SAT-138 ROLE OF GUT COMMENSAL BACTERIA IN ISCHEMIA/REPERFUSION INDUCED ACUTE KIDNEY INJURY

Abstract

Emerging evidence suggests the critical role of gut commensal bacteria in health and diseases by modulating local and systemic immune response. However, the role of the microbiome and gut-derived immunity in the development of kidney ischemia/reperfusion injury (IRI) is largely unknown. The purpose of this study is to examine the role of the gut microbiome and mucosal immunity in the development of kidney IRI and distant organ damage. C57BL/6 mice were fed with a combination of oral antibiotics (neomycin, ampicillin, metronidazole and vancomycin) or vehicle for 2 weeks and then underwent bilateral renal pedicle clamping. Renal function, histological kidney injury, gut permeability, gut-derived local and systemic immune response as well as microbiome analyses were performed. IRI induced renal functional, histological deterioration was accompanied by alteration of the gut microbiome. Kidney IRI resulted in a significant decrease in the diversity index of the microbiome, as well as the number of operational taxonomic units (OTUs). Among them, the reduction of short-chain fatty acid producing species such as Ruminococcaceae, Bacteroides, Christensenellaae, Lachnospiraceae was prominent. Altered microbiome after IRI was associated with the development of “leaky gut” and colitis that were associated with increased number of colon epithelial cell apoptosis, neutrophil and M1 macrophage infiltration in the colon. Gut microbiota depletion by oral antibiotic treatment but not by systemic antibiotics significantly attenuated kidney injury, as well as distant organ damage. The renoprotective effect of oral antibiotic treatment was associated with partial restoration of “leaky gut” with preserved tight junction proteins, decreased number of colon epithelial cell apoptosis or neutrophil or M1 macrophage-mediated colitis. This protective effect was also associated with a reduction of systemic proinflammatory cytokines and increase of anti-inflammatory cytokine IL-10. More importantly, alteration of the gut microbiome in oral antibiotics fed mice was associated significantly increased number of CD4+ CD25+ Tregs and Foxp3 expression in cervical lymph node and spleen following IRI. Our data showed the critical role of the commensal gut microbiome in the development of kidney IRI injury as well as distant organ injury. Antibiotic modification of gut microbiome induced renoprotective effect is thought to be partially mediated by modulating peripheral and systemic immune response toward Treg mediated immune tolerance. Targeting the gut might offer a new paradigm in the prevention of treatment of AKI.