Objectives: Septic acute kidney injury (AKI) is linked to an elevated subsequent risk Of chronic kidney disease (CKD) and increased mortality. Substantial research has illustrated that AKI leads to gut dysbiosis, compromised gut barrier function, and the promotion of bacterial components, such as Lipopolysaccharide (LPS), translocating into circulation. This translocation causes systemic inflammation, worsening AKI. The gut- kidney axis is a key pathophysiological factor in AKI patients, the precise mechanisms are presently under investigation. Previous research has suggested that FK506-binding protein 5 (FKBP5) may be involved in the progression and development of AKI. Therefore, we used FKBP5 knockout (FKKO) mice to study its role in the gut-kidney axis in LPS-induced septic AKI Methods: FKBP5 knockout (FKKO) and Wild-type (WT) mice were injected with LPS or vehicle control. Blood urea nitrogen (BUN) and creatinine levels were measured to evaluate the renal function. Flow cytometry analyzed the immune cell patterns of rodents. Intestinal barrier function was examined by Alexa-680-Dextran permeabilization and tight junction proteins expression. 16S rDNA PCR and full-length 16S were used to analyze bacterial diversity in the feces of mice Results: Mice lacking FKKO genes have better renal function after LPS injection than WT mice. LPS administration enhanced the gut epithelial barrier and inhibited immunological responses, as seen by the lower number of Ly6C+ monocytes in FKKO mice compared to WT mice. FKKO mice had significantly less LPS-secreted strains of Bacteroides thetaiotaomicron, Oscillibacter valericigenes, Parabacteroides, and Shigella-Flexnderi in their gut microbiota than WT mice. Conclusions: Our research has provided evidence of a bidirectional relationship that exists between the gut and the kidney in the context of septic AKI. The FKBP5 signaling pathway has been associated with gut dysbiosis, inflammatory responses, and leaky gut. Consequently, targeting the FKBP5 protein to modulate the gut-kidney axis could constitute an innovative therapeutic strategy for the management of AKI