A widely distributed gene cluster compensates for uricase loss in hominids

Yuanyuan Liu, J. Bryce Jarman, Yen S. Low, Hannah E. Augustijn, Steven Huang, Haoqing Chen, Mary E. DeFeo, Kazuma Sekiba, Bi Huei Hou, Xiandong Meng, Allison M. Weakley, Ashley V. Cabrera, Zhiwei Zhou, Gilles van Wezel, Marnix H. Medema, Calyani Ganesan, Alan C. Pao, Saurabh Gombar, Dylan Dodd* (Corresponding author)

*Corresponding author for this work

Research output: Contribution to journal/periodicalArticleScientificpeer-review

40 Citations (Scopus)
544 Downloads (Pure)

Abstract

Approximately 15% of US adults have circulating levels of uric acid above its solubility limit, which is causally linked to the disease gout. In most mammals, uric acid elimination is facilitated by the enzyme uricase. However, human uricase is a pseudogene, having been inactivated early in hominid evolution. Though it has long been known that uric acid is eliminated in the gut, the role of the gut microbiota in hyperuricemia has not been studied. Here, we identify a widely distributed bacterial gene cluster that encodes a pathway for uric acid degradation. Stable isotope tracing demonstrates that gut bacteria metabolize uric acid to xanthine or short chain fatty acids. Ablation of the microbiota in uricase-deficient mice causes severe hyperuricemia, and anaerobe-targeted antibiotics increase the risk of gout in humans. These data reveal a role for the gut microbiota in uric acid excretion and highlight the potential for microbiome-targeted therapeutics in hyperuricemia.

Original languageEnglish
Pages (from-to)3400-3413.e20
JournalCell
Volume186
Issue number16
DOIs
Publication statusPublished - 03 Aug 2023

Keywords

  • gout
  • hyperuricemia
  • microbiome
  • microbiota
  • uric acid
  • uricase
  • Gout/genetics
  • Humans
  • Hominidae/genetics
  • Urate Oxidase/genetics
  • Animals
  • Hyperuricemia/genetics
  • Mammals/metabolism
  • Adult
  • Uric Acid/metabolism
  • Mice
  • Evolution, Molecular

Fingerprint

Dive into the research topics of 'A widely distributed gene cluster compensates for uricase loss in hominids'. Together they form a unique fingerprint.

Cite this