Abstract Background Dysbiosis of the gut microbiota is closely linked to hyperuricemia. However, the effect of the microbiome on uric acid (UA) metabolism remains unclear. This study aimed to explore the mechanisms through which microbiomes affect UA metabolism with the hypothesis that modifying the intestinal microbiota influences the development of hyperuricemia. Results We proposed combining an antibiotic strategy with protein-protein interaction analysis to test this hypothesis. The data demonstrated that antibiotics altered the composition of gut microbiota as UA increased, and that the spectrum of the antibiotic was connected to the purine salvage pathway. The antibiotic-elevated UA concentration was dependent on the increase in microbiomes that code for the proteins involved in purine metabolism, and was paralleled by the depletion of bacteria-coding enzymes required for the purine salvage pathway. On the contrary, the microbiota with abundant purine salvage proteins decreased hyperuricemia. We also found that the antibiotic-increased microbiota coincided with a higher relative abundance of bacteria in hyperuricemia mice. Conclusions An antibiotic strategy combined with the prediction of microbiome bacterial function presents a feasible method for defining the key bacteria involved in hyperuricemia. Our investigations discovered that the core microbiomes of hyperuricemia may be related to the gut microbiota that enriches purine metabolism related-proteins. However, the bacteria that enrich the purine salvage-proteins may be a probiotic for decreasing urate, and are more likely to be killed by antibiotics. Therefore, the purine salvage pathway may be a potential target for the treatment of both hyperuricemia and antibiotic resistance.