Exploring the Role of Microbiota-mediated Gut-Kidney Axis in Acute Kidney Injury: Immunomodulation & Therapy

Background: Acute kidney injury (AKI) remains a major clinical problem characterized by high morbidity and an increased risk of progression to chronic kidney disease (CKD). Immune cell infiltration and activation are important features of AKI; however, the upstream mechanisms that shape this inflammatory response are not fully understood. Emerging evidence suggests that gut microbiota dysbiosis and systemic immune activation may contribute to renal injury, but the functional significance of the gut-kidney axis in AKI pathogenesis remains to be further clarified. Summary: This review synthesizes current evidence regarding gut-kidney crosstalk in AKI, with a focus on the immunometabolic impact of microbiota-derived metabolites. We discuss the potential roles of short-chain fatty acids, indole derivatives, indoxyl sulfate (IS), p-cresol sulfate (PCS), and trimethylamine-N-oxide (TMAO) in regulating T and B lymphocytes, macrophages, neutrophils, and other immune cell populations. Importantly, we distinguish direct AKI-related evidence from findings extrapolated from CKD, uremic conditions, or broader microbiome-immunity studies. Potential therapeutic interventions, including pharmacological modulation and probiotic strategies aimed at restoring gut-kidney homeostasis, are also highlighted. Key Messages: The gut-kidney axis is increasingly recognized as a potential contributor to immune-mediated injury and repair in AKI. However, the causal roles and temporal dynamics of several gut-derived uremic toxins, including IS, PCS, and TMAO, remain incompletely defined in AKI. By integrating direct AKI evidence with indirect evidence from CKD and broader microbiome-immunity studies, this review provides a more balanced conceptual framework for understanding renal immunopathology and identifying potential microbiome-targeted strategies to mitigate AKI and its progression to CKD.