In a recent issue of The Journal of Clinical Investigation, Nakamura et al1 published novel translational work highlighting the efficacy of antibiotic (Abx) pretreatment in ameliorating hepatic ischemia-reperfusion injury (IRI) and early allograft dysfunction. Studies included data from a murine model and human orthotopic liver transplant recipient.1 The authors' work explored the emerging interface between the gut microbiome and allograft outcomes and have provided some fascinating insights regarding the potential interplay, which may indeed prove useful in solid organ transplant recipients.
Allogeneic mice were transplanted with donor livers from BALB/c mice; recipients were split into a treatment group (Abx-treated) receiving amoxicillin in their drinking water for 10 days before transplantation or a control group, which did not receive antibiotic pretreatment. In mice pretreated with antibiotics, liver IRI was ameliorated, inflammation suppressed, and hepatocellular death following transplantation reduced. Further cell culture studies indicated that this response was likely due to the suppression of PGE2-dependent hepatocyte endoplasmic reticulum (ER) stress response and EP4-dependent enhancement of autophagy for which the gut microbiome appears to play an important role in regulating.
The role of the gut microbiome in immune regulation and disease has recently drawn attention. Some of the first studies to directly profile the gut microbiome in the context of immunosuppression and transplantation have been performed in allogenic hematopoietic stem cell transplant recipients, wherein low bacterial diversity and dominance of certain bacterial species had been identified as significant risk factors for bacteremia2,3 and pulmonary complications.4,5 Further studies have also implicated the gut microbiota in the development of urinary tract infections in kidney transplant recipients.6 With a yet limited mechanistic understanding, these studies support the gut microbiome as an important therapeutic target.
Going beyond studies in a murine liver transplant model, the authors also included retrospective data of clinical orthotopic liver transplant recipients and used liver biopsy specimens obtained from 2 groups receiving antibiotics for clinical indications (either >10 d before transplant, n = 24 or for <10 d, n = 28); patients who received antibiotic pretreatment for >10 d demonstrated enhanced hepatic EP4 signaling and a suppressed ER stress response while maintaining augmented autophagy and decreased levels of IRI.
Prostaglandin E2 from the gut appears to play an important role in activating the prostaglandin E2 receptor 4 on hepatocytes, which has been shown to confer protection against hepatic reperfusion injury.7,8 The authors hypothesized that this effect may play a key role in mediating the ER stress response while regulating autophagy. Autophagy appears to be important in liver transplantation, particularly in the perioperative period after prolonged ischemia, participating in a “clean-up” response for damaged and dying cells. Moreover, protective properties of autophagy may aid in restoring cellular homeostasis and graft function.9 Augmentation and regulation of this process may also play a critical part in mitigating IRI.
The authors also included retrospective clinical data of 264 adult orthotopic liver transplant recipients (with 156 patients receiving >10 d of antibiotics before transplantation). Pretreatment with Abx was associated with improved hepatocellular function and a decreased incidence of early allograft dysfunction. The study also investigated a subset of patients who received rifaximin (RFX) monotherapy (n = 57). Notably, and despite a more severe clinical acuity, RFX-treated patients had decreased transaminase levels and a significantly lower incidence of early allograft dysfunction.
Those findings are of clinical relevance for and beyond liver transplantation. Early allograft dysfunction and IRI are potent causes of increased morbidity, resource consumption, and mortality affecting donor organ(s) both acutely and downstream by way of increased chronic allograft dysfunction. The inevitable question, however, arises as to whether extended pretransplant antibiotic therapy is feasible in other solid organ transplant recipients when the active waiting list time may be appreciably longer than for high urgency liver transplant recipients? One target group may also be patients with respiratory failure due to cystic fibrosis, particularly those on assisted ventilation or extracorporeal membrane oxygenation for whom urgent lung transplantation is mandated.
Also, extended antibiotic therapy may have unappreciated potential adverse effects that will need to be investigated in a prospective clinical trial with rigorous adverse event reporting. The choice of RFX is of considerable interest. RFX, a close cousin of rifampicin, has a broad spectrum, however, low oral bioavailability, potentially explaining the agent’s utility especially in hepatic failure with encephalopathy when used to reduce the colonizing load of ammonia producing organisms, with or without concomitant lactulose treatment. Moreover, whether a particular threshold for antibiotic treatment time is necessary has not been explored in this study. However, a 10-day treatment appeared sufficient. Finally, how long is too long has also not been defined with potential risks of fungal dysbiosis or induction of mycobacterial resistance within the gut.
Ultimately, strategies employed here may provide novel insights into the dynamic relationship between the gut microbiome, alloimmunity, and the transplanted organ(s). Commendable is the rigor of providing both murine and clinical data of this potentially game-changing work.
1. Nakamura K, Kageyama S, Ito T, et al. Antibiotic pretreatment alleviates liver transplant damage in mice and humans.J Clin Invest20191293420–3434
2. Taur Y, Xavier JB, Lipuma L, et al. Intestinal domination and the risk of bacteremia in patients undergoing allogeneic hematopoietic stem cell transplantation.Clin Infect Dis201255905–914
3. Tamburini FB, Andermann TM, Tkachenko E, et al. Precision identification of diverse bloodstream pathogens in the gut microbiome.Nat Med2018241809–1814
4. Harris B, Morjaria SM, Littmann ER, et al. Gut microbiota predict pulmonary infiltrates after allogeneic hematopoietic cell transplantation.Am J Respir Crit Care Med2016194450–463
5. Haak BW, Littmann ER, Chaubard JL, et al. Impact of gut colonization with butyrate-producing microbiota on respiratory viral infection following allo-HCT.Blood20181312978–2986
6. Lee JR, Muthukumar T, Dadhania D, et al. Gut microbial community structure and complications after kidney transplantation: a pilot study.Transplantation201498697–705
7. Kuzumoto Y, Sho M, Ikeda N, et al. Role of EP4 prostaglandin E2 receptor in the ischemic liver.Transplant Proc200537422–424
8. Kuzumoto Y, Sho M, Ikeda N, et al. Significance and therapeutic potential of prostaglandin E2 receptor in hepatic ischemia/reperfusion injury in mice.Hepatology200542608–617
9. Van Erp AC, Hoeksma D, Rebolledo RA, et al. The crosstalk between ROS and autophagy in the field of transplantation medicine.Oxid Med Cell Longev201720177120962
The authors' work explored the emerging interface between the gut microbiome and allograft outcomes and have provided some fascinating insights regarding the potential interplay, which may indeed prove useful in solid organ transplant recipients.