Gut Microbiota-Derived butyric acid attenuates kidney stone formation in humans and mice.

Metabolic syndromes, particularly obesity, are associated with kidney stone formation (KSF). The gut microbiota and its metabolites, including butyrate, play critical roles in regulating inflammation and obesity-related disorders. In this study, using human tissue samples and in vivo mice experiments, we examined the effects of butyrate on KSF. We compared the gut microbiota of healthy individuals and patients with kidney stones, using 16 S rRNA gene sequencing. For in vivo analysis, five-week-old male C57BL/6J mice were administered butyric acid-supplemented water for 12 weeks, followed by intraperitoneal injection of glyoxylate (80 mg/kg) for 6 days to induce renal crystal formation (RCF). Patients with kidney stones exhibited reduced gut microbiota diversity (P = 0.037) and a lower abundance of butyrate-producing bacteria (P = 0.023) compared to healthy controls, although no significant differences were observed in the proportions of individual bacterial species. In mice, butyric acid administration significantly reduced RCF (P < 0.001). Moreover, butyric acid treatment attenuated inflammation, as evidenced by decreased expression of interleukin (Il)6 and C-C motif ligand 2 (Ccl2). The liver X receptor/retinoid X receptor (LXR/RXR) pathway was activated, as revealed by quantitative real-time polymerase chain reaction and RNA sequencing. Additionally, western blotting and transmission electron microscopy showed that butyric acid mitigated early mitochondrial and microvillar damage. In conclusion butyric acid protects against RCF by reducing inflammation and oxidative stress. This is the first report to elucidate the potential therapeutic role of butyrate, a gut microbiota-derived metabolite, based on both human and in vivo evidence.