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

doi:10.1016/j.cell.2023.06.010

A widely distributed gene cluster compensates for uricase loss in hominids

Cell. 2023 Aug 3;186(16):3400-3413.e20. doi: 10.1016/j.cell.2023.06.010.

Authors

Yuanyuan Liu¹, J Bryce Jarman¹, Yen S Low², Hannah E Augustijn³, Steven Huang⁴, Haoqing Chen¹, Mary E DeFeo⁵, Kazuma Sekiba¹, Bi-Huei Hou¹, Xiandong Meng⁶, Allison M Weakley⁶, Ashley V Cabrera⁶, Zhiwei Zhou¹, Gilles van Wezel⁷, Marnix H Medema³, Calyani Ganesan⁸, Alan C Pao⁹, Saurabh Gombar¹⁰, Dylan Dodd¹¹

Affiliations

¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
² Atropos Health, Palo Alto, CA, USA.
³ Bioinformatics Group, Wageningen University, Wageningen, the Netherlands; Institute of Biology, Leiden University, Leiden, the Netherlands.
⁴ Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
⁵ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁶ ChEM-H Institute, Stanford University, Stanford, CA 94305, USA.
⁷ Institute of Biology, Leiden University, Leiden, the Netherlands; Netherlands Institute of Ecology, Wageningen, the Netherlands.
⁸ Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
⁹ Division of Nephrology, Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Urology, Stanford University School of Medicine, Stanford, CA 94305, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA 94304, USA.
¹⁰ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Atropos Health, Palo Alto, CA, USA.
¹¹ Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, CA 94305, USA. Electronic address: ddodd2@stanford.edu.

PMID: 37541197
PMCID: PMC10421625 (available on 2024-08-03)
DOI: 10.1016/j.cell.2023.06.010

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.

Keywords: gout; hyperuricemia; microbiome; microbiota; uric acid; uricase.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Animals
Evolution, Molecular
Gout* / genetics
Gout* / metabolism
Hominidae* / genetics
Humans
Hyperuricemia* / genetics
Mammals / metabolism
Mice
Urate Oxidase / genetics
Uric Acid / metabolism

Substances

Urate Oxidase
Uric Acid

Abstract

Publication types

MeSH terms

Substances

Grants and funding