Fangji Huangqi Tang alleviated chronic kidney disease by regulating intestinal bacteria to inhibit the AHR/ROS pathway.

Abstract

BACKGROUND: Fangji Huangqi Tang (FHT) is a traditional Chinese herbal formula that is clinically effective and safe for chronic kidney disease (CKD). However, the mechanism of action of FHT remains unclear. PURPOSE: In this study, we investigated the mechanism of the targeted regulation of intestinal flora by Fangji Huangqi Tang to delay CKD. METHOD: A CKD model was established in rats and mice by tail vein injection of doxorubicin, and the rats and mice were administered FHT orally. Metagenomic sequencing analysis was employed to screen and identify FHT-regulated key gut bacteria in CKD model rats and mice. In vitro bacterial co-cultures of these taxa were analyzed for metabolite discovery. Oral supplementation of key bacteria in CKD mice was evaluated the therapeutic effects and validated the metabolic changes observed in vitro. Cellular Aryl Hydrocarbon Receptor (AHR) overexpression was conducted to clarify the mechanistic of the metabolite derived from microbiota. RESULTS: FHT significantly enriched Corynebacterium stationis (C. stationis) in both CKD rat and mice models. In vitro, C. stationis metabolized tryptophan into Indole-3-Carbinol (I3C) while reducing indole levels. Oral administration of C. stationis in CKD mice attenuated renal dysfunction and elevated systemic I3C. Additionally, it downregulated AHR expression and diminished the expression of ROS-related inflammatory factors, thereby ameliorating CKD. Crucially, AHR overexpression reversed I3C's cytoprotective effects in MPC5 injury models. CONCLUSIONS: This study reveals that FHT targets the enrichment of the gut bacterium C. stationis, driving tryptophan metabolism toward I3C conversion. This process suppresses AHR expression, reduces ROS levels and inflammatory injury, and ultimately retards the progression of CKD.