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Plasma trimethylamine N-oxide concentration is associated with choline, phospholipids, and methyl metabolism
Open accessAbstract
Background Elevated plasma concentrations of the gut bacteria choline metabolite trimethylamine N-oxide (TMAO) are associated with atherosclerosis. However, the determinants of TMAO in humans require additional assessment.Objective We examined cardiometabolic risk factors and pathways associated with TMAO concentrations in humans.Design A total of 283 individuals (mean ± SD age: 66.7 ± 9.0 y) were included in this observational study. Plasma concentrations of trimethylamine, TMAO, choline, lipids, phospholipids, and methyl metabolites were measured.Results Study participants were divided into 4 groups by median concentrations of TMAO and choline (4.36 and 9.7 μmol/L, respectively). Compared with the group with TMAO and choline concentrations that were less than the median (n = 82), the group with TMAO and choline concentrations that were at least the median (n = 83) was older and had lower high-density lipoprotein (HDL) cholesterol, phospholipids, and methylation potential, higher creatinine, betaine, S-adenosylhomocysteine (SAH), and S-adenosylmethionine (SAM), and higher percentages of men and subjects with diabetes. The difference in plasma TMAO concentrations between men and women (7.3 ± 10.0 compared with 5.4 ± 5.6 μmol/L, respectively) was NS after adjustment for age and creatinine (P = 0.455). The TMAO:trimethylamine ratio was higher in men (P < 0.001). Diabetes was associated with significantly higher plasma TMAO concentration (8.6 ± 12.2 compared with 5.4 ± 5.2 μmol/L) even after adjustments. Sex and diabetes showed an interactive effect on trimethylamine concentrations (P = 0.010) but not on TMAO concentrations (P = 0.950). Positive determinants of TMAO in a stepwise regression model that applied to the whole group were SAH, trimethylamine, choline, and female sex, whereas plasma phosphatidylcholine was a negative determinant.Conclusions High TMAO and choline concentrations are associated with an advanced cardiometabolic risk profile. Diabetes is related to higher plasma TMAO concentrations but also to alterations in interrelated pathways such as lipids, phospholipids, and methylation. Elevated plasma TMAO concentrations likely reflect a specific metabolic pattern characterized by low HDL and phospholipids in addition to hypomethylation. This trial was registered at clinicaltrials.gov as NCT02586181 and NCT02588898.
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“In fact, a large study reported that women have less TMAO formation than do men (89).”
From Trimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease (2017) · cites this paper as [89]
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Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., Feldstein, A. E., Britt, E. B., Fu, X., Chung, Y.-M., et al. (2011) · Nature · doi:10.1038/nature09922 · Cited by 5,597
Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis
Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., Britt, E. B., Fu, X., Wu, Y., Li, L., et al. (2013) · Nature Medicine · doi:10.1038/nm.3145 · Cited by 4,386
Interactions Between the Microbiota and the Immune System
Hooper, L. V., Littman, D. R., & Macpherson, A. J. (2012) · Science · doi:10.1126/science.1223490 · Cited by 4,173
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk
Tang, W. H. W., Wang, Z., Levison, B. S., Koeth, R. A., Britt, E. B., Fu, X., Wu, Y., & Hazen, S. L. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1109400 · Cited by 3,400
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Choline: an essential nutrient for public health
Zeisel, S. H., & da Costa, K.-A. (2009) · Nutrition Reviews · doi:10.1111/j.1753-4887.2009.00246.x · Cited by 1,062
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Janeiro, M., Ramírez, M., Milagro, F., Martínez, J., & Solas, M. (2018) · Nutrients · doi:10.3390/nu10101398 · Cited by 631
“Another study demonstrated that high plasma TMAO concentrations may reflect a specific metabolic pattern characterized by hypomethylation and low HDL and phospholipids [45,46] (Table 1).”
BackgroundTrimethylamine N -Oxide, the Microbiome, and Heart and Kidney Disease
Zeisel, S. H., & Warrier, M. (2017) · Annual Review of Nutrition · doi:10.1146/annurev-nutr-071816-064732 · Cited by 475
Trimethylamine N-Oxide Binds and Activates PERK to Promote Metabolic Dysfunction
Chen, S., Henderson, A., Petriello, M. C., Romano, K. A., Gearing, M., Miao, J., Schell, M., Sandoval-Espinola, W. J., Tao, J., Sha, B., et al. (2019) · Cell Metabolism · doi:10.1016/j.cmet.2019.08.021 · Cited by 427
Fennema, D., Phillips, I. R., & Shephard, E. A. (2016) · Drug Metabolism and Disposition · doi:10.1124/dmd.116.070615 · Cited by 355
Wang, R., Li, B., Lam, S. M., & Shui, G. (2019) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2019.11.009 · Cited by 346
Metadata
- Authors
- Obeid, R., Awwad, H. M., Rabagny, Y., Graeber, S., Herrmann, W., & Geisel, J.
- Affiliations
- Aarhus University (DK)
- Universitätsklinikum des Saarlandes (DE)
- Saarland University (DE)
- Corresponding author
- Obeid, Rima
- Venue
- The American Journal of Clinical Nutrition
- Publisher
- Elsevier BV
- Published
- 2016-03
- Volume
- 103
- Issue
- 3
- Pages
- 703-711
- ISSN
- 0002-9165 (ISSN-L)
- OpenAlex
- W2254612738
- Cited by
- 117
- References
- 43
- Citations by year
- 2026: 5 · 2025: 7 · 2024: 3 · 2023: 10 · 2022: 14 · 2021: 11 · 2020: 12 · 2019: 18 · 2018: 14 · 2017: 13 · 2016: 10
- FWCI
- 9.53
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- American Journal of Clinical Nutrition (publishedVersion)
- PubMed (publishedVersion)
- Funders
- German Research Foundation (63813068)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Nursing › Nutrition and Dietetics › Folate and B Vitamins Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolomics and Mass Spectrometry Studies
- Keywords
- trimethylamine N-oxide, trimethylamine, choline, phospholipids, phosphatidylcholine, S-adenosylhomocysteine, S-adenosylmethionine, betaine, HDL cholesterol, diabetes mellitus, sex differences, cardiometabolic risk, gut microbiota, atherosclerosis, creatinine
- MeSH terms
- Gastrointestinal Microbiome, Aged, Bacteria, Betaine, Cardiovascular Diseases, Choline, Creatinine, Diabetes Mellitus, Female, Humans, Lipoproteins, HDL, Male, Methylamines, Methylation, Middle Aged, Phosphatidylcholines, Phospholipids, S-Adenosylhomocysteine, S-Adenosylmethionine, Sex Factors
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