Deciphering and harnessing gut microbiota–associated immune regulation in acute graft-versus-host disease

Allogeneic hematopoietic stem cell transplantation represents a curative treatment of choice for numerous severe hematological malignancies. While donor-derived transplanted T cells can limit disease relapse (GvT/GvL effect), they also induce, in 30-50% of the patients, acute graft-versus-host disease (aGvHD), a severe condition with elevated mortality and comorbidity rates. Gut microbiota composition has been associated with aGvHD outcome. This observation created a substantial research interest, and individual gut microbiota commensals have been acknowledged for their ability to promote immune regulation, both locally and systemically, and thus limit aGvHD-related inflammation. The mechanisms by which commensals support immune homeostasis are being decrypted at a remarkable rate. However, the trillions of micro-organisms comprising the gut microbiome interact, both directly and indirectly, with local immune cells, which is all the more critical in the context of heavy conditioning regimens these patients undergo, themselves damaging mucosal tissues and prompting inflammation. Commensals can help preserve the gut barrier integrity by actively limiting deleterious inflammation processes. Mechanistically deciphering the intricate crosstalk between gut microbes and gut immune cells, both at the species level and globally, represents a colossal challenge, but holds great promise in predicting and harnessing numerous pathological processes, including aGvHD. This review aims to examine the acquired knowledge concerning immunoregulatory responses driven by gut microbiota in the context of aGvHD. Recent preclinical and clinical studies harnessing such pathways proved to be encouraging, while substantial hurdles subsist regarding how to successfully harness this complex host/microbiota interplay to constrain aGvHD.