Ureic clearance granule ameliorates chronic kidney disease by reshaping microbial dysbiosis via modulating bile acid metabolism

BACKGROUND: Chronic kidney disease (CKD) is a highly prevalent global public health problem that inevitably leads to renal failure. Although renin-angiotensin system blockers, as first-line therapy, can reduce proteinuria, they cannot prevent the progression to end-stage renal disease. Therefore, the development of new treatment strategies is urgently required. The uremic clearance granule (UCG) was widely used in patients with CKD. However, the underlying molecular mechanisms of UCG for CKD treatment remain unclear. METHODS: Fecal gut microbiota and serum metabolites were analyzed using metagenomics and metabolomics, respectively. The expression of extracellular matrix components, Takeda G protein-coupled receptor 5 (TGR5), glucagon-like peptide-1 receptor (GLP-1R), and nuclear factor kappa B (NF-κB) p65 was examined by in adenine-induced CKD rats. RESULTS: UCG improved renal function and alleviated kidney fibrosis in adenine-induced CKD rats. Mechanistically, significantly altered gut bacteria, including Helicobacter hepaticus, Gemella hemolysans, Bacteroides ovatus, Lactococcus cremoris, Bacteroides fragilis, Alistipes finegoldii, and Eubacterium limosum, showed strong linear correlations with serum creatinine levels in CKD rats. UCG treatment improved aberrant changes in these gut bacteria, indicating that UCG can reshape gut microbiota dysbiosis. Microbial-derived metabolites act as a bridge between gut microbiota and host. Further analysis showed that serum bile acids, including ursodeoxycholic acid (UDCA), taurodeoxycholic acid, and hyodeoxycholic acid (HDCA), were strongly correlated with serum creatinine levels in CKD rats, and these aberrant metabolites were reversed by UCG treatment. Notably, both UDCA and HDCA showed strong linear correlations with Bacteroides ovatus, Lactococcus cremoris, Bacteroides fragilis, and Eubacterium limosum, suggesting that UCG regulates microbial-derived metabolites. Moreover, UCG treatment upregulated protein expression of TGR5, GLP-1R, and downregulated NF-κB p65 protein expression in the kidney tissues of CKD rats, indicating that renoprotective effects of UCG are associated with modulation of microbial dysbiosis, regulation of bile acid metabolism and improvement of TGR5, GLP-1R, and NF-κB signaling. CONCLUSIONS: This study is the first to demonstrate that UCG ameliorates CKD and renal fibrosis by reshaping microbial dysbiosis and microbial-derived bile acid metabolism. Altered gut microbiota and metabolites may serve as biomarkers to evaluate efficacy of UCG. UCG may exert its renoprotective effects by enhancing TGR5, GLP-1R, and NF-κB p65 expression through regulating microbial dysbiosis-mediated bile acid metabolism.