Xiaoyu Xiezhuo Decoction Ameliorates Tubulointerstitial Fibrosis by Modulating Gut–Kidney Axis and Aldosterone Signaling Pathway in UUO Rats

ABSTRACT Chronic kidney disease (CKD) is a significant global health issue, and effective treatments are limited. Xiaoyu Xiezhuo Decoction (XYXZD), a traditional Chinese medicine, has shown potential in modulating the gut–kidney axis and related signaling pathways. This study investigates the effects of XYXZD in alleviating tubulointerstitial fibrosis (TIF) in a unilateral ureteral obstruction (UUO) rat model by targeting the aldosterone (ALD)/mineralocorticoid receptor (MR)/serum‐ and glucocorticoid‐inducible kinase‐1 (SGK‐1) signaling pathway and exploring the role of butyrate. UUO rats were divided into four groups: control, UUO model, XYXZD treatment, and irbesartan treatment. Renal function was assessed by measuring serum creatinine (Scr), blood urea nitrogen (BUN), and ALD levels. Fibrosis markers, including alpha‐smooth muscle actin (α‐SMA) and Collagen Type III (COL‐III), as well as signaling molecules such as phosphorylated SGK‐1 (p‐SGK‐1) and phosphorylated nuclear factor kappa B (p‐NF‐κB), were analyzed by Western blot and immunohistochemistry. Gut microbiota composition was evaluated using 16S ribosomal DNA (rDNA) sequencing, and the role of butyrate was examined via oral gavage treatment. XYXZD significantly improved renal function, reduced fibrosis, and restored gut microbiota balance by increasing butyrate‐producing bacteria. XYXZD also reduced serum ALD levels and inhibited SGK‐1 phosphorylation, suggesting modulation of the ALD/MR signaling pathway. Furthermore, butyrate treatment reduced MR nuclear translocation, supporting its role in the therapeutic effects of XYXZD. XYXZD alleviates renal injury in UUO rats by modulating the gut–kidney axis, particularly through the ALD/MR/SGK‐1 signaling pathway, with butyrate playing a critical role. These findings highlight a promising approach for CKD treatment by targeting gut microbiota and enhancing butyrate production.