Alistipes indistinctus-derived hippuric acid promotes intestinal urate excretion to alleviate hyperuricemia

Hyperuricemia induces inflammatory arthritis and accelerates the progression of renal and cardiovascular diseases. Gut microbiota has been linked to the development of hyperuricemia through unclear mechanisms. Here, we show that the abundance and centrality of Alistipes indistinctus are depleted in subjects with hyperuricemia. Integrative metagenomic and metabolomic analysis identified hippuric acid as the key microbial effector that mediates the uric-acid-lowering effect of A. indistinctus. Mechanistically, A. indistinctus-derived hippuric acid enhances the binding of peroxisome-proliferator-activated receptor γ (PPARγ) to the promoter of ATP-binding cassette subfamily G member 2 (ABCG2), which in turn boosts intestinal urate excretion. To facilitate this enhanced excretion, hippuric acid also promotes ABCG2 localization to the brush border membranes in a PDZ-domain-containing 1 (PDZK1)-dependent manner. These findings indicate that A. indistinctus and hippuric acid promote intestinal urate excretion and offer insights into microbiota-host crosstalk in the maintenance of uric acid homeostasis. [Display omitted] •High abundance of A. indistinctus associates with decreased risk of hyperuricemia•A. indistinctus promotes intestinal urate excretion to limit hyperuricemia•Metabolomic analysis suggests hippuric acid mediates A. indistinctus-induced excretion•Hippuric acid accelerates intestinal urate excretion via a PPARγ-ABCG2 axis Xu et al. find an inverse association between Alistipes indistinctus abundance and the risk of hyperuricemia in two geographically distinct human cohorts. In mice, A. indistinctus supplementation increases intestinal urate excretion, lowering serum uric acid. A. indistinctus-derived hippuric acid promotes ABCG2 expression and apical localization to facilitate intestinal urate excretion.