High-Salt Diet Promotes Kidney Stone Formation Through Gut Microbiota-Dependent Inflammatory Pathways.

Area of Science:

• Nephrology
• Microbiology
• Gastroenterology

Background:

• High salt intake is a known risk factor for calcium oxalate (CaOx) kidney stones.
• The precise biological mechanisms, beyond increased urinary calcium, are not fully understood.

Purpose of the Study:

• To investigate the role of gut microbiota-dependent inflammatory pathways involving trimethylamine (TMA), trimethylamine N-oxide (TMAO), and NF-κB signaling in high salt-induced CaOx kidney stone formation.

Main Methods:

• Clinical cohort analysis (153 subjects) and mouse models (C57BL/6J) with high-salt diets.
• 16S rRNA sequencing, fecal microbiota transplantation, and in vitro cell culture experiments (Caco-2, HK-2 cells).
• Measurement of TMA, TMAO, inflammatory markers (TNF-α, IL-6, IL-1β), and NF-κB activation.

Main Results:

• High salt intake correlated with CaOx stones in humans and induced kidney inflammation and CaOx crystal deposition in mice.
• High-salt diet altered gut microbiota, depleting beneficial bacteria and enriching TMA-producing bacteria.
• TMA disrupted intestinal barrier integrity, while TMAO activated NF-κB and increased CaOx crystal adhesion in renal cells, with TMA/TMAO levels altered in high-salt mice.

Conclusions:

• The gut microbiota-TMA/TMAO-NF-κB axis represents a novel mechanism linking high salt intake to CaOx kidney stone formation.
• Targeting gut microbiota and associated metabolites may offer new therapeutic strategies for preventing kidney stones.