ventilator-associated pneumonia in an acute-on-chronic liver failure patient in the ICU).
Lastly, antibiotic stewardship is very important in decompensated cirrhosis, especially in the setting of LT, in order to reduce pre-LT multidrug-resistant bacterial infection and colonization, which can produce detrimental effects in the early phase after LT (3-5).
In conclusion, we have really appreciated this translational study which provided innovative and exciting data on the use of ATB in LT recipients. More efforts should be added before considering it a valuable option, especially in the clinical setting. If validated, it would confirm a never-ending union between cirrhosis and antibiotic, not only for treating infections and lowering portal-hypertension but also to improve their early post-transplant outcome.
References:
1. Nakamura K, Kageyama S, Ito T, Hirao H, Kadono K, Aziz A, et al. Antibiotic pretreatment alleviates liver transplant damage in mice and humans. J Clin Invest. 2019;129(8):3420-34.
2. Olthoff KM, Kulik L, Samstein B, Kaminski M, Abecassis M, Emond J, et al. Validation of a current definition of early allograft dysfunction in liver transplant recipients and analysis of risk factors. Liver Transpl. 2010;16(8):943-9.
3. Fernández J, Bert F, Nicolas-Chanoine MH. The challenges of multi-drug-resistance in hepatology. J Hepatol. 2016;65(5):1043-54.
4. Martin Mateos R, Albillos A. Sepsis in Patients With Cirrhosis Awaiting Liver Transplantation: New Trends and Management. Liver Transpl. 2019;25(11):1700-9.
5. Berry PS, Rosenberger LH, Guidry CA, Agarwal A, Pelletier S, Sawyer RG. Intraoperative Versus Extended Antibiotic Prophylaxis in Liver Transplant Surgery: A Randomized Controlled Pilot Trial. Liver Transpl. 2019;25(7):1043-53.
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