Gegen Flavonoids and Huangqi Saponins Combination Ameliorates Diabetic Nephropathy By Modulating the Gut-Kidney Axis and Regulating Macrophage Polarization.

Diabetes nephropathy (DN) is a severe diabetic complication that is currently one of the most important causes of death in diabetic patients. Previous trials have shown that the combination of Gegen flavonoids and Huangqi saponins (FS) exerts renal protection in DN. The study aimed to investigate the therapeutic roles of FS in DN. Fourteen ingredients of the drug-containing serum were analyzed by UPLC-Q-Exactive Orbitrap-MS. The network pharmacology indicated that the AGEs-RAGE axis and NF-κB signaling pathway may be the prominent pathways for FS against DN. FS was validated to reduce inflammation and influence cell apoptosis, thereby protecting the kidneys of DN rats. In addition, FS led to the recombination of the rat microbial community, enhanced the richness and diversity of the colon microbiota, and alleviated the renal burden by preserving the intestinal barrier and reducing endotoxin infiltration into the bloodstream. Furthermore, FS suppressed M1 macrophage polarization in both the kidneys and intestines and reduced the release of inflammatory mediators, thereby attenuating kidney injury. These findings suggest that FS ameliorates DN by interrupting the detrimental gut-kidney feedback loop through regulation of the NF-κB pathway, reshaping the colon microbiota, protecting the intestinal barrier, and controlling macrophage polarization toward the M1 phenotype, which serves as a shared inflammatory amplifier in the kidney and colon.