Gut Bacteria Impact Host Uric Acid Burden and Its Association With Atherosclerosis

Abstract Humans with metabolic and inflammatory diseases, including atherosclerosis harbor dysbiotic gut communities. However, the microbes and microbial pathways that influence disease progression remain largely undefined. Here, we show that variation in atherosclerosis burden is in part driven by the gut microbiota and it is associated with circulating levels of the proinflammatory molecule uric acid both in mice and humans. We identify bacterial taxa present in the gut spanning multiple phyla, including Bacillota (Firmicutes), Fusobacteriota and Pseudomonadota (Proteobacteria), that use uric acid and adenine– a key precursor of nucleic acids in intestinal cells, as carbon and energy sources anaerobically, and uncover a gene cluster encoding key steps of purine degradation that is widely distributed among gut dwelling bacteria. Furthermore, we demonstrate that colonization of germ-free mice with purine-degrading bacteria modulates levels of uric acid and other purines in the gut and systemically. Altogether this work demonstrates that gut microbes are important drivers of host global purine homeostasis and uric acid levels, and suggests that gut bacterial catabolism of purines may represent a novel mechanism by which the gut microbiome influences host health.