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Trimethylamine-N-oxide: A Novel Biomarker for the Identification of Inflammatory Bowel Disease

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An Erratum to this article was published on 02 August 2015

Abstract

Background

The gastrointestinal (GI) microbiome is recognized for potential clinical relevance in inflammatory bowel disease (IBD). Data suggest that there is a disease-dependent loss of microbial diversity in IBD. Trimethylamine-N-oxide (TMAO) is generated by GI anaerobes through the digestion of dietary phosphatidylcholine and carnitine in a microbial-mammalian co-metabolic pathway. IBD-related changes in the gut microbiome may result in disease-specific changes in TMAO plasma concentrations.

Aim

To determine whether TMAO plasma levels in IBD are altered compared to controls and whether they correlate with disease presence or activity.

Methods

Liquid chromatography–tandem mass spectrometry was used to measure TMAO, choline, and carnitine plasma levels in 479 subjects (373 non-IBD controls, 106 IBD). Subjects were also genotyped for the flavin monooxygenase (FMO)3 variants, E158K and E308G.

Results

Plasma TMAO levels were 2.27 µM lower in the IBD population compared to the control population (p = 0.0001). Lower TMAO levels were similarly seen in active ulcerative colitis (UC) (1.56 µM) versus inactive disease (3.40 µM) (p = 0.002). No difference was seen in active Crohn’s disease (CD) versus inactive CD. No intergroup variation existed in plasma TMAO levels based on FMO3 genotype. Choline levels were higher in IBD, while carnitine levels were similar between the two groups, suggesting that lower TMAO levels in IBD were not due to dietary differences.

Conclusions

Decreased TMAO levels are seen in IBD compared to a non-IBD population. These data suggest that TMAO may have potential as a biomarker to support IBD diagnosis as well as to assess disease activity in UC.

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References

  1. Molodecky NA, Soon IS, Rabi DM, et al. Increasing incidence and prevalence of the inflammatory bowel diseases with time, based on systematic review. Gastroenterology. 2012;142:9.

    Article  Google Scholar 

  2. Ekbom A, Helmick C, Zack M, et al. The epidemiology of inflammatory bowel disease: a large, population-based study in Sweden. Gastroenterology. 1991;100:350–358.

    CAS  PubMed  Google Scholar 

  3. Su C, Lichtenstein GR. Sleisenger and Fordtran’s gastrointestinal and liver diseases: pathophysiology/diagnosis/management, vol. 2. Philadelphia, PA: Saunders Elsevier; 2006.

    Google Scholar 

  4. Prideaux L, De Cruz P, Ng SC, et al. Serological antibodies in inflammatory bowel disease: a systematic review. Inflamm Bowel Dis. 2012;18:1340–1355.

    Article  PubMed  Google Scholar 

  5. Iskandar HN, Ciorba MA. Biomarkers in inflammatory bowel disease: current practices and recent advances. Trans Res J Lab Clin Med. 2012;159:313–325.

    Article  CAS  Google Scholar 

  6. Lin JF, Chen JM, Zuo JH, et al. Meta-analysis: fecal calprotectin for assessment of inflammatory bowel disease activity. Inflamm Bowel Dis. 2014;20:1407–1415.

    Article  PubMed  Google Scholar 

  7. Vermeire S, Van Assche G, Rutgeerts P. C-reactive protein as a marker for inflammatory bowel disease. Inflamm Bowel Dis. 2004;10:661–665.

    Article  PubMed  Google Scholar 

  8. Sartor RB, Mazmanian SK. Intestinal microbes in inflammatory bowel diseases. Am J Gastroenterol Suppl. 2012;1:15–21.

    Article  CAS  Google Scholar 

  9. Frank DN, St. Amand AL, Feldman RA, et al. Molecular-phylogenetic characterization of microbial community imbalances in human inflammatory bowel diseases. Proc Natl Acad Sci USA. 2007;104:13780–13785.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Arumugam M, Raes J, Pelletier E, et al. Enterotypes of the human gut microbiome. Nature. 2011;473:174–180.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Hayashi H, Sakamoto M, Benno Y. Phylogenetic analysis of the human gut microbiota using 16s rDNA clone libraries and strictly anaerobic culture-based methods. Microbiol Immunol. 2002;46:535–548.

    Article  CAS  PubMed  Google Scholar 

  12. Lay C, Rigottier-Gois L, Holmstrom K, et al. Colonic microbiota signatures across five northern european countries. Appl Environ Microbiol. 2005;71:4153–4155.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Eckburg PB, Bik EM, Bernstein CN, et al. Diversity of the human intestinal microbial flora. Science (New York, NY). 2005;308:1635–1638.

    Article  Google Scholar 

  14. Gill SR, Pop M, DeBoy RT, et al. Metagenomic analysis of the human distal gut microbiome. Science (New York, NY). 2006;312:1355–1359.

    Article  CAS  Google Scholar 

  15. Wu GD, Chen J, Hoffmann C, et al. Linking long-term dietary patterns with gut microbial enterotypes. Science (New York, NY). 2011;334:105–108.

    Article  CAS  Google Scholar 

  16. Yatsunenko T, Rey FE, Manary MJ, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486:222–227.

    PubMed Central  CAS  PubMed  Google Scholar 

  17. Rajca S, Grondin V, Louis E, et al. Alterations in the intestinal microbiome (dysbiosis) as a predictor of relapse after infliximab withdrawal in Crohn’s disease. Inflamm Bowel Dis. 2014;20:978–986.

    PubMed  Google Scholar 

  18. Ott SJ, Musfeldt M, Wenderoth DF, et al. Reduction in diversity of the colonic mucosa associated bacterial microflora in patients with active inflammatory bowel disease. Gut. 2004;53:685–693.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Takaishi H, Matsuki T, Nakazawa A, et al. Imbalance in intestinal microflora constitution could be involved in the pathogenesis of inflammatory bowel disease. Int J Med Microbiol (IJMM). 2008;298:463–472.

    Article  CAS  Google Scholar 

  20. Schwiertz A, Jacobi M, Frick J-S, et al. Microbiota in pediatric inflammatory bowel disease. J Pediatr. 2010;157:240.e241–244.e241.

    Article  Google Scholar 

  21. Willing BP, Dicksved J, Halfvarson J, et al. A pyrosequencing study in twins shows that gastrointestinal microbial profiles vary with inflammatory bowel disease phenotypes. Gastroenterology. 2010;139:1844.e1841–1854.e1841.

    Article  Google Scholar 

  22. 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.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Wang Z, Klipfell E, Bennett BJ, et al. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature. 2011;472:57–63.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  24. Tang WH, Wang Z, Levison BS, et al. Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med. 2013;368:1575–1584.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  25. Ussher JR, Lopaschuk GD, Arduini A. Gut microbiota metabolism of l-carnitine and cardiovascular risk. Atherosclerosis. 2013;231:456–461.

    Article  CAS  PubMed  Google Scholar 

  26. Swann J, Richards S, Shen Q, et al. Culture-independent analysis of the human gut microbiota and their activities. New Jersey: Wiley; 2011.

    Book  Google Scholar 

  27. Krueger SK, Williams DE. Mammalian flavin-containing monooxygenases: structure/function, genetic polymorphisms and role in drug metabolism. Pharmacol Ther. 2005;106:357–387.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Cashman JR, Akerman BR, Forrest SM, et al. Population-specific polymorphisms of the human FMO3 gene: significance for detoxication. Drug Metab Dispos Biol Fate Chem. 2000;28:169–173.

    CAS  PubMed  Google Scholar 

  29. Treacy EP, Akerman BR, Chow LM, et al. Mutations of the flavin-containing monooxygenase gene (FMO3) cause trimethylaminuria, a defect in detoxication. Hum Mol Genet. 1998;7:839–845.

    Article  CAS  PubMed  Google Scholar 

  30. Zeisel SH, Wishnok JS, Blusztajn JK. Formation of methylamines from ingested choline and lecithin. J Pharmacol Exp Therap. 1983;225:320–324.

    CAS  Google Scholar 

  31. Craciun S, Balskus EP. Microbial conversion of choline to trimethylamine requires a glycyl radical enzyme. Proc Natl Acad Sci. 2012;109:21307–21312.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Katz R. Biomarkers and surrogate markers: an FDA perspective. NeuroRx. 2004;1:189–195.

    Article  PubMed Central  PubMed  Google Scholar 

  33. Parikh NI, Vasan RS. Assessing the clinical utility of biomarkers in medicine. Biomark Med. 2007;1:419–436.

    Article  CAS  PubMed  Google Scholar 

  34. Wang Z, Levison B, Hazen JE, Donahue L, Li X, Hazen SL. Measurement of trimethylamine-n-oxide by stable isotope dilution liquid chromatography tandem mass spectrometry. Anal Biochem. 2014;455:35–40.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Stein J, Schröder O, Milovic V, et al. Mercaptopropionate inhibits butyrate uptake in isolated apical membrane vesicles of the rat distal colon. Gastroenterology. 1995;108:673–679.

    Article  CAS  PubMed  Google Scholar 

  36. Stein J, Zores M, Schröder O. Short-chain fatty acid (SCFA) uptake into caco-2 cells by a pH-dependent and carrier mediated transport mechanism. Eur J Nutr. 2000;39:121–125.

    Article  CAS  PubMed  Google Scholar 

  37. Schröder O, Opritz J, Stein J. Substrate and inhibitor specificity of butyrate uptake in apical membrane vesicles of the rat distal colon. Digestion. 2000;62:152–158.

    Article  PubMed  Google Scholar 

  38. Harvey RF, Bradshaw JM. A simple index of Crohn’s-disease activity. Lancet. 1980;1:514.

    Article  CAS  PubMed  Google Scholar 

  39. Walmsley RS, Ayres RC, Pounder RE, et al. A simple clinical colitis activity index. Gut. 1998;43:29–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. R Core Team. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2014. Retrieved from http://www.R-project.org.

  41. Pinheiro J, Bates D, DebRoy S, Sarkar D, R Core Team. Nlme: linear and nonlinear mixed effects models. R package version 3.1-117. Vienna, Austria: R Foundation for Statistical Computing; 2014. Retrieved from http://CRAN.R-project.org/package=nlme.

  42. von Elm E, Altman DG, Egger M, et al. Strobe initiative. The strengthening the reporting of observational studies in epidemiology (strobe)statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61:344–349.

    Article  Google Scholar 

  43. Patel N, Alkhouri N, Eng K, et al. Metabolomic analysis of breath volatile organic compounds reveals unique breathprints in children with inflammatory bowel disease: a pilot study. Aliment Pharmacol Ther. 2014;40:498–507.

    PubMed Central  CAS  PubMed  Google Scholar 

  44. Kostic AD, Xavier RJ, Gevers D. The microbiome in inflammatory bowel disease: current status and the future ahead. Gastroenterology. 2014;146:1489–1499.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Khor B, Gardet A, Xavier RJ. Genetics and pathogenesis of inflammatory bowel disease. Nature. 2011;474:307–317.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Morgan XC, Tickle TL, Sokol H, et al. Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol. 2012;13:R79.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Guarner F, Malagelada J-R. Gut flora in health and disease. Lancet. 2003;361:512–519.

    Article  PubMed  Google Scholar 

  48. Zheng X, Xie G, Zhao A, et al. The footprints of gut microbial–mammalian co-metabolism. J Proteome Res. 2011;10:5512–5522.

    Article  CAS  PubMed  Google Scholar 

  49. Sepehri S, Kotlowski R, Bernstein CN, et al. Microbial diversity of inflamed and noninflamed gut biopsy tissues in inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:675–683.

    Article  PubMed  Google Scholar 

  50. Kang S, Denman SE, Morrison M, et al. Dysbiosis of fecal microbiota in Crohn’s disease patients as revealed by a custom phylogenetic microarray. Inflamm Bowel Dis. 2010;16:2034–2042.

    Article  PubMed  Google Scholar 

  51. Manichanh C, Rigottier-Gois L, Bonnaud E, et al. Reduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach. Gut. 2006;55:205–211.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  52. Dawiskiba T, Deja S, Mulak A, et al. Serum and urine metabolomic fingerprinting in diagnostics of inflammatory bowel diseases. World J Gastroenterol (WJG). 2014;20:163–174.

    Article  CAS  Google Scholar 

  53. Dhurandhar NV, Schoeller D, Brown AW, et al. Energy balance measurement: when something is not better than nothing. Int J Obes (Lond). 2014. doi:10.1038/ijo.2014.199.

    Google Scholar 

  54. David LA, Maurice CF, Carmody RN, et al. Diet rapidly and reproducibly alters the human gut microbiome. Nature. 2014;505:559–563.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  55. Bennett BJ, de Aguiar Vallim TQ, Wang Z, et al. Trimethylamine-n-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013;17:49–60.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Miller CA, Corbin KD, da Costa KA, et al. Effect of egg ingestion on trimethylamine-n-oxide production in humans: a randomized, controlled, dose-response study. Am J Clin Nutr. 2014;100:778–786.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Chen Y, Patel NA, Crombie A, et al. Bacterial flavin-containing monooxygenase is trimethylamine monooxygenase. Proc Natl Acad Sci USA. 2011;108:17791–17796.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Berrill JW, Green JT, Hood K, et al. Symptoms of irritable bowel syndrome in patients with inflammatory bowel disease: examining the role of sub-clinical inflammation and the impact on clinical assessment of disease activity. Aliment Pharmacol Ther. 2013;38:44–51.

    Article  CAS  PubMed  Google Scholar 

  59. Burgmann T, Clara I, Graff L, et al. The manitoba inflammatory bowel disease cohort study: prolonged symptoms before diagnosis—how much is irritable bowel syndrome? Clin Gastroenterol Hepatol. 2006;4:614–620.

    Article  PubMed  Google Scholar 

  60. Zschocke J, Kohlmueller D, Quak E, et al. Mild trimethylaminuria caused by common variants in FMO3 gene. Lancet. 1999;354:834–835.

    CAS  PubMed  Google Scholar 

  61. Raimondi F, Santoro P, Barone MV, et al. Bile acids modulate tight junction structure and barrier function of Caco-2 monolayers via EGFR activation. Am J Physiol Gastrointest Liver Physiol. 2008;294:G906–G913.

    Article  CAS  PubMed  Google Scholar 

  62. Cipriani S, Mencarelli A, Chini MG, et al. The bile acid receptor GPBAR-1 (TGR5) modulates integrity of intestinal barrier and immune response to experimental colitis. PLoS ONE [Electronic Resource]. 2011;6:e25637.

    Article  CAS  Google Scholar 

  63. Gadaleta RM, van Erpecum KJ, Oldenburg B, et al. Farnesoid X receptor activation inhibits inflammation and preserves the intestinal barrier in inflammatory bowel disease. Gut. 2011;60:10.

    Article  Google Scholar 

  64. Attinkara R, Mwinyi J, Truninger K, et al. Association of genetic variation in the NR1H4 gene, encoding the nuclear bile acid receptor FXR, with inflammatory bowel disease. BMC Res Notes. 2012;5:12.

    Article  Google Scholar 

  65. Nijmeijer RM, Gadaleta RM, van Mil SW, et al. Farnesoid X receptor (FXR) activation and FXR genetic variation in inflammatory bowel disease. PLoS ONE [Electronic Resource]. 2011;6:e23745.

    Article  CAS  Google Scholar 

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Acknowledgments

We kindly thank all members of the Division of Gastroenterology, Department of Medicine at Western University and London Health Sciences Centre for their contribution to this study. This work was supported by the Wolfe Medical Research Chair in Pharmacogenomics (RBK) and the Canadian Institutes of Health Research (MOP-89753 to RBK) as well as the Drug Safety and Effectiveness Network (DSEN-PREVENT, FRN-117588 to RBK), and Cancer Care Ontario (CCO Research Chair Award (Tier-1) in Experimental Therapeutics to RBK).

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Correspondence to Richard B. Kim.

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Wilson, A., Teft, W.A., Morse, B.L. et al. Trimethylamine-N-oxide: A Novel Biomarker for the Identification of Inflammatory Bowel Disease. Dig Dis Sci 60, 3620–3630 (2015). https://doi.org/10.1007/s10620-015-3797-3

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