Interplay of oxalate and dyslipidemia promote kidney stones and atherosclerosis dependent on gut microbiota

Background Chronic cardiovascular and kidney diseases often occur as co-morbidities, suggesting shared risk factors or common pathophysiological mechanisms. Recent evidence indicates that vascular plaque formation shares similarities with the early stages of renal tubular calcification observed in idiopathic urinary stone disease (USD), with interactions between oxalate metabolism and gut microbiome (GMB) dynamics potentially linking the two conditions. Results Oxalate supplementation, combined with dyslipidemia, contributes to atherosclerosis, USD and other crystalline disorders, dependent on the GMB. Specifically, variants in the apolipoprotein E gene (APOE), a known cardiovascular disease risk factor, were also strongly associated with USD in humans. Mice with a global knock-out of the Apoe gene exhibited an enhanced risk for both atherosclerosis and USD, when the GMB was exposed to exogenous oxalate. Disturbance of the GMB with antibiotics exacerbated atherosclerosis risk and shifted the USD phenotype to kidney injury. Phenotypes induced by oxalate and GMB disturbance were associated with changes in hepatic bile acid (BA) synthesis, kidney lipidome, systemic dyslipidemia, inflammation, and calcium oxalate (CaOx) mineralization of vascular plaques or kidney stones. Conclusion Findings from the present study support the hypothesis that the interplay between the GMB, oxalate, and dyslipidemia—a common feature of oxalate-based idiopathic USD—may represent a link in the synchronous development of this disorder and atherosclerosis, which are frequently observed as comorbid conditions.