High salt intake promotes calcium oxalate kidney stone formation through a gut microbiota-TMA/TMAO-NF-κB axis, confirmed by clinical association, animal models, fecal microbiota transplantation, and in vitro experiments.
High salt intake was independently associated with calcium oxalate kidney stones in a clinical cohort after multivariable adjustment.
The gut microbiota of high-salt diet stone formers showed enrichment of inflammation-associated bacteria and specific inflammatory signaling pathways.
A one-month high-salt diet in C57BL/6J mice disrupted intestinal barrier integrity, induced renal inflammation, and increased calcium oxalate crystal deposition.
16S rRNA sequencing revealed depletion of beneficial bacterial genera and enrichment of TMA-producing bacteria in high-salt diet mice.
High-salt diet mice showed elevated cecal TMA and plasma TMAO levels alongside reduced urinary TMA and TMAO, indicating impaired renal metabolite clearance.
Fecal microbiota transplantation from high-salt diet donor mice reproduced elevated TMAO, renal inflammation, and crystal deposition in recipient mice, confirming a causal role for gut microbiota.
TMA disrupted tight junction proteins in Caco-2 intestinal epithelial cells in vitro, an effect reversed by the NF-κB inhibitor QNZ.
TMAO activated NF-κB signaling and increased CaOx crystal adhesion in HK-2 renal tubular cells in vitro, effects reversed by the NF-κB inhibitor QNZ.
This research suggests that eating too much salt increases the risk of calcium oxalate kidney stones not only by raising calcium in the urine, but also by disrupting the community of bacteria living in the gut. In both a group of 153 people and in mouse experiments, high salt intake was linked to shifts in gut bacteria — specifically, a loss of beneficial bacteria like Akkermansia and Bifidobacterium and a rise in bacteria that produce a compound called TMA (trimethylamine). TMA and its derivative TMAO (trimethylamine N-oxide) then appear to damage the gut lining, promote kidney inflammation, and make it easier for kidney stone crystals to stick to kidney cells. The study used multiple lines of evidence to support this gut-kidney connection. Mice fed a high-salt diet for one month developed gut barrier damage, kidney inflammation, and more kidney stone crystal deposits. Crucially, when healthy mice received gut bacteria transplanted from high-salt diet mice, they also developed elevated TMAO levels, kidney inflammation, and crystal deposits — even without being on a high-salt diet themselves. In laboratory cell experiments, adding TMAO to kidney cells switched on an inflammatory signal called NF-κB and made crystals adhere more readily; blocking NF-κB reversed these effects. This research suggests that the harmful effects of high salt on kidney stone risk involve a chain of events: salt disrupts gut bacteria → disrupted bacteria produce more TMA/TMAO → TMAO inflames the kidneys via NF-κB → inflamed kidneys become more prone to crystal buildup. These findings open potential avenues for addressing kidney stone risk by targeting gut bacteria or the TMA/TMAO pathway, in addition to the standard advice of reducing salt intake.
Yuan C, Wang M, Yuan Y, Jin X, Wang K. (2026). High-Salt Diet Promotes Kidney Stone Formation Through Gut Microbiota-Dependent Inflammatory Pathways.. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. https://doi.org/10.1096/fj.202503466R