Abstract
OBJECTIVES: To investigate the causal relationship between gut microbiota and kidney stones. METHODS: Mendelian randomization analysis was conducted based on data from the MiBioGen consortium gut microbiota GWAS (exposure factors) and the IEU Open GWAS kidney stone dataset ukb-b-8297 (outcome variables) using the inverse variance weighted, MR-Egger regression, weighted median, weighted mode, and simple mode methods. Heterogeneity, pleiotropy, and leave-one-out sensitivity analyses were also performed. In the animal experiment, 12 male SD rats were randomized into control group with saline treatment and kidney stone model group treated with 1% ethylene glycol and 2% ammonium chloride for 28 consecutive days. Urine, blood, and intestinal samples of the rats were collected for testing the changes in renal function and intestinal barrier-related indicators, and kidney and colon pathologies were examined with histological staining and immunohistochemistry. The changes in diversity and abundance of gut microbiota were analyzed using 16S rRNA gene sequencing. RESULTS: Mendelian randomization analysis showed that decreased abundances of Lachnospiraceae NK4A136 group (OR=0.9974, 95% CI: 0.9948-0.9999, P=0.0393) and Gordonibacter (OR=0.9987, 95% CI: 0.9974-0.9999, P=0.0403) were associated with an increased risk of kidney stones without significant heterogeneity or horizontal pleiotropy, and sensitivity analyses suggested robustness of the results. The rat models of kidney stones exhibited significant renal function impairment and calcium oxalate crystal deposition, accompanied by decreased expressions of intestinal barrier-related proteins with lowered intestinal α- and β-diversity indices. Intestinal Gordonibacter abundance was significantly reduced in the rat models while the Lachnospiraceae NK4A136 group did not differ significantly between the control and model groups. CONCLUSIONS: Decreased Gordonibacter abundance in gut microbiota is associated with an increased risk of kidney stones. The protective role of the Lachnospiraceae NK4A136 group against kidney stones as suggested by Mendelian randomization analysis fails to be supported by the experimental evidence and awaits further investigation.