A widely distributed gene cluster compensates for uricase loss in hominids

Approximately 15% of US adults have circulating levels of uric acid above its solubility limit, which is causally linked to the disease gout. In most mammals, uric acid elimination is facilitated by the enzyme uricase. However, human uricase is a pseudogene, having been inactivated early in hominid evolution. Though it has long been known that uric acid is eliminated in the gut, the role of the gut microbiota in hyperuricemia has not been studied. Here, we identify a widely distributed bacterial gene cluster that encodes a pathway for uric acid degradation. Stable isotope tracing demonstrates that gut bacteria metabolize uric acid to xanthine or short chain fatty acids. Ablation of the microbiota in uricase-deficient mice causes severe hyperuricemia, and anaerobe-targeted antibiotics increase the risk of gout in humans. These data reveal a role for the gut microbiota in uric acid excretion and highlight the potential for microbiome-targeted therapeutics in hyperuricemia. [Display omitted] •Anaerobic uric acid metabolism is widespread among the gut microbiota•Gut bacteria use a conserved gene cluster to convert uric acid to SCFAs•Microbiota depletion in uricase-deficient mice causes severe hyperuricemia•Antibiotics with anaerobic coverage increase risk for gout in humans Anaerobic bacteria of the gut microbiome are able to metabolize uric acid, compensating for the uricase deficiency of their host. This conversion of uric acid to xanthine or SCFAs is important for maintaining low levels of uric acid in serum, lowering gout risk.