Skip to main content
Top

08-02-2016 | Microbiome | Article

Intestinal microbiota distinguish gout patients from healthy humans

Authors: Zhuang Guo, Jiachao Zhang, Zhanli Wang, Kay Ying Ang, Shi Huang, Qiangchuan Hou, Xiaoquan Su, Jianmin Qiao, Yi Zheng, Lifeng Wang, Eileen Koh, Ho Danliang, Jian Xu, Yuan Kun Lee, Heping Zhang

Abstract

Current blood-based approach for gout diagnosis can be of low sensitivity and hysteretic. Here via a 68-member cohort of 33 healthy and 35 diseased individuals, we reported that the intestinal microbiota of gout patients are highly distinct from healthy individuals in both organismal and functional structures. In gout, Bacteroides caccae and Bacteroides xylanisolvens are enriched yet Faecalibacterium prausnitzii and Bifidobacterium pseudocatenulatum depleted. The established reference microbial gene catalogue for gout revealed disorder in purine degradation and butyric acid biosynthesis in gout patients. In an additional 15-member validation-group, a diagnosis model via 17 gout-associated bacteria reached 88.9% accuracy, higher than the blood-uric-acid based approach. Intestinal microbiota of gout are more similar to those of type-2 diabetes than to liver cirrhosis, whereas depletion of Faecalibacterium prausnitzii and reduced butyrate biosynthesis are shared in each of the metabolic syndromes. Thus the Microbial Index of Gout was proposed as a novel, sensitive and non-invasive strategy for diagnosing gout via fecal microbiota.

Sci Rep 2016; 6: 20602. doi:10.1038/srep20602

Gout is an auto-inflammatory disease caused by a disorder in purine metabolism and the resulted chronic elevation of blood uric acid (i.e., hyperuricemia)1. With increased intake of high protein food in many societies, incidents of gout has been expanding at an alarm rate worldwide2. In 2011, prevalence of gout in US adults is about 3.9%, and that of hyperuricemia which is a precondition for developing gout reached up to 21%3. In UK, prevalence of gout has risen to 2.5% of the general population in 2012, an increase of 63.9% since 19974. In China, gout was previously extremely rare, yet the number of confirmed cases has reached 75 million by the end of 20105.

Literature
  1. Burns, C. M. & Wortmann, R. L. Gout therapeutics: new drugs for an old disease. Lancet 377, 165–177 (2011). ISI | CAS | PubMed | Article
  2. Richette, P. & Bardin, T. Gout. Lancet 375, 318–328 (2010). ISI | CAS | PubMed | Article
  3. Zhu, Y., Pandya, B. J. & Choi, H. K. Comorbidities of gout and hyperuricemia in the US general population: NHANES 2007–2008. Am J Med 125, 679–687 (2012). ISI | PubMed | Article
  4. Kuo, C. F., Grainge, M. J., Mallen, C., Zhang, W. & Doherty, M.Rising burden of gout in the UK but continuing suboptimal management: a nationwide population study. Ann Rheum Dis 74, 661–667 (2014). PubMed | Article
  5. Guo, M. et al. Polymorphism of rs7688672 and rs10033237 in cGKII/PRKG2 and gout susceptibility of Han population in northern China. Gene 562, 50–54 (2015). CAS | PubMed | Article
  6. Krishnan, E. et al. Serum urate and incidence of kidney disease among veterans with gout. J Rheumatol 40, 1166–1172 (2013). PubMed | Article
  7. Lee, S. et al. Uric Acid Level Is Not An Independent Predictor Of Cardiovascular Diseases In Gout Patients With Treatment; Long-Term Follow-Up Data In Single Tertiary Center In South Korea. Arthritis and rheumatism 65, S856–S856 (2013).
  8. McQueen, F. M. Gout in 2013. Imaging, genetics and therapy: gout research continues apace. Nat Rev Rheumatol 10, 67–69 (2014). PubMed | Article
  9. Chang, W. C. Dietary intake and the risk of hyperuricemia, gout and chronic kidney disease in elderly Taiwanese men. Aging Male14, 195–202 (2011). CAS | PubMed | Article
  10. Sorensen, L. B. & Levinson, D. J. Origin and extrarenal elimination of uric acid in man. Nephron 14, 7–20 (1975). CAS | PubMed | Article
  11. Nicholson, J. K. et al. Host-gut microbiota metabolic interactions. Science 336, 1262–1267 (2012). ISI | CAS | PubMed | Article
  12. Kau, A. L., Ahern, P. P., Griffin, N. W., Goodman, A. L. & Gordon, J. I. Human nutrition, the gut microbiome and the immune system. Nature 474, 327–336 (2011). ISI | CAS | PubMed | Article
  13. Jumpertz, R. et al. Energy-balance studies reveal associations between gut microbes, caloric load, and nutrient absorption in humans. Am J Clin Nutr 94, 58–65 (2011). ISI | CAS | PubMed | Article
  14. Gordon, J. I., Dewey, K. G., Mills, D. A. & Medzhitov, R. M. The Human Gut Microbiota and Undernutrition. Sci Transl Med 4, (2012).
  15. Xu, J. & Gordon, J. I. Honor thy symbionts. Proc Natl Acad Sci USA100, 10452–10459 (2003). CAS | PubMed | Article
  16. Crane, J. K., Naeher, T. M., Broome, J. E. & Boedeker, E. C. Role of host xanthine oxidase in infection due to enteropathogenic and Shiga-toxigenic Escherichia coli. Infect Immun 81, 1129–1139 (2013). CAS | PubMed | Article
  17. Sathisha, K. R. et al. Synthesis and xanthine oxidase inhibitory activity of 7-methyl-2-(phenoxymethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives. Bioorg Med Chem 19, 211–220 (2011). CAS | PubMed | Article
  18. Hsieh, C. Y., Lin, H. J., Chen, C. H., Lai, E. C. & Yang, Y. H. Chronic kidney disease and stroke. Lancet Neurol 13, 1071 (2014). PubMed | Article
  19. Hosomi, A., Nakanishi, T., Fujita, T. & Tamai, I. Extra-renal elimination of uric acid via intestinal efflux transporter BCRP/ABCG2. PloS One 7, e30456 (2012). CAS | PubMed | Article
  20. Nielsen, H. B. et al. Identification and assembly of genomes and genetic elements in complex metagenomic samples without using reference genomes. Nat Biotechnol 32, 822–828 (2014). ISI | CAS | PubMed | Article
  21. Wei, B. et al. Molecular cloning of a Bacteroides caccae TonB-linked outer membrane protein identified by an inflammatory bowel disease marker antibody. Infect Immun 69, 6044–6054 (2001). CAS | PubMed | Article
  22. Ulsemer, P. et al. Safety and tolerance of Bacteroides xylanisolvens DSM 23964 in healthy adults. Benef Microbes 3, 99–111 (2012). CAS | PubMed | Article
  23. Ulsemer, P., Toutounian, K., Schmidt, J., Karsten, U. & Goletz, S.Preliminary safety evaluation of a new Bacteroides xylanisolvens isolate. Appl Environ Microbiol 78, 528–535 (2012). CAS | PubMed | Article
  24. Eckburg, P. B. et al. Diversity of the human intestinal microbial flora. Science 308, 1635–1638 (2005). ISI | PubMed | Article
  25. Li, G., Yao, W. & Jiang, H. Short-chain fatty acids enhance adipocyte differentiation in the stromal vascular fraction of porcine adipose tissue. J Nutr 144, 1887–1895 (2014). ISI | CAS | PubMed | Article
  26. Qin, N. et al. Alterations of the human gut microbiome in liver cirrhosis. Nature 513, 59–64 (2014). ISI | CAS | PubMed | Article
  27. Qin, J. J. et al. A metagenome-wide association study of gut microbiota in type 2 diabetes. Nature 490, 55–60 (2012). ISI | CAS | PubMed | Article
  28. Karlsson, F. H. et al. Gut metagenome in European women with normal, impaired and diabetic glucose control. Nature 498, 99–103 (2013). ISI | CAS | PubMed | Article
  29. Griffiths, M. The mechanism of the diabetogenic action of uric acid. J Biol Chem 184, 289–298 (1950). CAS | PubMed
  30. Tsouli, S. G., Liberopoulos, E. N., Mikhailidis, D. P., Athyros, V. G. & Elisaf, M. S. Elevated serum uric acid levels in metabolic syndrome: an active component or an innocent bystander?Metabolism 55, 1293–1301 (2006). ISI | CAS | PubMed | Article
  31. Facchini, F., Chen, Y. D., Hollenbeck, C. B. & Reaven, G. M.Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. Jama 266, 3008–3011 (1991). ISI | CAS | PubMed | Article
  32. Li, J. et al. An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol 32, 834–841 (2014). ISI | CAS | PubMed | Article
  33. Matsuo, H. et al. ABCG2 dysfunction causes hyperuricemia due to both renal urate underexcretion and renal urate overload. Sci Rep4, 3375 (2014).
  34. Caporaso, J. G. et al. PyNAST: a flexible tool for aligning sequences to a template alignment. Bioinformatics 26, 266–267 (2010). ISI | CAS | PubMed | Article
  35. Claesson, M. J. et al. Comparative Analysis of Pyrosequencing and a Phylogenetic Microarray for Exploring Microbial Community Structures in the Human Distal Intestine. PloS One 4, e6669 (2009). CAS | PubMed | Article
  36. Peng, Y., Leung, H. C. M., Yiu, S. M. & Chin, F. Y. L. IDBA-UD: a de novo assembler for single-cell and metagenomic sequencing data with highly uneven depth. Bioinformatics 28, 1420–1428 (2012). ISI | CAS | PubMed | Article
  37. Zhu, W. H., Lomsadze, A. & Borodovsky, M. Ab initio gene identification in metagenomic sequences. Nucleic Acids Research38, e132 (2010). CAS | PubMed | Article
  38. Li, W. Z. & Godzik, A. Cd-hit: a fast program for clustering and comparing large sets of protein or nucleotide sequences. Bioinformatics 22, 1658–1659 (2006). ISI | CAS | PubMed | Article
  39. Langmead, B., Trapnell, C., Pop, M. & Salzberg, S. L. Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biology 10, R25 (2009). CAS | PubMed | Article
  40. McArdle, B. H. & Anderson, M. J. Fitting multivariate models to community data: A comment on distance-based redundancy analysis. Ecology 82, 290–297 (2001). ISI | Article
  41. Zapala, M. A. & Schork, N. J. Multivariate regression analysis of distance matrices for testing associations between gene expression patterns and related variables. Proc Natl Acad Sci USA103, 19430–19435 (2006). CAS | PubMed | Article
  42. Robin, X. et al. pROC: an open-source package for R and S plus to analyze and compare ROC curves. Bmc Bioinformatics 12, 77 (2011). PubMed | Article