Astragaloside IV Mitigated Diabetic Nephropathy by Restructuring Intestinal Microflora and Ferroptosis

Abstract

ScopeTo investigate the underlying mechanism of Astragaloside IV (AS‐IV) in ameliorating diabetic nephropathy (DN) by regulating intestinal microbiota ecology and intestinal mucosal barrier.Methods and resultsGenetically db/db mice are used to establish DN mouse model to monitor the therapeutic effects of AS‐IV and fecal microbiota transplantation (FMT) against DN. Supplementation with AS‐IV dramatically attenuates several clinical indicators of DN in db/db mice. In addition, AS‐IV markedly improves intestinal barrier function, modifies intestinal permeability, and reduces inflammation. Moreover, AS‐IV treatment remarkably improves intestinal dysbiosis in db/db mice, characterized by an elevated abundance of Akkermansia, Ligilactobacillus, and Lactobacillus, indicating the fundamental role of the microbiome in DN progression. Furthermore, FMT derived from AS‐IV‐treated db/db mice is potentially efficient in antagonizing renal dysfunction, rebalancing gut microbiota, and improving intestinal permeability in recipient db/db mice. AS‐IV‐enriched Akkermansia muciniphila dramatically alleviates DN and intestinal mucosal barrier dysfunction in db/db mice. Intriguingly, AS‐IV intervention dramatically diminishes ferroptosis in the kidney and colon tissues.Conclusion Intestinal microbiome alterations and ferroptosis modulation by AS‐IV may play instrumental roles in this mechanism, providing compelling evidence for the role of the gut‐renal axis in DN.