Original articles
Libin Pan, Pei Han, Shurong Ma, Ran Peng, Can Wang, Weijia Kong, Lin Cong, Jie Fu, Zhengwei Zhang, Hang Yu, Yan Wang, Jiandong Jiang. Abnormal metabolism of gut microbiota reveals the possible molecular mechanism of nephropathy induced by hyperuricemia[J]. Acta Pharmaceutica Sinica B, 2020, 10(2): 249-261

Abnormal metabolism of gut microbiota reveals the possible molecular mechanism of nephropathy induced by hyperuricemia
Libin Pana, Pei Hana, Shurong Maa, Ran Penga, Can Wanga, Weijia Kongb, Lin Conga, Jie Fua, Zhengwei Zhanga, Hang Yua, Yan Wanga, Jiandong Jianga
a State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100050, China;
b Insitute of Medicinal Biotechnology, Chinese Academy of Medical Sciences/Peking Union Medical College, Beijing 100050, China
Abstract:
The progression of hyperuricemia disease is often accompanied by damage to renal function. However, there are few studies on hyperuricemia nephropathy, especially its association with intestinal flora. This study combines metabolomics and gut microbiota diversity analysis to explore metabolic changes using a rat model as well as the changes in intestinal flora composition. The results showed that amino acid metabolism was disturbed with serine, glutamate and glutamine being downregulated whilst glycine, hydroxyproline and alanine being upregulated. The combined glycine, serine and glutamate could predict hyperuricemia nephropathy with an area under the curve of 1.00. Imbalanced intestinal flora was also observed. Flavobacterium, Myroides, Corynebacterium, Alcaligenaceae, Oligella and other conditional pathogens increased significantly in the model group, while Blautia and Roseburia, the shortchain fatty acid producing bacteria, declined greatly. At phylum, family and genus levels, disordered nitrogen circulation in gut microbiota was detected. In the model group, the uric acid decomposition pathway was enhanced with reinforced urea liver-intestine circulation. The results implied that the intestinal flora play a vital role in the pathogenesis of hyperuricemia nephropathy. Hence, modulation of gut microbiota or targeting at metabolic enzymes, i.e., urease, could assist the treatment and prevention of this disease.
Key words:    Hyperuricemia    Renal function    Gut microbiota    Metabolomics    Urease   
Received: 2019-07-11     Revised: 2019-10-05
DOI: 10.1016/j.apsb.2019.10.007
Funds: The project was supported by the National Natural Science Foundation of China (Nos. 81573493 and 81973290), CAMS Innovation Fund for Medical Sciences (CIFMS, No. 2016-I2M-3-011, China), Beijing Key Laboratory of Non-Clinical Drug Metabolism and PK/PDstudy(Z141102004414062,China), the National Megaprojectfor Innovative Drugs (Nos. 2018ZX09711001-002-002 and 2018ZX09302015, China), and Beijing Natural Sciences Fund Key Projects (NO. 7181007). We also thank Shimadzu (China) Co., Ltd. for the technological supports in this study.
Corresponding author: Yan Wang, Jiandong Jiang     Email:wangyan@imm.ac.cn;jiang.jdong@163.com
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Authors
Libin Pan
Pei Han
Shurong Ma
Ran Peng
Can Wang
Weijia Kong
Lin Cong
Jie Fu
Zhengwei Zhang
Hang Yu
Yan Wang
Jiandong Jiang

References:
1. Qin Z, Wang S, Lin Y, Zhao Y, Yang S, Song J, et al. Antihyperuricemic effect of mangiferin aglycon derivative J99745 by inhibiting xanthine oxidase activity and urate transporter 1 expression in mice. Acta Pharm Sin B 2018;8:306-15.
2. Dalbeth N, Merriman TR, Stamp LK. Gout. Lancet 2016;388:2039-52.
3. Johnson RJ, Nakagawa T, Jalal D, Sánchez-Lozada LG, Kang DH, Ritz E. Uric acid and chronic kidney disease:which is chasing which?. Nephrol Dial Transplant 2013;28:2221-8.
4. Towiwat P, Chhana A, Dalbeth N. The anatomical pathology of gout:a systematic literature review. BMC Muscoskelet Disord 2019;20:140.
5. Chou YC, Kuan JC, Yang T, Chou WY, Hsieh PC, Bai CH, et al. Elevated uricacidlevelasa significantpredictor of chronickidney disease:a cohort study with repeated measurements. J Nephrol 2015;28:457-62.
6. Yan D, Tu Y, Jiang F, Wang J, Zhang R, Sun X, et al. Uric acid is independently associated with diabetic kidney disease:a cross-sectional study in a Chinese population. PLoS One 2015;10. e0129797-e.
7. Bartáková V, Kuricová K, Pácal L, Nová Z, Dvořáková V, Švrčková M, et al. Hyperuricemia contributes to the faster progression of diabetic kidney disease in type 2 diabetes mellitus. J Diabet Complicat 2016; 30:1300-7.
8. Sharaf El Din UAA, Salem MM, Abdulazim DO. Uric acid in the pathogenesis of metabolic, renal, and cardiovascular diseases:a review. J Adv Res 2017;8:537-48.
9. Almeida A, Mitchell AL, Boland M, Forster SC, Gloor GB, Tarkowska A, et al. A new genomic blueprint of the human gut microbiota. Nature 2019;568:499-504.
10. Wang Y, Tong Q, Shou JW, Zhao ZX, Li XY, Zhang XF, et al. Gut microbiota-mediated personalized treatment of hyperlipidemia using berberine. Theranostics 2017;7:2443-51.
11. Wang Y, Jiang J. A new research mode of drug PKePD mediated by the gut microbiota:insights into the pharmacokinetics of berberine. Yao Xue Xue Bao 2018;53:659-66.
12. Feng R, Shou JW, Zhao ZX, He CY, Ma C, Huang M, et al. Transforming berberine into its intestine-absorbable form by the gut microbiota. Sci Rep 2015;5:12155.
13. Wang Y, Shou JW, Li XY, Zhao ZX, Fu J, He CY, et al. Berberineinduced bioactive metabolites of the gut microbiota improve energy metabolism. Metabolism 2017;70:72-84.
14. Zhao ZX, Fu J, Ma SR, Peng R, Yu JB, Cong L, et al. Gutebrain axis metabolic pathway regulates antidepressant efficacy of albiflorin. Theranostics 2018;8:5945-59.
15. Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A 2009;106:3698-703.
16. Feng YL, Cao G, Chen DQ, Vaziri ND, Chen L, Zhang J, et al. Microbiomeemetabolomics reveals gut microbiota associated with glycine-conjugated metabolites and polyamine metabolism in chronic kidney disease. Cell Mol Life Sci 2019;76:4961-78.
17. Chung S, Barnes JL, Astroth KS. Gastrointestinal microbiota in patients with chronic kidney disease:a systematic review. Adv Nutr 2019;10:888-901.
18. Aron-Wisnewsky J, Clément K. The gut microbiome, diet, and links to cardiometabolic and chronic disorders. Nat Rev Nephrol 2015;12:169-81.
19. Guo Z, Zhang J, Wang Z, Ang KY, Huang S, Hou Q, et al. Intestinal microbiota distinguish gout patients from healthy humans. Sci Rep 2016;6:20602.
20. Crane JK, Naeher TM, Broome JE, Boedeker EC. Role of host xanthine oxidase in infection due to enteropathogenic and Shigatoxigenic Escherichia coli. Infect Immun 2013;81:1129-39.
21. Beger RD, Dunn W, Schmidt MA, Gross SS, Kirwan JA, Cascante M, et al. Metabolomics enables precision medicine:"A white paper, community perspective". Metabolomics 2016;12:149.
22. Rochfort S. Metabolomics reviewed:a new "omics" platform technology for systems biology and implications for natural products research. J Nat Prod 2005;68:1813-20.
23. Tachibana C. What's next in omics:the metabolome. Science 2014; 345:1519-21.
24. Carter RA, Pan K, Harville EW, McRitchie S, Sumner S. Metabolomics to reveal biomarkers and pathways of preterm birth:a systematic review and epidemiologic perspective. Metabolomics 2019;15:124.
25. Gao Y, Li W, Chen J, Wang X, Lv Y, Huang Y, et al. Pharmacometabolomic prediction of individual differences of gastrointestinal toxicity complicating myelosuppression in rats induced by irinotecan. Acta Pharm Sin B 2019;9:157-66.
26. Tso VK, Sydora BC, Foshaug RR, Churchill TA, Doyle J, Slupsky CM, et al. Metabolomic profiles are gender, disease and time specific in the interleukin-10 gene-deficient mouse model of inflammatory bowel disease. PLoS One 2013;8:e67654.
27. Chen MX, Wang SY, Kuo CH, Tsai IL. Metabolome analysis for investigating hostegut microbiota interactions. J Formos Med Assoc 2019;118:S10-22.
28. Holmes E, Li Jia V, Marchesi Julian R, Nicholson Jeremy K. Gut microbiota composition and activity in relation to host metabolic phenotype and disease risk. Cell Metab 2012;16:559-64.
29. Vernocchi P, Del Chierico F, Putignani L. Gut microbiota profiling:metabolomics based approach to unravel compounds affecting human health. Front Microbiol 2016;7:1144.
30. Han P, Huang Y, Xie Y, Yang W, Xiang W, Hylands PJ, et al. Metabolomics reveals immunomodulation as a possible mechanism for the antibiotic effect of Persicaria capitata (Buch.-Ham. ex D. Don) H. Gross. Metabolomics 2018;14:91.
31. Snowden SG, Ebshiana AA, Hye A, An Y, Pletnikova O, O'Brien R, et al. Association between fatty acid metabolism in the brain and Alzheimer disease neuropathology and cognitive performance:a nontargeted metabolomic study. PLoS Med 2017;14:e1002266.
32. Chen DQ, Cao G, Chen H, Argyopoulos CP, Yu H, Su W, et al. Identification of serum metabolites associating with chronic kidney disease progression and anti-fibrotic effect of 5-methoxytryptophan. Nat Commun 2019;10:1476.
33. Tang R, Wei Y, Li Y, Chen W, Chen H, Wang Q, et al. Gut microbial profile is altered in primary biliary cholangitis and partially restored after UDCA therapy. Gut 2018;67:534-41.
34. Zhernakova DV, Le TH, Kurilshikov A, Atanasovska B, Bonder MJ, Sanna S, et al. Individual variations in cardiovascular-disease-related protein levels are driven by genetics and gut microbiome. Nat Genet 2018;50:1524-32.
35. Jenq RR, Taur Y, Devlin SM, Ponce DM, Goldberg JD, Ahr KF, et al. Intestinal Blautia is associated with reduced death from graft-versushost disease. Biol Blood Marrow Transplant 2015;21:1373-83.
36. Tamanai-Shacoori Z, Smida I, Bousarghin L, Loreal O, Meuric V, Fong SB, et al. Roseburia spp.:a marker of health?. Future Microbiol 2017;12:157-70.
37. Sanders ME, Merenstein DJ, Reid G, Gibson GR, Rastall RA. Probiotics and prebiotics in intestinal health and disease:from biology to the clinic. Nat Rev Gastroenterol Hepatol 2019;16:605-16.
38. Yang L, Chang B, Guo Y, Wu X, Liu L. The role of oxidative stressmediated apoptosis in the pathogenesis of uric acid nephropathy. Ren Fail 2019;41:616-22.
39. Ye Y, Zhang Y, Wang B, Walana W, Wei J, Gordon JR, et al. CXCR1/CXCR2 antagonist G31P inhibits nephritis in a mouse model of uric acid nephropathy. Biomed Pharmacother 2018;107:1142-50.
40. Wang YN, Ma SX, Chen YY, Chen L, Liu BL, Liu QQ, et al. Chronic kidney disease:biomarker diagnosis to therapeutic targets. Clin Chim Acta 2019;499:54-63.
41. Newsholme P, Procopio J, Lima MM, Pithon-Curi TC, Curi R. Glutamine and glutamatedtheir central role in cell metabolism and function. Cell Biochem Funct 2003;21:1-9.
42. Tapiero H, Mathe G, Couvreur P, Tew KD. II. Glutamine and glutamate. Biomed Pharmacother 2002;56:446-57.
43. Spanaki C, Plaitakis A. The role of glutamate dehydrogenase in mammalian ammonia metabolism. Neurotox Res 2012;21:117-27.
44. Dryer SE. Glutamate receptors in the kidney. Nephrol Dial Transplant 2015;30:1630-8.
45. Tizianello A, De Ferrari G, Garibotto G, Gurreri G, Robaudo C. Renal metabolism of amino acids and ammonia in subjects with normal renal function and in patients with chronic renal insufficiency. J Clin Invest 1980;65:1162-73.
46. Taylor L, Curthoys NP. Glutamine metabolism:role in acid-base balance. Biochem Mol Biol Educ 2004;32:291-304.
47. Kamm DE, Strope GL. The effects of acidosis and alkalosis on the metabolism of glutamine and glutamate in renal cortex slices. J Clin Invest 1972;51:1251-63.
48. Vinay P, Khoury N, Soowamber M, Gougoux A. Renal extraction of glutamine from plasma and whole blood:studies in dogs and rats. Can J Physiol Pharmacol 1985;63:886-92.
49. Øvrehus MA, Bruheim P, Ju W, Zelnick LR, Langlo KA, Sharma K, et al. Gene expression studies and targeted metabolomics reveal disturbed serine, methionine, and tyrosine metabolism in early hypertensive nephrosclerosis. Kidney Int Rep 2018;4:321-33.
50. Kalhan SC, Hanson RW. Resurgence of serine:an often neglected but indispensable amino acid. J Biol Chem 2012;287:19786-91.
51. Lowry M, Hall DE, Hall MS, Brosnan JT. Renal metabolism of amino acids in vivo:studies on serine and glycine fluxes. Am J Physiol 1987; 252:F304-9.
52. van de Poll MC, Soeters PB, Deutz NE, Fearon KC, Dejong CH. Renal metabolism of amino acids:its role in interorgan amino acid exchange. Am J Clin Nutr 2004;79:185-97.
53. Martinez M, Cuskelly GJ, Williamson J, Toth JP, Gregory 3rd JF. Vitamin B-6 deficiency in rats reduces hepatic serine hydroxymethyltransferase and cystathionine beta-synthase activities and rates of in vivo protein turnover, homocysteine remethylation and transsulfuration. J Nutr 2000;130:1115-23.
54. Lacour B, Parry C, Drueke T, Touam M, Kreis H, Bailly M, et al. Pyridoxal 5'-phosphate deficiency in uremic undialyzed, hemodialyzed, and non-uremic kidney transplant patients. Clin Chim Acta 1983;127:205-15.
55. Busch M, Gobert A, Franke S, Ott U, Gerth J, Muller A, et al. Vitamin B6 metabolism in chronic kidney diseasedrelation to transsulfuration, advanced glycation and cardiovascular disease. Nephron Clin Pract 2010;114:38-46.
56. Hijmans RS, Rasmussen DGK, Yazdani S, Navis G, van Goor H, Karsdal MA, et al. Urinary collagen degradation products as early markers of progressive renal fibrosis. J Transl Med 2017;15:63.
57. McKleroy W, Lee T-H, Atabai K. Always cleave up your mess:targeting collagen degradation to treat tissue fibrosis. Am J Physiol Lung Cell Mol Physiol 2013;304:L709-21.
58. Arata J, Hatakenaka K, Oono T. Effect of topical application of glycine and proline on recalcitrant leg ulcers of prolidase deficiency. Arch Dermatol 1986;122:626-7.
59. Li P, Wu G. Roles of dietary glycine, proline, and hydroxyproline in collagen synthesis and animal growth. Amino Acids 2018;50:29-38.
60. Wang Y, Fan P-S, Kahaleh B. Association between enhanced type I collagen expression and epigenetic repression of the FLI1 gene in scleroderma fibroblasts. Arthritis Rheum 2006;54:2271-9.
61. Song YN, Dong S, Wei B, Liu P, Zhang YY, Su SB. Metabolomic mechanisms of gypenoside against liver fibrosis in rats:an integrative analysis of proteomics and metabolomics data. PLoS One 2017;12:e0173598.
62. Forslund K, Hildebrand F, Nielsen T, Falony G, Le Chatelier E, Sunagawa S, et al. Disentangling type 2 diabetes and metformin treatment signatures in the human gut microbiota. Nature 2015;528:262-6.
63. Niwa T. Phenol and p-cresol accumulated in uremic serum measured by HPLC with fluorescence detection. Clin Chem 1993; 39:108-11.
64. Nowak A, Libudzisz Z. Influence of phenol, p-cresol and indole on growth and survival of intestinal lactic acid bacteria. Anaerobe 2006; 12:80-4.
65. Nakabayashi I, Nakamura M, Kawakami K, Ohta T, Kato I, Uchida K, et al. Effects of synbiotic treatment on serum level of p-cresol in haemodialysis patients:a preliminary study. Nephrol Dial Transplant 2011;26:1094-8.
66. Vanholder R, Glorieux G. The intestine and the kidneys:a bad marriage can be hazardous. Clin Kidney J 2015;8:168-79.
67. Miyazaki K, Masuoka N, Kano M, Iizuka R. Bifidobacterium fermented milk and galacto-oligosaccharides lead to improved skin health by decreasing phenols production by gut microbiota. Benef Microbes 2014;5:121-8.
68. Ni J, Shen T-CD, Chen EZ, Bittinger K, Bailey A, Roggiani M, et al. A role for bacterial urease in gut dysbiosis and Crohn's disease. Sci Transl Med 2017;9:eaah6888.
69. Hartwich K, Poehlein A, Daniel R. The purine-utilizing bacterium Clostridium acidurici 9a:a genome-guided metabolic reconsideration. PLoS One 2012;7. e51662-e.
70. Barker HA, Beck JV. Clostridium acidi-uridi and Clostridium cylindrosporum, organisms fermenting uric acid and some other purines. J Bacteriol 1942;43:291-304.
71. Marzocco S, Fazeli G, Di Micco L, Autore G, Adesso S, Dal Piaz F, et al. Supplementation of short-chain fatty acid, sodium propionate, in patients on maintenance hemodialysis:beneficial effects on inflammatory parameters and gut-derived uremic toxins, a pilot study (PLAN Study). J Clin Med 2018;7:315.
72. Shewmaker PL, Whitney AM, Gulvik CA, Humrighouse BW, Gartin J, Moura H, et al. Vagococcus bubulae sp. nov., isolated from ground beef, and Vagococcus vulneris sp. nov., isolated from a human foot wound. Int J Syst Evol Microbiol 2019;69:2268-76.
73. Mukhopadhyay R, Joaquin J, Hogue R, Kilaru A, Jospin G, Mars K, et al. Complete genome sequence of a Paenalcaligenes hominis strain isolated from a paraplegic patient with neurogenic bladder using single-molecule real-time sequencing technology. Genome Announc 2017;5. e00252-17.
74. Pearce MM, Hilt EE, Rosenfeld AB, Zilliox MJ, Thomas-White K, Fok C, et al. The female urinary microbiome:a comparison of women with and without urgency urinary incontinence. MBio 2014;5. e01283-14.
75. Gootenberg DB, Paer JM, Luevano J-M, Kwon DS. HIV-associated changes in the enteric microbial community:potential role in loss of homeostasis and development of systemic inflammation. Curr Opin Infect Dis 2017;30:31-43.
76. Lau WL, Vaziri ND. Urea, a true uremic toxin:the empire strikes back. Clin Sci (Lond) 2017;131:3-12.