Metabolic Insights into Urinary Stone Formation: Evidence from Mendelian Randomization, Clinical, and in vivo Studies.

INTRODUCTION: The global rise in urinary stone prevalence has become a significant health and economic challenge. Linked to metabolic disorders such as obesity and diabetes, urinary stones represent a complex systemic condition that requires a comprehensive understanding of metabolic profiles for effective management. METHODS: The methodological quality of this study was evaluated in accordance with the STROBE-MR checklist. Using genome-wide association study (GWAS) data for 1,091 blood and 1,172 urine metabolites, we conducted a two-sample Mendelian randomization (MR) analysis, validated by meta-analysis, to explore metabolic influences on stone formation. Multivariable and mediation MR analyses were performed to identify independent metabolite influences and their interaction with gut microbiota and metabolism-related genes. Clinical metabolomic analysis and further animal experiments substantiated our findings. RESULTS: Univariable MR identified 119 blood and 63 urine metabolites associated with urinary stones, with 16 blood and 2 urine metabolites showing robust associations post-correction. Notably, mannose and 3-aminoisobutyrate emerged as independent influencers of stone formation. Mediation MR suggested these metabolites as potential mediators in the gut microbiota's influence on stone formation. Clinical urine sample analysis indicates higher mannose levels in normal renal sides than stone sides. Animal studies confirmed mannose's protective role by reducing renal calcium oxalate crystal deposition. CONCLUSION: Our study establishes causal links between specific metabolites and urinary stones, shedding light on the intricate biological mechanisms of stone formation. The discovery of mannose as a protective factor opens avenues for future research and clinical applications, offering promising directions for the prevention and treatment of stones.