A high concentration of oxalate is associated with an increased risk of kidney calcium oxalate (CaOx) stones, and the degradation of exogenous oxalate mostly depends on oxalate-degrading enzymes from the intestinal microbiome. We found that zinc gluconate supplement to patients with CaOx kidney stones could significantly improve the abundance of oxalate metabolizing bacteria in humans through clinical experiments on patients also subjected to antibiotic treatment. The analysis of clinical samples revealed that an imbalance of Lactobacillus and oxalate decarboxylase (OxDC) was involved in the formation of CaOx kidney stones. Then, we identified that Zn2+ could be used as an external factor to improve the activity of OxDC and promote Lactobacillus in the intestinal flora, and this treatment achieved a therapeutic effect on rats with stones aggravated by antibiotics. Finally, by analyzing the three-dimensional structure of OxDC and completing in vitro experiments, we propose a model of the Zn2+-induced reduction of CaOx kidney stone symptoms in rats by increasing the metabolism of oxalate through the positive effects of Zn2+ on Lactobacillus and OxDC.Copyright © 2023. Published by Elsevier B.V.