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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.
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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]
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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
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