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TMAO, creatine and 1-methylhistidine in serum and urine are potential biomarkers of cod and salmon intake: a randomised clinical trial in adults with overweight or obesity

  • Ingrid V. Hagen
  • Anita Helland
  • Marianne Bratlie
  • Øivind Midttun
  • Adrian McCann
  • Harald Sveier
  • Grethe Rosenlund
  • Gunnar Mellgren
  • Per Magne Ueland
  • Oddrun Anita GudbrandsenEmail author
Original Contribution
  • 53 Downloads

Abstract

Purpose

To identify biomarkers to assess participants’ compliance in an intervention study with high intake of cod or salmon, compared to a fish-free diet.

Methods

In this randomised clinical trial, 62 healthy overweight/obese participants consumed 750 g/week of either cod (N = 21) or salmon (N = 22) across 5 weekly dinners, or were instructed to continue their normal eating habits but avoid fish intake (Control group, N = 19) for 8 weeks.

Results

After cod intake, serum concentrations of trimethylamine N-oxide (TMAO, p = 0.0043), creatine (p = 0.024) and 1-methylhistidine (1-MeHis, p = 0.014), and urine concentrations (relative to creatinine) of TMAO (p = 2.8 × 10−5), creatine (p = 8.3 × 10−4) and 1-MeHis (p = 0.016) were increased when compared to Control group. After salmon intake, serum concentrations of 1-MeHis (p = 2.0 × 10−6) and creatine (p = 6.1 × 10−4), and urine concentrations (relative to creatinine) of 1-MeHis (p = 4.2 × 10−6) and creatine (p = 4.0 × 10−5) were increased when compared to Control group. Serum and urine concentrations of TMAO were more increased following cod intake compared to salmon intake (p = 0.028 and 2.9 × 10−4, respectively), and serum and urine 1-MeHis concentrations were more increased after salmon intake compared to cod intake (p = 8.7 × 10−5 and 1.2 × 10−4, respectively). Cod and salmon intake did not affect serum and urine concentrations of 3-methylhistidine, and only marginally affected concentrations of free amino acids and amino acid metabolites.

Conclusion

TMAO measured in serum or urine is a potential biomarker of cod intake, and 1-MeHis measured in serum or urine is a potential biomarker of salmon intake.

Keywords

Cod Salmon TMAO Creatine 1-Methylhistidine 3-Methylhistidine Amino acids 

Notes

Author contributions

HS, GR, GM and OAG formulated the research question and designed the study. IVH, AH, MB and OAG conducted the clinical study. ØM, AM, PMU and OAG analysed the data and performed statistical analyses. OAG drafted the paper and had primary responsibility for the final content. All authors have contributed to the writing and approved the final manuscript. We thank all participants who have contributed to the current study. The kind contribution of fish for the intervention trial by Lerøy Seafood Group ASA (Bergen, Norway) is highly appreciated.

Funding

The present research has been supported by funding from the Bergen Medical Research Foundation. The sponsor was not involved in the design of the study, data collection, analysis and interpretation of data, writing of the article or in the decision to submit the article for publication.

Compliance with ethical standards

Conflict of interest

HS and GR are employed in Skretting Aquaculture Research Centre AS and Lerøy Seafood Group ASA, respectively. Skretting Aquaculture Research Centre AS is a global leader in providing innovative and sustainable nutritional solutions for the aquaculture industry. Lerøy Seafood Group ASA is the leading exporter of seafood from Norway and the world’s second largest producer of Atlantic salmon. Skretting Aquaculture Research Centre AS and Lerøy Seafood Group ASA were not involved in on-site data collection. The other authors declare no conflicts of interest.

Supplementary material

394_2019_2076_MOESM1_ESM.docx (59 kb)
Supplementary material 1 (DOCX 59 kb)

References

  1. 1.
    Zheng J, Huang T, Yu Y, Hu X, Yang B, Li D (2012) Fish consumption and CHD mortality: an updated meta-analysis of seventeen cohort studies. Public Health Nutr 15:725–737CrossRefGoogle Scholar
  2. 2.
    Virtanen JK, Mozaffarian D, Chiuve SE, Rimm EB (2008) Fish consumption and risk of major chronic disease in men. Am J Clin Nutr 88:1618–1625CrossRefGoogle Scholar
  3. 3.
    Nkondjock A, Receveur O (2003) Fish-seafood consumption, obesity, and risk of type 2 diabetes: an ecological study. Diabetes Metab 29:635–642. https://www.em-consulte.com/article/80269/alertePM
  4. 4.
    Alhassan A, Young J, Lean MEJ, Lara J (2017) Consumption of fish and vascular risk factors: a systematic review and meta-analysis of intervention studies. Atherosclerosis 266:87–94CrossRefGoogle Scholar
  5. 5.
    Feskens EJ, Bowles CH, Kromhout D (1991) Inverse association between fish intake and risk of glucose intolerance in normoglycemic elderly men and women. Diabetes Care 14:935–941CrossRefGoogle Scholar
  6. 6.
    Whelton SP, He J, Whelton PK, Muntner P (2004) Meta-analysis of observational studies on fish intake and coronary heart disease. Am J Cardiol 93:1119–1123CrossRefGoogle Scholar
  7. 7.
    Kromhout D, Bosschieter EB, de Lezenne Coulander C (1985) The inverse relation between fish consumption and 20-year mortality from coronary heart disease. N Engl J Med 312:1205–1209CrossRefGoogle Scholar
  8. 8.
    Djousse L, Akinkuolie AO, Wu JH, Ding EL, Gaziano JM (2012) Fish consumption, omega-3 fatty acids and risk of heart failure: a meta-analysis. Clin Nutr 31:846–853CrossRefGoogle Scholar
  9. 9.
    He K, Song Y, Daviglus ML, Liu K, Van Horn L, Dyer AR, Goldbourt U, Greenland P (2004) Fish consumption and incidence of stroke: a meta-analysis of cohort studies. Stroke 35:1538–1542CrossRefGoogle Scholar
  10. 10.
    He K, Song Y, Daviglus ML, Liu K, Van Horn L, Dyer AR, Greenland P (2004) Accumulated evidence on fish consumption and coronary heart disease mortality: a meta-analysis of cohort studies. Circulation 109:2705–2711CrossRefGoogle Scholar
  11. 11.
    Patel PS, Forouhi NG, Kuijsten A, Schulze MB, van Woudenbergh GJ, Ardanaz E, Amiano P, Arriola L, Balkau B, Barricarte A, Beulens JW, Boeing H, Buijsse B, Crowe FL, de Lauzon-Guillan B, Fagherazzi G, Franks PW, Gonzalez C, Grioni S, Halkjaer J, Huerta JM, Key TJ, Kuhn T, Masala G, Nilsson P, Overvad K, Panico S, Quiros JR, Rolandsson O, Sacerdote C, Sanchez MJ, Schmidt EB, Slimani N, Spijkerman AM, Teucher B, Tjonneland A, Tormo MJ, Tumino R, der van AD, van der Schow YT, Sharp SJ, Langenberg C, Feskens EJ, Riboli E, Wareham NJ (2012) The prospective association between total and type of fish intake and type 2 diabetes in 8 European countries: EPIC-InterAct Study. Am J Clin Nutr 95:1445–1453CrossRefGoogle Scholar
  12. 12.
    van Woudenbergh GJ, van Ballegooijen AJ, Kuijsten A, Sijbrands EJ, van Rooij FJ, Geleijnse JM, Hofman A, Witteman JC, Feskens EJ (2009) Eating fish and risk of type 2 diabetes: a population-based, prospective follow-up study. Diabetes Care 32:2021–2026CrossRefGoogle Scholar
  13. 13.
    Schulze MB, Manson JE, Willett WC, Hu FB (2003) Processed meat intake and incidence of Type 2 diabetes in younger and middle-aged women. Diabetologia 46:1465–1473CrossRefGoogle Scholar
  14. 14.
    Ascherio A, Rimm EB, Giovannucci EL, Spiegelman D, Stampfer M, Willett WC (1996) Dietary fat and risk of coronary heart disease in men: cohort follow up study in the United States. BMJ 313:84–90CrossRefGoogle Scholar
  15. 15.
    Kaushik M, Mozaffarian D, Spiegelman D, Manson JE, Willett WC, Hu FB (2009) Long-chain omega-3 fatty acids, fish intake, and the risk of type 2 diabetes mellitus. Am J Clin Nutr 90:613–620CrossRefGoogle Scholar
  16. 16.
    Djousse L, Gaziano JM, Buring JE, Lee IM (2011) Dietary omega-3 fatty acids and fish consumption and risk of type 2 diabetes. Am J Clin Nutr 93:143–150CrossRefGoogle Scholar
  17. 17.
    Drotningsvik A, Midttun O, McCann A, Ueland PM, Hogoy I, Gudbrandsen OA (2018) Dietary intake of cod protein beneficially affects concentrations of urinary markers of kidney function and results in lower urinary loss of amino acids in obese Zucker fa/fa rats. Br J Nutr 120:740–750CrossRefGoogle Scholar
  18. 18.
    Drotningsvik A, Midttun O, Vikoren LA, McCann A, Ueland PM, Mellgren G, Gudbrandsen OA (2019) Urine and plasma concentrations of amino acids and plasma vitamin status differs, and are differently affected by salmon intake, in obese Zucker fa/fa rats with impaired kidney function and in Long-Evans rats with healthy kidneys. Br J Nutr.  https://doi.org/10.1017/S0007114519001284 Google Scholar
  19. 19.
    Yazdekhasti N, Brandsch C, Schmidt N, Schloesser A, Huebbe P, Rimbach G, Stangl GI (2016) Fish protein increases circulating levels of trimethylamine-N-oxide and accelerates aortic lesion formation in apoE null mice. Mol Nutr Food Res 60:358–368CrossRefGoogle Scholar
  20. 20.
    Schmedes M, Balderas C, Aadland EK, Jacques H, Lavigne C, Graff IE, Eng O, Holthe A, Mellgren G, Young JF, Sundekilde UK, Liaset B, Bertram HC (2018) The effect of lean-seafood and non-seafood diets on fasting and postprandial serum metabolites and lipid species: results from a randomized crossover intervention study in healthy adults. Nutrients 10:598–614CrossRefGoogle Scholar
  21. 21.
    Helland A, Bratlie M, Hagen IV, Mjos SA, Sornes S, Ingvar Halstensen A, Brokstad KA, Sveier H, Rosenlund G, Mellgren G, Gudbrandsen OA (2017) High intake of fatty fish, but not of lean fish, improved postprandial glucose regulation and increased the n-3 PUFA content in the leucocyte membrane in healthy overweight adults: a randomised trial. Br J Nutr 117:1368–1378CrossRefGoogle Scholar
  22. 22.
    Midttun O, Kvalheim G, Ueland PM (2013) High-throughput, low-volume, multianalyte quantification of plasma metabolites related to one-carbon metabolism using HPLC-MS/MS. Anal Bioanal Chem 405:2009–2017CrossRefGoogle Scholar
  23. 23.
    Midttun O, McCann A, Aarseth O, Krokeide M, Kvalheim G, Meyer K, Ueland PM (2016) Combined measurement of 6 fat-soluble vitamins and 26 water-soluble functional vitamin markers and amino acids in 50 muL of serum or plasma by high-throughput mass spectrometry. Anal Chem 88:10427–10436CrossRefGoogle Scholar
  24. 24.
    Midttun O, Hustad S, Ueland PM (2009) Quantitative profiling of biomarkers related to B-vitamin status, tryptophan metabolism and inflammation in human plasma by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 23:1371–1379CrossRefGoogle Scholar
  25. 25.
    Christman AA (1971) Determination of anserine, carnosine, and other histidine compounds in muscle extractives. Anal Biochem 39:181–187CrossRefGoogle Scholar
  26. 26.
    Bidlingmeyer BA, Cohen SA, Tarvin TL, Frost B (1987) A new, rapid, high-sensitivity analysis of amino acids in food type samples. J Assoc Off Anal Chem 70:241–247Google Scholar
  27. 27.
    Nitrogen. Determination in foods and feeds according to Kjeldahl. NMKL 2003; Method No. 6, 4. EdGoogle Scholar
  28. 28.
    Streiner DL (2015) Best (but oft-forgotten) practices: the multiple problems of multiplicity-whether and how to correct for many statistical tests. Am J Clin Nutr 102:721–728CrossRefGoogle Scholar
  29. 29.
    van Waarde A (1988) Biochemistry of non-protein nitrogenous compounds in fish including the use of amino acids for anaerobic energy production. Comp Biochem Physiol B Comp Biochem 91B:207–228CrossRefGoogle Scholar
  30. 30.
    Davey CL (1960) The significance of carnosine and anserine in striated skeletal muscle. Arch Biochem Biophys 89:303–308CrossRefGoogle Scholar
  31. 31.
    Crush KG (1970) Carnosine and related substances in animal tissues. Comp Biochem Physiol 34:3–30CrossRefGoogle Scholar
  32. 32.
    Sjolin J, Hjort G, Friman G, Hambraeus L (1987) Urinary excretion of 1-methylhistidine: a qualitative indicator of exogenous 3-methylhistidine and intake of meats from various sources. Metabolism 36:1175–1184CrossRefGoogle Scholar
  33. 33.
    Clark JF (1998) Creatine: a review of its nutritional applications in sport. Nutrition 14:322–324CrossRefGoogle Scholar
  34. 34.
    Dyer WJ (1952) Amines in fish muscle. VI. Trimethylamine oxide content of fish and marine invertebrates. J Fish Res Board Can 8:314–324.  https://doi.org/10.1139/f50-020 CrossRefGoogle Scholar
  35. 35.
    Cho CE, Taesuwan S, Malysheva OV, Bender E, Tulchinsky NF, Yan J, Sutter JL, Caudill MA (2017) Trimethylamine-N-oxide (TMAO) response to animal source foods varies among healthy young men and is influenced by their gut microbiota composition: A randomized controlled trial. Mol Nutr Food Res 61. http://www.ncbi.nlm.nih.gov/pubmed/27377678
  36. 36.
    Al-Waiz M, Mitchell SC, Idle JR, Smith RL (1987) The metabolism of 14C-labelled trimethylamine and its N-oxide in man. Xenobiotica 17:551–558CrossRefGoogle Scholar
  37. 37.
    Brosnan ME, Brosnan JT (2016) The role of dietary creatine. Amino Acids 48:1785–1791CrossRefGoogle Scholar
  38. 38.
    Abe H, Okuma E, Sekine H, Maeda A, Yoshiue S (1993) Human urinary excretion of l-histidine-related compounds after ingestion of several meats and fish muscle. Int J Biochem 25:1245–1249CrossRefGoogle Scholar
  39. 39.
    Marliss EB, Wei CN, Dietrich LL (1979) The short-term effects of protein intake on 3-methylhistidine excretion. Am J Clin Nutr 32:1617–1621CrossRefGoogle Scholar
  40. 40.
    Agustsson I, Strom AR (1981) Biosynthesis and turnover of trimethylamine oxide in the teleost cod, Gadus morhua. J Biol Chem 256:8045–8049Google Scholar
  41. 41.
    Baker JR, Struempler A, Chaykin S (1963) A comparative study of trimethylamine-N-oxide biosynthesis. Biochim Biophys Acta 71:58–64CrossRefGoogle Scholar
  42. 42.
    Fennema D, Phillips IR, Shephard EA (2016) Trimethylamine and trimethylamine N-oxide, a flavin-containing monooxygenase 3 (FMO3)-mediated host-microbiome metabolic axis implicated in health and disease. Drug Metab Dispos 44:1839–1850CrossRefGoogle Scholar
  43. 43.
    Li XS, Wang Z, Cajka T, Buffa JA, Nemet I, Hurd AG, Gu X, Skye SM, Roberts AB, Wu Y, Li L, Shahen CJ, Wagner MA, Hartiala JA, Kerby RL, Romano KA, Han Y, Obeid S, Luscher TF, Allayee H, Rey FE, DiDonato JA, Fiehn O, Tang WHW, Hazen SL (2018) Untargeted metabolomics identifies trimethyllysine, a TMAO-producing nutrient precursor, as a predictor of incident cardiovascular disease risk. JCI Insight 3. http://www.ncbi.nlm.nih.gov/pubmed/29563342
  44. 44.
    Zeisel SH, Warrier M (2017) Trimethylamine N-oxide, the microbiome, and heart and kidney disease. Annu Rev Nutr 37:157–181CrossRefGoogle Scholar
  45. 45.
    Abe H, Dobson GP, Hoeger U, Parkhouse WS (1985) Role of histidine-related compounds to intracellular buffering in fish skeletal muscle. Am J Physiol 249:R449–R454Google Scholar
  46. 46.
    USDA Food Composition Databases. https://ndb.nal.usda.gov/ndb/search/list. Accessed Sept 2016
  47. 47.
    Adeva-Andany M, Souto-Adeva G, Ameneiros-Rodriguez E, Fernandez-Fernandez C, Donapetry-Garcia C, Dominguez-Montero A (2018) Insulin resistance and glycine metabolism in humans. Amino Acids 50:11–27CrossRefGoogle Scholar
  48. 48.
    Vikoren LA, Drotningsvik A, Mwakimonga A, Leh S, Mellgren G, Gudbrandsen OA (2018) Diets containing salmon fillet delay development of high blood pressure and hyperfusion damage in kidneys in obese Zucker fa/fa rats. J Am Soc Hypertens 12:294–302CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Ingrid V. Hagen
    • 1
  • Anita Helland
    • 1
  • Marianne Bratlie
    • 1
  • Øivind Midttun
    • 2
  • Adrian McCann
    • 2
  • Harald Sveier
    • 3
  • Grethe Rosenlund
    • 4
  • Gunnar Mellgren
    • 5
    • 6
  • Per Magne Ueland
    • 2
  • Oddrun Anita Gudbrandsen
    • 1
    Email author
  1. 1.Dietary Protein Research Group, Department of Clinical MedicineUniversity of Bergen, Haukeland University HospitalBergenNorway
  2. 2.Bevital ASBergenNorway
  3. 3.Lerøy Seafood Group ASABergenNorway
  4. 4.Skretting Aquaculture Research Centre ASStavangerNorway
  5. 5.Mohn Nutrition Research Laboratory, Department of Clinical ScienceUniversity of Bergen, Haukeland University HospitalBergenNorway
  6. 6.Hormone LaboratoryHaukeland University HospitalBergenNorway

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