Project Summary Immune suppression and bone marrow dysfunction are ubiquitous among critically ill patients. Short term, this places an already vulnerable population at additional risk of life-threatening infections. Long term, immune suppression can persist in the form of chronic critical illness which significantly worsens functional outcomes. There is a need to rescue immune function early in the care of critically ill patients to avoid detrimental short and long term consequences of critical illness. Many studies have attempted to do this but have generally failed, and targetable therapies are still lacking. This may be in part due to lack of consideration about the integral role of the gut microbiome in regulating hematopoiesis and immune function. Emerging research has identified fundamental links between immunity and the gut microbiome. An onslaught of publications have shown the microbiome shapes the immune system at various stages, including during hematopoiesis. Recent murine studies have illustrated antibiotic induced dysbiosis impairs hematopoiesis and suppresses bone marrow function. Clinically, our group completed some of the first genomic studies illustrating microbiota derangements in critically ill patients, likely as a result of liberal use of antibiotics. In addition to antibiotics, most critically ill patients rely on enteral nutrition which shapes their microbiome. Previously we have shown artificial enteral nutrition (AEN), the default and most commonly used formula for patients requiring enteral nutrition promotes dysbiosis. In contrast, high fiber plant based enteral nutrition is well tolerated, promotes the growth of healthy commensal gut anaerobes, and improves outcomes in murine models. In this proposal, unpublished data demonstrates PBEN is superior to AEN in mitigating ABx induced lymphopenia, anemia, and neutrophilia. We also provide evidence that critically ill patients randomized to PBEN have higher lymphocyte and lower neutrophil counts than those that received AEN. Still, how antibiotics and diet shape hematopoiesis after ABx induced bone marrow suppression has never been directly tested. Here, we will test the hypothesis that PBEN expedites immune recovery from antibiotic-induced bone marrow suppression via repopulation of the gut with SCFA producing commensals that mitigate myeloid skewing by 1) evaluating if PBEN is superior to AEN in restoring steady state balance between myelopoiesis and lymphopoiesis in the bone marrow during recovery from ABx induced bone marrow suppression and 2) testing the hypothesis that expedited immune recovery from ABx induced bone marrow suppression with PBEN is mediated by microbial production of short chain fatty acids. Completion of these aims will highlight nutrition as a previously underappreciated therapeutic target for improving immune recovery of critically ill patients.