PROJECT SUMMARY Sepsis, a syndrome of life-threatening organ dysfunction associated with the host response to infection, afflicts approximately 50 million people worldwide annually. Acute kidney injury (AKI) is a frequent complication of sepsis, contributing to morbidity, mortality, and increased costs, yet we still do not understand why some septic patients develop AKI while others do not. This clinical heterogeneity has been a major barrier to progress in clinical practice and research. In both animal models and humans, the bacterial communities of the gut are associated with the severity of systemic injury and risk of death in critical illness. Yet, to date, the contribution of gut microbiota to the pathogenesis of sepsis-associated AKI has been unexplored in both experimental models and human cohort studies. In pilot work, I have discovered that among genetically-identical but microbiologically-divergent mice with sepsis, the community composition of cecal microbiota is significantly associated with the severity of AKI. A single bacterial family (Lachnospiraceae) explains 25% of the variation in kidney injury severity. Further, in a retrospective cohort study of patients with suspected sepsis, I have found that early exposure to anti-anaerobic antibiotics (which deplete the gut of anaerobic commensals) increases patients’ risk of developing AKI (odds ratio 1.68, adjusted for confounders). Therefore, in this proposal, I seek to establish and interrogate the gut microbiome as a source of biological heterogeneity in sepsis. My rationale is that the gut microbiome is an unexplored therapeutic target for the prevention and treatment of AKI. This proposal will test the hypothesis that the gut microbiome contributes to the pathogenesis of sepsis-associated AKI. I will test this hypothesis through two Specific Aims: 1) Identify and interrogate the gut bacteria in human patients that predict the onset and outcomes of sepsis-associated AKI; and 2) Determine the microbially- derived mediators of AKI in a murine model of sepsis. Experiments for these Aims will be completed with the use of 1) a large biorepository of human rectal swabs collected at the University of Michigan from 2016 to 2020 and 2) a well-established murine model of sepsis and experimental gut microbiome modulation techniques. The results from these innovative studies may identify novel therapeutic targets for the prevention and treatment of AKI and its complications. In executing this research plan, I will receive rigorous training in experimental design, implementation, and interpretation that will help me become a successful, independent scientist.