Uric acid nephrolithiasis is part of the spectrum of disorders integral to the metabolic syndrome. The sine qua non uric acid stone formation is excessively acidic urine pH promoting protonation of urate to the sparingly soluble uric acid resulting in precipitation and lithogenesis. Obesity is associated with a different gut microbiota and uric acid stone formers yet have more specific microbiota. Our working hypothesis is that the origin of aciduria starts in the gut lumen where the microbiota-host interaction contributes to uric acid nephrolithiasis by provision of enriched organic fatty acids, compounded by hepatic steatosis resulting in delivery of more acid to the kidney. The impaired ability of the kidney to buffer the acid eventually cumulates in unduly acidic urine pH. The underlying pathobiology stems from hepatic and renal steatosis and lipotoxicity. The combination of this microbiota-hepatic-renal defect generates and amplifies the aciduria which is the prerequisite in uric acid lithogenesis.