To debug or not to debug, a question worth asking

Abstract:

Recipient antibiotic pre-treatment protects both mice and humans from ischemia-reperfusion injury after liver transplantation.

Ischemia-reperfusion injury (IRI) increases the risk of rejection of a transplanted liver. Antibiotic treatment prior to transplant has been shown in multiple animal models to reduce IRI and improve overall graft survival. Antibiotics are commonly used as pre-transplant prophylaxis for liver recipients, yet it is unknown whether and how these treatments protect patients from IRI. Using a combination of an in vivo mouse model and clinical samples, Nakamura, Kupiec-Weglinski and colleagues address both of these questions.

The authors first use a clinically relevant mouse model of allogeneic liver transplantation with prolonged ex vivo cold storage. Treatment of recipient mice with antibiotics for 10 days prior to allogeneic liver transplantation reduced the degree of IRI, inflammatory mediators MCP1 and HMGB1, immune infiltration and hepatocellular death. Treatment also increased gut expression of the cytoprotective lipid prostaglandin E2 (PGE2) and hepatic expression of its receptor EP4, leading to suppression of ER stress and enhancement of autophagy through an mTORC1-mediated pathway. Either fecal microbiome transplant or antagonism of EP4 in antibiotic-treated liver recipients abrogate the beneficial effects provided by antibiotic pre-treatment.

Having identified a mechanism for antibiotic-induced protection from IRI using a murine model, the authors moved to human transplant recipients. Similar to results in mice, pre-transplant antibiotics were associated with elevated EP4, lower ER stress, lower immune infiltration in the liver, and improved liver function demonstrated from biopsy specimens obtained two hours post-reperfusion. This study demonstrates a direct connection between the antibiotic treatment and hepatocyte EP4 expression and that elevated EP4 correlates with protect against IRI in both humans and mice. Several unanswered questions remain. Is this mechanism of IRI protection isolated to liver transplant due to the organ’s unique anatomic location and physiologic functions? What specific changes in the composition of microbiota were beneficial? Findings here and in subsequent studies may help guide clinical practice and improve short and long-term outcomes in liver transplantation.