The main goal of this proposal is to determine the role of the aging gut microbiome as a driver of acute kidney injury (AKI) during sepsis. It is well established that the development of organ failure, specifically AKI, is a strong predictor of mortality during sepsis. It is also well recognized that the aging population is especially vulnerable to poor sepsis outcomes including an increased incidence of septic AKI. Despite these associations, the mechanisms underlying the development of AKI during sepsis remain undetermined. This proposal addresses two key knowledge gaps in our current understanding of the interaction between aging and septic kidney injury: 1) Our preliminary findings suggest that the pattern of septic kidney injury is fundamentally different in aged animals versus young animals. Our data indicate that the increased severity of septic AKI occurring in aged mice primarily reflects heightened glomerular dysfunction and loss of glomerular filtration rate (GFR). Given the fact that traditional indirect measures of GFR lack specificity in aging populations, there is a need to directly quantify GFR using advanced methods. We propose to use state-of-the art, complementary methods in mice (inulin clearance) and rats (intravital microscopy) to accurately phenotype sepsis related glomerular dysfunction in young and aged animals (Aim 1). 2) The factors that predispose the aging population to more frequent and severe septic AKI are incompletely understood. Accordingly, prior research focused on alterations in host inflammatory and immunosuppressive responses have failed to identify any successful clinical therapies. Excitingly, preliminary work from our laboratory has linked the gut microbiome to increased septic AKI severity in aged animals. Intraperitoneal injection of fecal slurry isolated from the stool of aged mice induced worse glomerular dysfunction in young mice than did the injection of fecal slurry isolated from the stool of young mice. We hypothesize that longevity related alterations in gut microbiome lead to bacteria that have increased virulence and ability to induce AKI during sepsis. We propose to expand upon these preliminary findings by rigorously determining the composition of the gut microbiome in both aged and young rodents (Aim 2). In addition, we will experimentally manipulate the gut microbiome to determine its impact on aging-related AKI during experimental sepsis (Aim 3). We believe that in-depth analysis of glomerular dysfunction, and the novel concept of microbiome-driven septic AKI severity, will lead to a mechanistic understanding of worsened AKI in the aging population and identify novel, clinically-relevant therapeutic targets.
This research seeks to understand why older individuals face increased risk of kidney injury during sepsis, a critical illness that arises from a dysregulated response to infection. By exploring new factors (such as the host gut microbiome) that may be responsible for aging-related susceptibility to septic kidney injury, we seek to identify new therapies that can improve the health of critically-ill older adults.
