De-bugging the system: could antibiotics improve liver transplant outcomes?
Jonathan S. Bromberg, … , Joseph R. Scalea, Emmanuel F. Mongodin
Jonathan S. Bromberg, … , Joseph R. Scalea, Emmanuel F. Mongodin
Published July 22, 2019
Citation Information: J Clin Invest. 2019;129(8):3054-3057. https://doi.org/10.1172/JCI130314.
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Commentary

De-bugging the system: could antibiotics improve liver transplant outcomes?

Abstract

Organ transplantation is now a preferred treatment for end-stage organ failure. Among the challenges for ensuring excellent clinical outcomes for transplant recipients is good initial allograft function at the time of organ implantation. This is determined in part by the functional status of the donor and donor organ, functional status of the recipient, and conduct of the operative procedure. Despite optimization of these variables, organ transplantation is still often plagued by substantial initial dysfunction, variably referred to as slow or delayed graft function, or in the most extreme cases, primary graft nonfunction necessitating urgent regrafting. In this issue of the JCI, Nakamura, Kageyama, Ito, Hirao, and colleagues investigate a potential role for the recipient’s microbiome in determining graft function after liver transplantation and demonstrate the benefits of antibiotic pretreatment in both a mouse model and in human patients.

Authors

Jonathan S. Bromberg, Joseph R. Scalea, Emmanuel F. Mongodin

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Figure 1

Antibiotic treatment prior to liver transplantation is protective against IRI.

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Antibiotic treatment prior to liver transplantation is protective agains...
In this issue, Nakamura, Kageyama, Ito, Hirao, and colleagues show that the transplant recipient’s microbiome influences graft function after liver transplantation. Liver transplantation in mice is accompanied by an increase in the microbe-mediated proinflammatory mediators HMGB1 and MCP1, which promote inflammatory responses in macrophages and neutrophils. The increase in proinflammatory immune cells is associated with decreased serum levels of PGE2 and reduced EP4 expression in the liver. EP4 antagonism in these animals increases the measures of IRI, including transaminitis, apoptosis, and hepatic and systemic inflammatory infiltrates and cytokines. Treatment of mice with antibiotics prior to allogeneic liver transplantation depletes the gut microbiota. This depletion results in a decrease in the inflammatory response and promotes antiinflammatory and homeostatic responses that lead to an increase in serum PGE2 and upregulation of hepatic EP4. Stimulation of EP4 enhances autophagy and suppresses ER stress and mTORC1 activity, thereby protecting against IRI. Abx, antibiotics. Illustrated by Rachel Davidowitz.