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



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


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.


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.


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.


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


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.


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)


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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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