The Gut Microbiome in Hyperuricemia and Gout

Humans develop hyperuricemia via decreased urate elimination and excess urate production, consequently promoting monosodium urate crystal deposition and incident gout. Normally, approximately two‐thirds of urate elimination is renal. However, chronic kidney disease (CKD) and other causes of decreased renal urate elimination drive hyperuricemia in most with gout. This places more demand on elimination of urate via the gut, where diet, purine metabolism, and microbiota intersect. Heritable impairment of urate transport into the gut is common and promotes hyperuricemia, renal urate overload, and early‐onset and palpable tophaceous gout phenotypes. Lactobacilli , by sequestering and modifying ambient purines, are being studied for the potential to suppress diet‐induced urate generation and associated gout flares. Landmark preclinical studies recently revealed much higher‐capacity urate‐lowering effects of diverse, obligate, and facultative anaerobic human and mouse gut microbiota (predominantly of the Bacillota phylum) termed purine‐degrading bacteria (PDB). A conserved gene cluster in PDB drives urate conversion to lactate or anti‐inflammatory short‐chain fatty acids. When mice are rendered deficient in hepatic uricase to mimic human uricase absence, microbiota depletion rapidly elevates both cecal and serum urate, which is reversible by PDB administration. In healthy human volunteers with normal renal function, antibiotic‐induced gut microbiota depletion decreases the urate‐lowering gene cluster unique to PDB and elevates fecal urate. Also, prior exposure to antibiotics with anaerobic coverage has been linked to heightened incident gout risk. Notably, intestinal dysbiosis that includes Bacillota depletion has been observed in gout cohorts. Therefore, the capacity of diverse gut bacterial strains to biochemically compensate for human limits in urate disposition suggests novel probiotic treatment approaches for gout with inadequate pharmacologic control of both flares and hyperuricemia. This is particularly so for severe CKD, which limits the options and maximal doses for use of conventional oral urate‐lowering drugs. image