The Carnitine-butyrobetaine-trimethylamine-N-oxide pathway and its association with cardiovascular mortality in patients with carotid atherosclerosis
Open accessAbstract
Background and purpose γ-butyrobetaine (γBB) is a metabolite from dietary Carnitine, involved in the gut microbiota-dependent conversion from Carnitine to the pro-atherogenic metabolite trimethylamine-N-oxide (TMAO). Orally ingested γBB has a pro-atherogenic effect in experimental studies, but γBB has not been studied in relation to atherosclerosis in humans. The aim of this study was to evaluate associations between serum levels of γBB, TMAO and their common precursors Carnitine and trimethyllysine (TML) and carotid atherosclerosis and adverse outcome.Methods Serum γBB, Carnitine, TML and TMAO were quantified by high performance liquid chromatography in patients with carotid artery atherosclerosis (n = 264) and healthy controls (n = 62).Results Serum γBB (p = 0.024) and Carnitine (p = 0.001), but not TMAO or TML, were increased in patients with carotid atherosclerosis. Higher levels of γBB and TML, but not TMAO or Carnitine were independently associated with cardiovascular death also after adjustment for age and eGFR (adjusted HR [95%] 3.3 [1.9-9.1], p = 0.047 and 6.0 [1.8-20.34], p = 0.026, respectively).Conclusions Patients with carotid atherosclerosis had increased serum levels of γBB, and elevated levels of γBB and its precursor TML were associated with cardiovascular mortality. Long-term clinical studies of γBB, as a cardiovascular risk marker, and safety studies regarding dietary supplementation of γBB, are warranted.
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Another 3 studies did not show a significantly elevated RR when TMAO was analyzed as a continuous variable in model.
“Also, another 3 studies did not show a significantly elevated RR when TMAO was analyzed as a continuous variable in model.10, 14, 17”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [17]
Median TMAO concentrations in healthy individuals were reported as ranges of 3 to 6 μmol/L.
“Nonetheless, median values of TMAO concentrations in healthy individuals were reported as ranges of 3 to 6 μmol/L,8, 17, 18, 19 and the study by Shafi et al22 consisted of hemodialysis patients with the substantially high mean vale of TMAO (101.9 μmol/L among total participants).”
From Gut Microbiota Metabolites and Risk of Major Adverse Cardiovascular Disease Events and Death: A Systematic Review and Meta‐Analysis of Prospective Studies (2017) · cites this paper as [17]
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- Authors
- Skagen, K., Trøseid, M., Ueland, T., Holm, S., Abbas, A., Gregersen, I., Kummen, M., Bjerkeli, V., Reier-Nilsen, F., Russell, D., Svardal, A., Karlsen, T. H., Aukrust, P., Berge, R. K., Hov, J. E. R., Halvorsen, B., & Skjelland, M.
- Affiliations
- Oslo University Hospital (NO)
- University of Oslo (NO)
- Akershus University Hospital (NO)
- University of Bergen (NO)
- Haukeland University Hospital (NO)
- Corresponding author
- Skagen, Karolina
- ORCID
- Venue
- Atherosclerosis
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 247
- Pages
- 64-69
- ISSN
- 0021-9150 (ISSN-L)
- OpenAlex
- W2257321757
- Cited by
- 139
- References
- 4
- Citations by year
- 2026: 2 · 2025: 9 · 2024: 8 · 2023: 12 · 2022: 26 · 2021: 19 · 2020: 18 · 2019: 13 · 2018: 14 · 2017: 8 · 2016: 9
- FWCI
- 7.62
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Atherosclerosis (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Servier
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Keywords
- gamma-butyrobetaine, trimethylamine N-oxide, L-carnitine, trimethyllysine, carotid atherosclerosis, cardiovascular mortality, gut microbiota, cardiovascular risk markers, supplement safety
- MeSH terms
- Aged, Betaine, Carnitine, Cause of Death, Chromatography, High Pressure Liquid, Female, Humans, Lysine, Male, Methylamines, Middle Aged, Myocardial Infarction, Prognosis, Risk Factors, Severity of Illness Index, Biomarkers, Proportional Hazards Models, Case-Control Studies, Carotid Stenosis, Risk Assessment, Ultrasonography, Doppler, Color, Stroke, Kaplan-Meier Estimate
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