Clostridium butyricum attenuates calcium oxalate nephrolithiasis via gut microbiota and GHDCA-VDR axis

The gut–kidney axis links the microbiota and metabolites to nephrolithiasis. We investigated the role of Clostridium butyricum (CB) in calcium oxalate (CaOx) nephrolithiasis. Metagenomics showed reduced CB abundance in patients compared with healthy controls. The CaOx crystal deposition models were induced in rats with 1% ethylene glycol; the CB group received CB bacterial powder by gavage. Micro-computed tomography (Micro-CT), biochemical assays, and histological staining demonstrated that CB mitigated renal injury and CaOx crystal deposition. 16S ribosomal RNA (rRNA) sequencing revealed increased gut microbial diversity and richness with CB, corroborated by fecal microbiota transplantation (FMT). Untargeted and targeted metabolomics identified glycohyodeoxycholic acid (GHDCA) as a key bile acid mediating the CB effect. In vitro , GHDCA exacerbated oxalate-induced cell injury via the vitamin D receptor (VDR) in HK-2 and NRK-52E cells, which was validated in vivo using GHDCA-supplemented chow and a VDR inhibitor (ZK168281). In patients, GHDCA levels were elevated and inversely correlated with CB abundance. In summary, CB suppresses CaOx crystal deposition by modulating the gut microbiota and the GHDCA–VDR axis, supporting probiotic and small-molecule therapeutic strategies for CaOx nephrolithiasis.