Gut bacteria degrade purines via the 2,8-dioxopurine pathway

Abstract

Approximately one-third of urate, which at elevated levels contributes to hyperuricaemia and gout, is excreted into the intestinal tract of healthy individuals where bacteria aid its elimination. However, the molecular details of purine metabolism in the gut microbiome are unclear. Here we uncovered the 2,8-dioxopurine pathway, an anaerobic route for purine degradation in the gut bacteria, Clostridium sporogenes and Escherichia coli. Reconstitution with purified enzymes and mutational analysis combined with isotope tracking and mass spectrometry identified a selenium-dependent enzyme, 2,8-dioxopurine dehydrogenase (DOPDH), and seven additional enzymes that connect purine metabolism to short-chain fatty acid synthesis and ATP generation (measured via luciferase assay). Competition experiments in gnotobiotic mice showed that bacteria harbouring this pathway exhibit a fitness advantage, with wild-type bacteria rapidly outcompeting a DOPDH-deficient strain. Widespread presence of these genes across host-associated microbiomes suggests a host-microbe symbiosis, where host-secreted urate fosters a metabolic niche for bacteria that break it down. These findings could have therapeutic implications for the modification and enhancement of intestinal elimination of urate.