Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease

Circulation Research

Volumn 116, Issue 3, 2014, Pages 448-455

  Tang, W H Wilson ^a   Wang, Zeneng ^a   Kennedy, David J ^a   Wu, Yuping ^b   Buffa, Jennifer A ^a   Agatisa Boyle, Brendan ^a   Li, Xinmin S ^a   Levison, Bruce S ^a   Hazen, Stanley L ^a  

^a LERNER RESEARCH INSTITUTE   (United States)

^b CLEVELAND STATE UNIVERSITY   (United States)

Author keywords

Cardiovascular diseases; Chronic kidney disease; Fibrosis; Gut microbiota; Trimethylamine N oxide

Indexed keywords

C REACTIVE PROTEIN; CARNITINE; CYSTATIN C; PHOSPHATIDYLCHOLINE; TRIMETHYLAMINE OXIDE; BIOLOGICAL MARKER; METHYLAMINE; TRIMETHYLOXAMINE;

ADULT; AGED; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BLOOD LEVEL; CHRONIC KIDNEY DISEASE; CONTROLLED STUDY; CORONARY ARTERY DISEASE; DISEASE ASSOCIATION; FEMALE; GLOMERULUS FILTRATION RATE; HUMAN; INTESTINE FLORA; KIDNEY FAILURE; KIDNEY FIBROSIS; LONG TERM SURVIVAL; MALE; MORTALITY; MOUSE; NONHUMAN; PRIORITY JOURNAL; PROGNOSIS; RISK ASSESSMENT; ANIMAL; BLOOD; C57BL MOUSE; CASE CONTROL STUDY; INTESTINE; METABOLISM; MICROBIOLOGY; MICROFLORA; MIDDLE AGED; RENAL INSUFFICIENCY; RENAL INSUFFICIENCY, CHRONIC; RISK FACTOR; VERY ELDERLY;

AGED; AGED, 80 AND OVER; ANIMALS; BIOMARKERS; CASE-CONTROL STUDIES; FEMALE; HUMANS; INTESTINES; MALE; METHYLAMINES; MICE; MICE, INBRED C57BL; MICROBIOTA; MIDDLE AGED; PROGNOSIS; RENAL INSUFFICIENCY; RENAL INSUFFICIENCY, CHRONIC; RISK FACTORS;

EID: 84925862053     PISSN: 00097330     EISSN: 15244571     Source Type: Journal    
DOI: 10.1161/CIRCRESAHA.116.305360     Document Type: Article

References (42)

1. Mafra D, Lobo JC, Barros AF, Koppe L, Vaziri ND, Fouque D. Role of altered intestinal microbiota in systemic inflammation and cardiovascular disease in chronic kidney disease. Future Microbiol. 2014;9:399-410.
2. Vaziri ND, Wong J, Pahl M, Piceno YM, Yuan J, DeSantis TZ, Ni Z, Nguyen TH, Andersen GL. Chronic kidney disease alters intestinal microbial flora. Kidney Int. 2013;83:308-315.
3. Stenvinkel P, Alvestrand A. Inflammation in end-stage renal disease: sources, consequences, and therapy. Semin Dial. 2002;15:329-337.
4. Anders HJ, Andersen K, Stecher B. The intestinal microbiota, a leaky gut, and abnormal immunity in kidney disease. Kidney Int. 2013;83:1010-1016.
5. Lee CT, Hsu CY, Tain YL, Ng HY, Cheng BC, Yang CC, Wu CH, Chiou TT, Lee YT, Liao SC. Effects of AST-120 on blood concentrations of protein-bound uremic toxins and biomarkers of cardiovascular risk in chronic dialysis patients. Blood Purif. 2014;37:76-83.
6. Lekawanvijit S, Kompa AR, Wang BH, Kelly DJ, Krum H. Cardiorenal syndrome: the emerging role of protein-bound uremic toxins. Circ Res. 2012;111:1470-1483.
7. Ramezani A, Raj DS. The gut microbiome, kidney disease, and targeted interventions. J Am Soc Nephrol. 2014;25:657-670.
8. Koeth RA, Wang Z, Levison BS, et al. Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 2013;19:576-585
9. Tang WH, Wang Z, Levison BS, Koeth RA, Britt EB, Fu X, Wu Y, Hazen SL. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368:1575-1584.
10. Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472:57-63
11. Wang Z, Tang WH, Buffa JA, Fu X, Britt EB, Koeth RA, Levison BS, Fan Y, Wu Y, Hazen SL. Prognostic value of choline and betaine depends on intestinal microbiota-generated metabolite trimethylamine-N-oxide. Eur Heart J. 2014;35:904-910.
12. Tang WH, Hazen SL. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest. 2014;124:4204-4211.
13. Tang WH, Wang Z, Fan Y, Levison BS, Hazen JE, Donahue L, Wu Y, Hazen SL. Prognostic value of elevated levels of intestinal microbe-generated metabolite trimethylamine-N-oxide in patients with heart failure: refining the gut hypothesis. J Am Coll Cardiol. 2014;2014:1908-1914
14. Bennett BJ, de Aguiar Vallim TQ, Wang Z, Shih DM, Meng Y, Gregory J, Allayee H, Lee R, Graham M, Crooke R, Edwards PA, Hazen SL, Lusis AJ. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013;17:49-60.
15. Koeth RA, Levison BS, Culley MK, Buffa JA, Wang Z, Gregory JC, Org E, Wu Y, Li L, Smith JD, Tang WH, DiDonato JA, Lusis AJ, Hazen SL. G-butyrobetaine is a pro-atherogenic intermediate in gut microbial metabolism of l-carnitine to TMAO. Cell Metab. 2014;20:799-812.
16. Bain MA, Faull R, Fornasini G, Milne RW, Evans AM. Accumulation of trimethylamine and trimethylamine-N-oxide in end-stage renal disease patients undergoing haemodialysis. Nephrol Dial Transplant. 2006;21:1300-1304.
17. Bain MA, Faull R, Milne RW, Evans AM. Oral L-carnitine: metabolite formation and hemodialysis. Curr Drug Metab. 2006;7:811-816.
18. Bell JD, Lee JA, Lee HA, Sadler PJ, Wilkie DR, Woodham RH. Nuclear magnetic resonance studies of blood plasma and urine from subjects with chronic renal failure: identification of trimethylamine-N-oxide. Biochim Biophys Acta. 1991;1096:101-107.
19. Robert R, Guilhot J, Pinsard M, Longeard PL, Jacob JP, Gissot V, Hauet T, Seguin F. A pair analysis of the delayed graft function in kidney recipient: the critical role of the donor. J Crit Care. 2010;25:582-590.
20. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Feldman HI, Greene T, Kusek JW, Manzi J, Van Lente F, Zhang YL, Coresh J, Levey AS; CKDEPI Investigators. Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med. 2012;367:20-29.
21. Wang Z, Levison BS, Hazen JE, Donahue L, Li XM, Hazen SL. Measurement of trimethylamine-N-oxide by stable isotope dilution liquid chromatography tandem mass spectrometry. Anal Biochem. 2014;455:35-40.
22. Pencina MJ, D'Agostino RB, Sr., D'Agostino RB, Jr., Vasan RS. Evaluating the added predictive ability of a new marker: From area under the roc curve to reclassification and beyond. Stat Med. 2008;27:157-172
23. Qu X, Li X, Zheng Y, Ren Y, Puelles VG, Caruana G, Nikolic-Paterson DJ, Li J. Regulation of renal fibrosis by Smad3 thr388 phosphorylation. Am J Pathol. 2014;184:944-952.
24. Al-Waiz M, Mitchell SC, Idle JR, Smith RL. The metabolism of 14C-labelled trimethylamine and its N-oxide in man. Xenobiotica. 1987;17:551-558.
25. Smith JL, Wishnok JS, Deen WM. Metabolism and excretion of methylamines in rats. Toxicol Appl Pharmacol. 1994;125:296-308.
26. Zeisel SH, daCosta KA, Youssef M, Hensey S. Conversion of dietary choline to trimethylamine and dimethylamine in rats: dose-response relationship. J Nutr. 1989;119:800-804.
27. Hauet T, Mothes D, Bon D, Baumert H, Le Moyec L, Goujon JM, Robert R, Caritez JC, Tallineau C, Carretier M, Eugene M. Proton NMR spectroscopy as a novel approach to the monitoring of citrate and trimethylamine-N-oxide excretion after kidney preservation. Transplant Proc. 1997;29:2323-2325.
28. Le Moyec L, Pruna A, Eugène M, Bedrossian J, Idatte JM, Huneau JF, Tomé D. Proton nuclear magnetic resonance spectroscopy of urine and plasma in renal transplantation follow-up. Nephron. 1993;65:433-439.
29. Serkova N, Fuller TF, Klawitter J, Freise CE, Niemann CU. H-NMRbased metabolic signatures of mild and severe ischemia/reperfusion injury in rat kidney transplants. Kidney Int. 2005;67:1142-1151.
30. Foxall PJ, Mellotte GJ, Bending MR, Lindon JC, Nicholson JK. NMR spectroscopy as a novel approach to the monitoring of renal transplant function. Kidney Int. 1993;43:234-245.
31. Walkin L, Herrick SE, Summers A, Brenchley PE, Hoff CM, Korstanje R, Margetts PJ. The role of mouse strain differences in the susceptibility to fibrosis: a systematic review. Fibrogenesis Tissue Repair. 2013;6:18.
32. Runyan CE, Schnaper HW, Poncelet AC. Smad3 and PKCdelta mediate TGF-beta1-induced collagen I expression in human mesangial cells. Am J Physiol Renal Physiol. 2003;285:F413-F422.
33. Rhee EP, Clish CB, Ghorbani A, et al. A combined epidemiologic and metabolomic approach improves ckd prediction. J Am Soc Nephrol. 2013;24:1330-1338.
34. Lin J, Hu FB, Curhan GC. Associations of diet with albuminuria and kidney function decline. Clin J Am Soc Nephrol. 2010;5:836-843.
35. Zeisel SH. Choline: clinical nutrigenetic/nutrigenomic approaches for identification of functions and dietary requirements. J Nutrigenet Nutrigenomics. 2010;3:209-219.
36. Hegazy SK, El-Bedewy MM. Effect of probiotics on pro-inflammatory cytokines and NF-kappaB activation in ulcerative colitis. World J Gastroenterol. 2010;16:4145-4151.
37. Seth A, Yan F, Polk DB, Rao RK. Probiotics ameliorate the hydrogen peroxide-induced epithelial barrier disruption by a PKC-and MAP kinase-dependent mechanism. Am J Physiol Gastrointest Liver Physiol. 2008;294:G1060-G1069.
38. Simenhoff ML, Dunn SR, Zollner GP, Fitzpatrick ME, Emery SM, Sandine WE, Ayres JW. Biomodulation of the toxic and nutritional effects of small bowel bacterial overgrowth in end-stage kidney disease using freeze-dried Lactobacillus acidophilus. Miner Electrolyte Metab. 1996;22:92-96.
39. Takayama F, Taki K, Niwa T. Bifidobacterium in gastro-resistant seamless capsule reduces serum levels of indoxyl sulfate in patients on hemodialysis. Am J Kidney Dis. 2003;41:S142-S145.
40. Ranganathan N, Patel B, Ranganathan P, Marczely J, Dheer R, Chordia T, Dunn SR, Friedman EA. Probiotic amelioration of azotemia in 5/6th nephrectomized Sprague-Dawley rats. ScientificWorldJournal. 2005;5:652-660.
41. Ranganathan N, Ranganathan P, Friedman EA, Joseph A, Delano B, Goldfarb DS, Tam P, Rao AV, Anteyi E, Musso CG. Pilot study of probiotic dietary supplementation for promoting healthy kidney function in patients with chronic kidney disease. Adv Ther. 2010;27:634-647.
42. Niwa T, Ise M. Indoxyl sulfate, a circulating uremic toxin, stimulates the progression of glomerular sclerosis. J Lab Clin Med. 1994;124:96-104.