The Gut Microbiome in Urate Homeostasis and Gout

Humans, who lack endogenous uricase, develop hyperuricemia via decreased urate elimination and excess urate production, consequently promoting urate crystal deposition and incident gout. Approximately two thirds of urate elimination is renal in healthy subjects. Decreased renal urate elimination drives hyperuricemia in most gout patients, placing more demand on elimination of urate via the gut, where diet, purine metabolism and microbiota intersect. Impaired urate transport into the gut promotes hyperuricemia, renal urate overload, and early onset and palpable tophaceous gout. The intestines contain diverse microbiota that modulate enterocyte urate transport and impact gout comorbidities that limit renal urate elimination. Recently, landmark studies revealed central, mutable effects of facultative or obligate anaerobic gut microbiota that reduce circulating urate in murine model hyperuricemia. Various human gut obligate anaerobic bacteria, predominantly of the Bacillota phylum, employ a conserved gene cluster for high-capacity consumption of certain purines and conversion of urate to xanthine or to lactate and anti-inflammatory short chain fatty acids (SCFA). These anaerobic bacteria do not employ the enzyme uricase, which is oxygen-dependent and likely has low activity in the anaerobic lumen of the gut. Significantly, microbiota depletion rapidly elevates cecal and serum urate in uricase-deficient mice, and microbiota-dependent variations in murine atherosclerosis are correlated with altered purine metabolites in plasma. Furthermore, gout-associated gut dysbiosis includes Bacillota depletion, and the risk of incident gout is elevated by prior exposure to antibiotics with anaerobic coverage. Collective evidence also supports the likelihood that serum urate is regulated by the rate of urate consumption by PDB, relative to the rate of urate reabsorption from the gut into the circulation. As such, anaerobic gut bacterial high-capacity urate degradation and purine consumption, by compensating for limitations in human urate homeostasis and generating SCFA, offers a novel therapeutic pathway to complement existing gout therapeutics.