The DOI matches its Crossref record; 65 of the 65 references it cites were found in a registry or an index.
l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans
Open accessAbstract
BACKGROUND: l-Carnitine, an abundant nutrient in red meat, accelerates atherosclerosis in mice via gut microbiota-dependent formation of trimethylamine (TMA) and trimethylamine N-oxide (TMAO) via a multistep pathway involving an atherogenic intermediate, γ-butyrobetaine (γBB). The contribution of γBB in gut microbiota-dependent l-carnitine metabolism in humans is unknown. METHODS: Omnivores and vegans/vegetarians ingested deuterium-labeled l-carnitine (d3-l-carnitine) or γBB (d9-γBB), and both plasma metabolites and fecal polymicrobial transformations were examined at baseline, following oral antibiotics, or following chronic (≥2 months) l-carnitine supplementation. Human fecal commensals capable of performing each step of the l-carnitine→γBB→TMA transformation were identified. RESULTS: Studies with oral d3-l-carnitine or d9-γBB before versus after antibiotic exposure revealed gut microbiota contribution to the initial 2 steps in a metaorganismal l-carnitine→γBB→TMA→TMAO pathway in subjects. Moreover, a striking increase in d3-TMAO generation was observed in omnivores over vegans/vegetarians (>20-fold; P = 0.001) following oral d3-l-carnitine ingestion, whereas fasting endogenous plasma l-carnitine and γBB levels were similar in vegans/vegetarians (n = 32) versus omnivores (n = 40). Fecal metabolic transformation studies, and oral isotope tracer studies before versus after chronic l-carnitine supplementation, revealed that omnivores and vegans/vegetarians alike rapidly converted carnitine to γBB, whereas the second gut microbial transformation, γBB→TMA, was diet inducible (l-carnitine, omnivorous). Extensive anaerobic subculturing of human feces identified no single commensal capable of l-carnitine→TMA transformation, multiple community members that converted l-carnitine to γBB, and only 1 Clostridiales bacterium, Emergencia timonensis, that converted γBB to TMA. In coculture, E. timonensis promoted the complete l-carnitine→TMA transformation. CONCLUSION: In humans, dietary l-carnitine is converted into the atherosclerosis- and thrombosis-promoting metabolite TMAO via 2 sequential gut microbiota-dependent transformations: (a) initial rapid generation of the atherogenic intermediate γBB, followed by (b) transformation into TMA via low-abundance microbiota in omnivores, and to a markedly lower extent, in vegans/vegetarians. Gut microbiota γBB→TMA/TMAO transformation is induced by omnivorous dietary patterns and chronic l-carnitine exposure. TRIAL REGISTRATION: ClinicalTrials.gov NCT01731236. FUNDING: NIH and Office of Dietary Supplements grants HL103866, HL126827, and DK106000, and the Leducq Foundation.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Prior research42,43 has suggested that vegans have lower TMAO levels than meat or fish eaters because of the TMAO precursors choline and carnitine in animal products.”
From Cardiometabolic Effects of Omnivorous vs Vegan Diets in Identical Twins: A Randomized Clinical Trial (2023) · cites this paper as [42]
Experimental — accuracy not yet measuredIn the citing paper
“Interestingly, in small cross-sectional observational studies, plasma levels of TMAO were modestly increased in omnivores relative to vegans/vegetarians, and in recent clinical challenge studies, TMA and TMAO generation from oral carnitine was observed to be substantially reduced in vegans/vegetarians.3,19”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [19]
In the citing paper
“Some of these TMA containing compounds can participate in TMA/TMAO formation in a gut microbiota-dependent manner, and also be generated by gut microbiota metabolism of L-carnitine.1,3,16,19”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [19]
In the citing paper
“Beyond choline and carnitine, potential nutrient precursors for TMA production have been reported, including the carnitine related metabolites c-butyrobetaine and crotonobetaine, and the choline oxidation product betaine.1,16,19”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [19]
In the citing paper
“Interestingly, in small cross-sectional observational studies, plasma levels of TMAO were modestly increased in omnivores relative to vegans/vegetarians, and in recent clinical challenge studies, TMA and TMAO generation from oral carnitine was observed to be substantially reduced in vegans/vegetarians.3,19”
From Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women (2019) · cites this paper as [19]
In the citing paper
“The gut microbiota-derived metabolite TMAO has been linked to atherosclerotic heart disease in both mice and humans.185”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [185]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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
Self-citationIntestinal 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
Self-citationIntestinal 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
Self-citationDiet Drives Convergence in Gut Microbiome Functions Across Mammalian Phylogeny and Within Humans
Muegge, B. D., Kuczynski, J., Knights, D., Clemente, J. C., González, A., Fontana, L., Henrissat, B., Knight, R., & Gordon, J. I. (2011) · Science · doi:10.1126/science.1198719 · Cited by 1,988
Seng, P., Drancourt, M., Gouriet, F., La Scola, B., Fournier, P., Rolain, J. M., & Raoult, D. (2009) · Clinical Infectious Diseases · doi:10.1086/600885 · Cited by 1,983
Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk
Zhu, W., Gregory, J. C., Org, E., Buffa, J. A., Gupta, N., Wang, Z., Li, L., Fu, X., Wu, Y., Mehrabian, M., et al. (2016) · Cell · doi:10.1016/j.cell.2016.02.011 · Cited by 1,968
Self-citationCarnitine—metabolism and functions
Bremer, J. (1983) · Physiological Reviews · doi:10.1152/physrev.1983.63.4.1420 · Cited by 1,666
Wang, Z., Roberts, A. B., Buffa, J. A., Levison, B. S., Zhu, W., Org, E., Gu, X., Huang, Y., Zamanian-Daryoush, M., Culley, M. K., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.055 · Cited by 1,317
Self-citationTang, W. H. W., Wang, Z., Kennedy, D. J., Wu, Y., Buffa, J. A., Agatisa-Boyle, B., Li, X. S., Levison, B. S., & Hazen, S. L. (2015) · Circulation Research · doi:10.1161/circresaha.116.305360 · Cited by 1,223
Self-citationBennett, B. J., Vallim, T. Q. D. A., Wang, Z., Shih, D. M., Meng, Y., Gregory, J., Allayee, H., Lee, R., Graham, M., Crooke, R., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2012.12.011 · Cited by 1,070
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Items 301–327 of 327
Ferranti, E. P., Alvarez, J. A., & Christie, C. (2024) · Springer eBooks · doi:10.1007/978-3-031-53705-9_12
Kobelkova, I. V., & Korosteleva, M. M. (2024) · Sports medicine research and practice · doi:10.47529/2223-2524.2024.1.7
Messiha, D., Rinke, M., Amos, A. S. M., Tratnik, A., Hendgen-Cotta, U. B., Lortz, J., Hogrebe, K., Kehrmann, J., Buer, J., Rassaf, T., et al. (2025) · Dietetics · doi:10.3390/dietetics4010001
Yang, Q., Xu, S., Cai, Y., Pan, Y., Huang, J., Zhu, K., Chen, M., & Xu, X. (2025) · Cardiology Discovery · doi:10.1097/cd9.0000000000000153
Tsai, W., Peng, P., Jhou, P.-S., Tsai, Y., Hung, W., Lin, Y., Jhuo, S., Huang, T., Chou, L.-F., Lin, T., et al. (2026) · International Journal of Medical Sciences · doi:10.7150/ijms.126417
Tan, Z., Ding, C., Li, J., Cao, T., Liu, L., Song, Y., Chen, P., Zhang, Y., Li, J., Huo, Y., et al. (2024) · Precision Nutrition · doi:10.1097/pn9.0000000000000075
Cai, L., Liu, G.-Q., Zeng, C.-M., Xu, W., Jiang, R., & Chen, H. (2025) · Frontiers in Microbiology · doi:10.3389/fmicb.2025.1647668
Wu, W.-K., Panyod, S., Liu, P.-Y., Chen, C.-C., Kao, H.-L., Chuang, H.-L., Chen, Y.-H., Zou, H.-B., Kuo, H.-C., Kuo, C.-H., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13265669
Self-citationSteric and Electronic Effects in the Enzymatic Catalysis of Choline-TMA Lyase
Gogonea, V., & Hazen, S. L. (2025) · Biomolecules · doi:10.3390/biom16010037
Self-citationGupta, H., Kumari, P., & Singh, R. P. (2026) · Glycoscience & Therapy · doi:10.1016/j.glycos.2026.100029
Metabolic reprogramming in aortic diseases: insights from metabolomics and therapeutic opportunities
Liu, Y., Zhao, L., Zhang, C., Ruan, X., Yu, H., Cao, Y., Ju, W., & Lu, H. (2026) · Medical Review · doi:10.1515/mr-2026-0010
Xie, W., Han, D. K., Tan, J., Zhao, D., Dong, J., Wu, J., Yang, X., & Xie, S. (2026) · Frontiers in Microbiology · doi:10.3389/fmicb.2026.1786725
Qian, M.-X., Lu, Y., Zhang, R., Deng, X., Wu, Y.-N., Peng, R.-H., Bai, H., Yang, X.-C., Wang, J., Zhang, Q.-L., et al. (2026) · BMC Pregnancy and Childbirth · doi:10.1186/s12884-026-09166-2
Self-citationNakayama, N. (2026) · Springer eBooks · doi:10.1007/978-981-95-7797-2_9
Haarhuis, J. E., Ahn‐Jarvis, J. H., Savva, G. M., Day-Walsh, P. E., Ferns, C., Hughes, S., Triller, S., Al-Jaibaji, O., Philo, M., Acaröz, E., et al. (2026) · Frontiers in Nutrition · doi:10.3389/fnut.2026.1822840
Havers, T., Eggelbusch, M., Meinhold, M., Sing, K., Okrojek, R., Artati, A., Witting, M. A., Lutter, D., Kieker, C. V., Starke, C., et al. (2026) · Experimental Physiology · doi:10.1113/ep094096
Design and Therapeutic Applications of Hydrogel Dressings in Diverse Wound Management
Kong, W., Zhang, Y., Liang, H., & Yuan, H. (2026) · ACS Omega · doi:10.1021/acsomega.6c05049
Effect of a Vegetarian Diet on Cardiovascular Diseases
Chen, J., Shi, R., & Zheng, J. (2026) · Royal Society of Chemistry eBooks · doi:10.1039/9781837678907-00232
Stø, K., Skagen, K., Bjerkeli, V., Ueland, P. M., Hov, J. R., Trøseid, M., Aukrust, P., Ueland, T., Halvorsen, B. L., & Skjelland, M. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1796312
Metabolic regulation of the microbiome-dependent metabolites and cardiovascular function
Wang, Y., Shi, Y., Jin, L., & Ni, Y. (2026) · Elsevier eBooks · doi:10.1016/b978-0-443-34186-1.00023-2
From cooperation to collapse: the diet-microbiota-host gene triad in disease and aging
Bhattacharjee, S., & Mukhopadhyay, A. (2026) · Frontiers in Microbiomes · doi:10.3389/frmbi.2026.1872481
Thrombophlebitis in an Adolescent Patient With Primary Carnitine Deficiency: A Case Report
Kaouani, D., Ryad, N., Lagrine, M., Ouassil, S., Ahmanna, H. C., Qadiry, R. E., Nassih, H., Abourrahouat, A., Jalal, H., & Aitsab, I. (2026) · Cureus · doi:10.7759/cureus.117164
The role of dietary protein in the treatment and prevention of metabolic diseases
Ilovayskaya, I. (2026) · Pharmacoinformatics and pharmaconutritiology Current trends in data analysis · doi:10.63769/3034-7459-2026-2-2-88-98
Gut microbiota shaping fatty liver disease progression
Wysokińska, M., Mysza, M., Uryga, A., & Kolodziejczyk, A. A. (2026) · Life Science Alliance · doi:10.26508/lsa.202603756
Wu, Q., Lin, G., Ou, Y., Ji, B., Pan, Z., & Shao, Y. (2026) · Frontiers in Physiology · doi:10.3389/fphys.2026.1983362
Gao, Y., Gao, X., Wang, K., Qiao, J., & Jiang, C. (2026) · Science China Life Sciences · doi:10.1007/s11427-026-3413-3
Ullah, H., Entero, M. A., & Tocmo, R. (2026) · Food Reviews International · doi:10.1080/87559129.2026.2757075
Metadata
- Authors
- Koeth, R. A., Lam-Galvez, B. R., Kirsop, J., Wang, Z., Levison, B. S., Gu, X., Copeland, M. F., Bartlett, D., Cody, D. B., Dai, H. J., Culley, M. K., Li, X. S., Fu, X., Wu, Y., Li, L., DiDonato, J. A., Tang, W. H. W., Garcia-Garcia, J. C., & Hazen, S. L.
- Affiliations
- Cleveland Clinic (US)
- Cleveland Clinic Lerner College of Medicine (US)
- Procter & Gamble (United States) (US)
- Cleveland State University (US)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2018-12-10
- Volume
- 129
- Issue
- 1
- Pages
- 373-387
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- PMC
- PMC6307959
- OpenAlex
- W2903641122
- Cited by
- 327
- References
- 65
- Citations by year
- 2026: 25 · 2025: 44 · 2024: 37 · 2023: 48 · 2022: 47 · 2021: 51 · 2020: 51 · 2019: 23 · 2018: 1
- FWCI
- 11.21
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH and Office of Dietary Supplements (HL103866, HL126827, DK106000)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gut microbiota and health
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Nutritional Studies and Diet
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Polyamine Metabolism and Applications
- Keywords
- L-carnitine, trimethylamine N-oxide, trimethylamine, gamma-butyrobetaine, gut microbiota, atherosclerosis, omnivorous diet, vegan diet, Clostridiales, antibiotic exposure, plasma carnitine
- MeSH terms
- Vegans, Eubacteriales, Clostridiales, Gastrointestinal Microbiome, Animals, Betaine, Carnitine, Female, Humans, Male, Methylamines, Pilot Projects, Atherosclerosis, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
