Haikun Shenxi Capsule Ameliorates Renal Fibrosis by Modulating Gut Microbiota and Metabolism.

OBJECTIVE: To investigate the specific biological mechanisms by which Haikun Shenxi capsule (HKSX) alleviates renal fibrosis (RF), with a particular focus on the interplay between gut microbiota regulation and host metabolic modulation. Methods The therapeutic effects of HKSX were evaluated using a unilateral ureteral obstruction (UUO) mouse model. METHODS: The therapeutic effects of HKSX were evaluated using a unilateral ureteral obstruction (UUO) mouse model. Untargeted metabolomic analyses were performed on serum and fecal samples to identify metabolic changes. Gut microbiota composition was assessed via 16S rRNA sequencing. Renal injury and fibrosis were evaluated by histopathological examination and by measuring the expression of fibrotic markers, including α-smooth muscle actin (α-SMA) and type I collagen (collagen I). RESULTS: HKSX modulates metabolic homeostasis by regulating the concentrations of pyruvic acid and ornithine in mouse serum and feces. These alterations affect key pathways, including the pentose phosphate pathway, tricarboxylic acid (TCA) cycle, and amino acid metabolism, contributing to the restoration of metabolic equilibrium. Concurrently, 16S rRNA sequencing revealed that HKSX improved the gut microbiota composition by increasing microbial diversity and increasing the abundance of beneficial bacteria, particularly Akkermansia. Moreover, HKSX alleviated UUO-induced renal damage and suppressed the expression of α-SMA and collagen I. CONCLUSION: These findings provide strong evidence that HKSX exerts its renoprotective effects through bidirectional regulation of gut microbiota and host metabolism. The integration of traditional Chinese medicine (TCM) with modern systems biology offers fresh perspectives for developing improved natural therapies for RF and related metabolic disorders.