Gut microbiome and metabolites mediate the benefits of caloric restriction in mice after acute kidney injury

Abstract

The role of gut microbiome in acute kidney injury (AKI) is increasing recognized. Caloric restriction (CR) has been shown to enhance the resistance to ischemia/reperfusion injury to the kidneys in rodents. Nonetheless, it is unknown whether intestinal microbiota mediated CR protection against ischemic/reperfusion-induced injury (IRI) in the kidneys. Herein, we showed that CR ameliorated IRI-elicited renal dysfunction, oxidative stress, apoptosis, and inflammation, along with enhanced intestinal barrier function. In addition, gut microbiota depletion blocked the favorable effects of CR in AKI mice. 16S rRNA and metabolomics analysis showed that CR enriched the gut commensal Parabacteroides goldsteinii ( P. goldsteinii ) and upregulated the level of serum metabolite dodecafluorpentan. Intestinal colonization of P. goldsteinii and oral administration of dodecafluorpentan showed the similar beneficial effects as CR in AKI mice. RNA sequencing and experimental data revealed that dodecafluorpentan protected against AKI-induced renal injury by antagonizing oxidative burst and NFκB-induced NLRP3 inflammasome activation. In addition, we screened and found that Hamaudol improved renal insufficiency by boosting the growth of P. goldsteinii . Our results shed light on the role of intestinal microbiota P. goldsteinii and serum metabolites dodecafluorpentan in CR benefits to AKI. • The role of intestinal microbiota-mediated caloric restriction (CR) in ischemic/reperfusion-induced injury (IRI) in the kidneys is rarely known. • Intestinal microbiota Parabacteroides goldsteinii ( P. goldsteinii ) contributes to CR protection against renal damage induced by acute kidney injury (AKI). • Serum metabolites dodecafluorpentan alleviates the renal dysfunction after IRI. • Hamaudol is a chromone isolated from Saposhnikovia divaricate , exhibiting a protection against renal IRI by boosting the growth of P. goldsteinii.