Dysbiosis of the gut microbiota in calcium oxalate nephrolithiasis is associated with impaired short-chain fatty acid production and systemic metabolomic disruptions.

BACKGROUND: The prevalence of calcium oxalate (CaOx) kidney stones is increasing, yet the underlying mechanisms remain incompletely understood. Emerging evidence suggests that gut microbiota-particularly short-chain fatty acid (SCFA)-producing bacteria-may modulate host metabolism and inflammation, thereby influencing stone formation. However, the mechanistic links between gut dysbiosis, metabolic disturbances, and CaOx stone pathophysiology remain to be fully elucidated. This study investigates gut microbiota composition, SCFA levels, and metabolomic alterations in CaOx stone formers (CSF), aiming to uncover potential pathophysiological mechanisms and therapeutic targets. RESULTS: Among 59 CSF and 60 healthy controls (HC), CSF exhibited significantly reduced microbial richness, with marked depletion of SCFA-producing bacteria such as Faecalibacterium prausnitzii and Eubacterium rectale. This dysbiosis was associated with decreased fecal and plasma SCFA levels, reduced 24-h urinary citrate, and widespread metabolic disturbances, particularly in tryptophan metabolism and the citrate cycle. Plasma SCFA levels were positively correlated with urinary citrate excretion, suggesting a regulatory link within the gut-kidney axis. Mendelian randomization analysis suggested that Bacteroides thetaiotaomicron may be a potential microbial risk factor for stone formation (OR = 1.26, 95% CI: 1.03-1.54, p = 0.028). In a hyperoxaluria rat model, interventions with F. prausnitzii, E. rectale, or sodium butyrate reduced renal CaOx crystal deposition and kidney injury. CONCLUSIONS: Our findings highlight the central role of SCFA-producing bacteria and their metabolites in maintaining metabolic balance and protecting against CaOx stone formation. Gut dysbiosis and reduced SCFA levels appear to drive metabolic changes that contribute to stone development. B. thetaiotaomicron may increase stone risk, while F. prausnitzii, E. rectale, and sodium butyrate show therapeutic potential. These insights support further exploration of microbiome-based strategies for the prevention and personalized management of kidney stones. Video Abstract.