MICRO-ICU Humanized Microbiota Mouse Model Raw sequence reads
Critically ill patients in intensive care units (ICUs) display widespread immunological alterations that contribute to a profound susceptibility to nosocomial (hospital-acquired) infections, yet the drivers of this immune impairment is incompletely understood, and no therapies are available to restore immune protection against infection. Pathological alterations of the gut microbiota in critical illness represents a potentially modifiable culprit in the dysregulation of immune responses. Using a humanized microbiome mouse (HMM) model of ICU gut dysbiosis, we identified that microbiota dysbiosis induced a program of maladaptive trained immunity in the bone marrow involving metabolic, epigenomic, and hematopoietic alterations of neutrophil development, yielding immature neutrophils with impaired defense against pathogens. Therapeutic editing of ICU gut dysbiosis with a rationally-designed consortium of anaerobic commensal bacteria corrected neutrophil training in the bone marrow, improved neutrophil anti-pathogen functions, and augmented defense against infection challenge. Taken together, this work establishes critical illness gut microbiota dysbiosis as a therapeutically modifiable driver of neutrophil dysfunction, and thus a putative therapeutic target to reduce the overwhelming burden of nosocomial infections in vulnerable critically ill patients.