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

High salt intake is a recognized risk factor for calcium oxalate (CaOx) kidney stones, but the underlying biological mechanisms beyond urinary calcium excretion remain unclear. We investigated whether a high-salt diet promotes CaOx stone formation through gut microbiota-dependent inflammatory pathways involving trimethylamine (TMA), trimethylamine N-oxide (TMAO), and NF-κB signaling. In a clinical cohort of 153 subjects, high salt intake was independently associated with CaOx stones after multivariable adjustment (adjusted OR 2.52, 95% CI 1.10-5.94, p = 0.031). The gut microbiota of high-salt diet stone formers was enriched for inflammation-associated bacteria and NF-κB, tight junction, and sodium-calcium reabsorption pathways. In C57BL/6J mice, a one-month high-salt diet disrupted intestinal barrier integrity, induced renal inflammation with elevated TNF-α, IL-6, and IL-1β, and increased CaOx crystal deposition. 16S rRNA sequencing showed depletion of beneficial genera (Akkermansia, Bifidobacterium) and enrichment of TMA-producing bacteria. Cecal TMA and plasma TMAO were elevated in high-salt mice, while urinary TMA and TMAO were reduced, indicating impaired renal metabolite clearance. Fecal microbiota transplantation from high-salt diet donors reproduced the elevated TMAO, renal inflammation, and crystal deposition in recipient mice, confirming a causal role for the gut microbiota. In vitro, TMA disrupted tight junction proteins in Caco-2 intestinal epithelial cells, and TMAO activated NF-κB and increased CaOx crystal adhesion in HK-2 renal tubular cells; both effects were reversed by the NF-κB inhibitor QNZ. These findings identify the gut microbiota-TMA/TMAO-NF-κB axis as a mechanism linking high salt intake to CaOx kidney stone formation.