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Original research
Interplay between diet and gut microbiome, and circulating concentrations of trimethylamine N-oxide: findings from a longitudinal cohort of US men
  1. Jun Li1,2,
  2. Yanping Li1,
  3. Kerry L Ivey1,3,
  4. Dong D Wang1,4,
  5. Jeremy E Wilkinson5,
  6. Adrian Franke6,
  7. Kyu Ha Lee1,2,5,
  8. Andrew Chan7,8,
  9. Curtis Huttenhower5,8,9,
  10. Frank B Hu1,2,4,
  11. Eric B Rimm1,2,4,
  12. Qi Sun1,2,4
  1. 1Nutrition, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
  2. 2Epidemiology, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
  3. 3Department of Nutrition and Dietetics, Flinders University College of Nursing and Health Sciences, Adelaide, South Australia, Australia
  4. 4Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA
  5. 5Biostatistics, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
  6. 6Analytical Biochemistry Shared Resource, University of Hawai'i Cancer Center, Honolulu, Hawaii, USA
  7. 7Clinical and Translational Epidemiology Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
  8. 8Immunology and Infectious Diseases, Harvard University T H Chan School of Public Health, Boston, Massachusetts, USA
  9. 9Eli and Edythe L. Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
  1. Correspondence to Dr Qi Sun, Department of Nutrition, Harvard University T H Chan School of Public Health, Boston, MA 02115, USA; qisun{at}hsph.harvard.edu

Abstract

Objectives Gut-produced trimethylamine N-oxide (TMAO) is postulated as a possible link between red meat intake and poor cardiometabolic health. We investigated whether gut microbiome could modify associations of dietary precursors with TMAO concentrations and cardiometabolic risk markers among free-living individuals.

Design We collected up to two pairs of faecal samples (n=925) and two blood samples (n=473), 6 months apart, from 307 healthy men in the Men’s Lifestyle Validation Study. Diet was assessed repeatedly using food-frequency questionnaires and diet records. We profiled faecal metagenome and metatranscriptome using shotgun sequencing and identified microbial taxonomic and functional features.

Results TMAO concentrations were associated with the overall microbial compositions (permutational analysis of variance (PERMANOVA) test p=0.001). Multivariable taxa-wide association analysis identified 10 bacterial species whose abundance was significantly associated with plasma TMAO concentrations (false discovery rate <0.05). Higher habitual intake of red meat and choline was significantly associated with higher TMAO concentrations among participants who were microbial TMAO-producers (p<0.05), as characterised based on four abundant TMAO-predicting species, but not among other participants (for red meat, P-interaction=0.003; for choline, P-interaction=0.03). Among abundant TMAO-predicting species, Alistipes shahii significantly strengthened the positive association between red meat intake and HbA1c levels (P-interaction=0.01). Secondary analyses revealed that some functional features, including choline trimethylamine-lyase activating enzymes, were associated with TMAO concentrations.

Conclusion We identified microbial taxa that were associated with TMAO concentrations and modified the associations of red meat intake with TMAO concentrations and cardiometabolic risk markers. Our data underscore the interplay between diet and gut microbiome in producing potentially bioactive metabolites that may modulate cardiometabolic health.

  • intestinal microbiology
  • cardiovascular disease
  • diet
  • epidemiology
  • nutrition

Data availability statement

Data are available upon reasonable request. Sequence data have been deposited in the Sequence Read Archive under BioProject ID: PRJNA354235. De-identified phenotype data from the MLVS (demographic, clinical, diet, and biomarkers) and from the Health Professionals Follow-up Study (HPFS), can be obtained through written application. According to standard controlled access procedure, applications to use HPFS resources will be reviewed by our External Collaborators Committee for scientific aims, evaluation of the fit of the data for the proposed methodology, and verification that the proposed use meets the guidelines of the Ethics and Governance Framework and the consent that was provided by the participants. Investigators wishing to use HFPS or MLVS data are asked to submit a brief (two pages) description of the proposed project (’letter of intent’) to E.B.R. (HPFS Director; erimm@hsph.harvard.edu).

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Data availability statement

Data are available upon reasonable request. Sequence data have been deposited in the Sequence Read Archive under BioProject ID: PRJNA354235. De-identified phenotype data from the MLVS (demographic, clinical, diet, and biomarkers) and from the Health Professionals Follow-up Study (HPFS), can be obtained through written application. According to standard controlled access procedure, applications to use HPFS resources will be reviewed by our External Collaborators Committee for scientific aims, evaluation of the fit of the data for the proposed methodology, and verification that the proposed use meets the guidelines of the Ethics and Governance Framework and the consent that was provided by the participants. Investigators wishing to use HFPS or MLVS data are asked to submit a brief (two pages) description of the proposed project (’letter of intent’) to E.B.R. (HPFS Director; erimm@hsph.harvard.edu).

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Footnotes

  • EBR and QS contributed equally.

  • Contributors JL, EBR and QS designed the study. EBR, QS, FH, AC and CH obtained funding. EBR, QS, AC, CH, JEW, AF, KLI collected biospecimen and collected/generated the data. JL and YL conducted and reviewed the data analyses. JL drafted the manuscript. JL, YL, CH, EBR and QS interpreted the data and provided critically important revisions to the manuscripts. All authors revised the manuscripts, approved the final version of the manuscript, and the submission of the manuscript to your journal.

  • Funding This study is supported by research grant R01HL035464 from the National Heart, Lung, and Blood Institute (NHLBI), and DK119268 and DK126698 from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). The Men’s Lifestyle Validation Study was supported by U01CA152904 from the National Cancer Institute (NCI). The Health Professionals Follow-Up Study is supported by U01CA167552 from NCI and R01HL35464 from NHLBI. Studies of nutrition and diet in these cohorts are supported by DK120870 from NIDDK and HL060712 from NHLBI. JL is supported by K99DK122128 from NIDDK and the NIDDK-funded (P30DK046200) Boston Nutrition Obesity Research Centre.

  • Disclaimer The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and the decision to submit the manuscript for publication.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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