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Evaluation of potential metabolomic-based biomarkers of protein, carbohydrate and fat intakes using a controlled feeding study

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Abstract

Purpose

Objective biomarkers of dietary exposure are needed to establish reliable diet-disease associations. Unfortunately, robust biomarkers of macronutrient intakes are scarce. We aimed to assess the utility of serum, 24-h urine and spot urine high-dimensional metabolites for the development of biomarkers of daily intake of total energy, protein, carbohydrate and fat, and the percent of energy from these macronutrients (%E).

Methods

A 2-week controlled feeding study mimicking the participants’ habitual diets was conducted among 153 postmenopausal women from the Women’s Health Initiative (WHI). Fasting serum metabolomic profiles were analyzed using a targeted liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay for aqueous metabolites and a direct-injection-based quantitative lipidomics platform. Urinary metabolites were analyzed using 1H nuclear magnetic resonance (NMR) spectroscopy at 800 MHz and by untargeted gas chromatography–mass spectrometry (GC–MS). Variable selection was performed to build prediction models for each dietary variable.

Results

The highest cross-validated multiple correlation coefficients (CV-R2) for protein intake (%E) and carbohydrate intake (%E) using metabolites only were 36.3 and 37.1%, respectively. With the addition of established dietary biomarkers (doubly labeled water for energy and urinary nitrogen for protein), the CV-R2 reached 55.5% for energy (kcal/d), 52.0 and 45.0% for protein (g/d, %E), 55.9 and 37.0% for carbohydrate (g/d, %E).

Conclusion

Selected panels of serum and urine metabolites, without the inclusion of doubly labeled water and urinary nitrogen biomarkers, give a reliable and robust prediction of daily intake of energy from protein and carbohydrate.

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Availability of data and materials

Data used in this study will not be publicly available. Formal request via the Women’s Health Initiative is needed to get access the data.

Code availability

R code used in this study will not be publicly available. Please request code access via email.

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Acknowledgements

The authors acknowledge the following investigators in the WHI Program:

Program Office: (National Heart, Lung, and Blood Institute, Bethesda, Maryland) Jacques Rossouw, Shari Ludlam, Joan McGowan, Leslie Ford, and Nancy Geller

Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg

Investigators and Academic Centers: (Brigham and Women's Hospital, Harvard Medical School, Boston, MA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA) Jennifer Robinson; (University of Pittsburgh, Pittsburgh, PA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC) Sally Shumaker; (University of Nevada, Reno, NV) Robert Brunner

Women’s Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC) Mark Espeland

For a list of all the investigators who have contributed to WHI science, please visit: https://www-whi-org.s3.us-west-2.amazonaws.com/wp-content/uploads/WHI-Investigator-Long-List.pdf

Funding

This work was supported by National Cancer Institute grant R01 CA119171 and Office of Research Infrastructure Programs grant S10 OD021562. The Women’s Health Initiative (WHI) is supported by the National Heart, Lung, and Blood Institute, NIH, US Department of Health and Human Services through contracts HHSN268201600046C (Fred Hutchinson Cancer Research Center), HHSN268201600001C (State University of New York, Buffalo), HHSN268201600002C (The Ohio State University), HHSN268201600003C (Stanford University), HHSN268201600004C (Wake Forest University), and HHSN271201600004C (WHI Memory Study) and grants P30 CA015704 and P30 CA023074.

Author information

Authors and Affiliations

  1. Department of Biostatistics, University of Nebraska Medical Center, Omaha, NE, USA

    Cheng Zheng

  2. Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA

    G. A. Nagana Gowda, Daniel Raftery, Lisa Bettcher, Robert Pepin, Danijel Djukovic, Haiwei Gu & Gregory A. Barding Jr.

  3. Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    Daniel Raftery, Marian L. Neuhouser, Lesley F. Tinker, Ross L. Prentice, Shirley A. A. Beresford, Xiaoling Song & Johanna W. Lampe

  4. Department of Epidemiology, University of Washington, Seattle, WA, USA

    Shirley A. A. Beresford

  5. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA

    Yiwen Zhang

Authors
  1. Cheng Zheng
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  2. G. A. Nagana Gowda
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  7. Shirley A. A. Beresford
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  9. Lisa Bettcher
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  10. Robert Pepin
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  14. Xiaoling Song
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  15. Johanna W. Lampe
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Contributions

The authors’ responsibilities were as follows: CZ, DR, MLN, LFT, RLP, SAAB, and JWL: designed the research; MLN, LFT, RLP, JWL: conducted the feeding study; GANG, DR, DD, HG, RP, LB, GAB, XS: collected metabolite and biospecimen data; CZ and YZ: performed statistical analysis; CZ, GANG, DR, JWL: led the manuscript drafting; MLN, LFT, SAAB and RLP: provided critical review; JWL: had primary responsibility for the final content; and all authors: read and approved the final manuscript.

Corresponding author

Correspondence to Johanna W. Lampe.

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Conflicts of interest

None of the authors reported a conflict of interest related to the study.

Ethics approval

The study was approved by the IRB of Fred Hutchinson Cancer Research Center.

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Consent to participate in research has been obtained.

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Zheng, C., Gowda, G.A.N., Raftery, D. et al. Evaluation of potential metabolomic-based biomarkers of protein, carbohydrate and fat intakes using a controlled feeding study . Eur J Nutr 60, 4207–4218 (2021). https://doi.org/10.1007/s00394-021-02577-1

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  • DOI: https://doi.org/10.1007/s00394-021-02577-1

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