Therapeutic Perspectives and Mechanistic Insights of Phage Therapy in Allotransplantation.

Bacterio(phages) are bacteria-infecting viruses that employ host translation machinery to replicate, and upon cell lysis, release new particles into the environment. As a result, phages are prey-specific, thus making targeted phage therapy (PT) possible. Indeed, pre- and posttransplant bacterial infections pose a substantial risk to allograft recipients in their clinical course. Moreover, with the increasing threat of antibiotic resistance, the interest in PT as a potential solution to the crisis of multidrug-resistant bacterial pathogens has rapidly grown. Although little is known about the specific characteristics of the phage-directed immune responses, recent studies indicate phages exert anti-inflammatory and immunomodulatory functions, which could be beneficial in allotransplantation (allo-Tx). PT targeting multidrug-resistant Klebsiella pneumoniae, Mycobacterium abscessus, and Pseudomonas aeruginosa have been successfully applied in renal, lung, and liver allo-Tx patients. In parallel, the gastrointestinal microbiota appears to influence allo-Tx immunity by modulating the endoplasmic reticulum stress and autophagy signaling pathways through hepatic EP4/CHOP/LC3B platforms. This review highlights the current relevant immunobiology, clinical developments, and management of PT, and lays the foundation for future potential standard care use of PT in allo-Tx to mitigate early allograft dysfunction and improve outcomes. In conclusion, with novel immunobiology and metabolomics insights, harnessing the potential of PT to modulate microbiota composition/diversity may offer safe and effective refined therapeutic means to reduce risks of infections and immunosuppression in allo-Tx recipients.