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L-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans.

ABSTRACT: 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, ?-butyrobetaine (?BB). The contribution of ?BB 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 ?BB (d9-?BB), 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??BB?TMA transformation were identified. RESULTS:Studies with oral d3-l-carnitine or d9-?BB before versus after antibiotic exposure revealed gut microbiota contribution to the initial 2 steps in a metaorganismal l-carnitine??BB?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 ?BB 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 ?BB, whereas the second gut microbial transformation, ?BB?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 ?BB, and only 1 Clostridiales bacterium, Emergencia timonensis, that converted ?BB 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 ?BB, followed by (b) transformation into TMA via low-abundance microbiota in omnivores, and to a markedly lower extent, in vegans/vegetarians. Gut microbiota ?BB?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.

SUBMITTER: Koeth RA

PROVIDER: S-EPMC6307959 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans.

Koeth Robert A RA Lam-Galvez Betzabe Rachel BR Kirsop Jennifer J Wang Zeneng Z Levison Bruce S BS Gu Xiaodong X Copeland Matthew F MF Bartlett David D Cody David B DB Dai Hong J HJ Culley Miranda K MK Li Xinmin S XS Fu Xiaoming X Wu Yuping Y Li Lin L DiDonato Joseph A JA Tang W H Wilson WHW Garcia-Garcia Jose Carlos JC Hazen Stanley L SL

The Journal of clinical investigation 20181210 1

<h4>Background</h4>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.<h4>Methods</h4>Omnivores and vegans/vegetarians ingested deuterium-labeled l-carnitine (d3-l-carnitine) or γBB (d9-γBB ...[more]

PMID: 30530985

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Project description:BackgroundDietary patterns which exclude whole food groups, such as vegetarian, vegan and low carbohydrate high fat diet (LCHF), are increasingly popular in general public. When carefully planned, all these diets have some known benefits for health, but concerns are also raised in particular for LCHF. The quality of LCHF diet which individuals follow in real life without supervision is not known.MethodsOne hundred thirty healthy individuals with stable body mass following LCHF, vegan, vegetarian and omnivorous diet for at least six months, were compared in a cross-sectional study. Diet was analyzed through 3-day food records and FFQ, anthropometric measurements were performed and serum metabolic biomarkers determined from fasting blood.ResultsParticipants on LCHF diet had the intakes of micronutrients comparable to other groups, while the intakes of macronutrients differed in line with the definition of each diet. The intakes of saturated fats, cholesterol and animal proteins were significantly higher and the intakes of sugars and dietary fibers were lower compared to other groups. Healthy eating index 2015 in this group was the lowest. There were no differences in the levels of glucose, triacylglycerols and CRP among groups. Total and LDL cholesterol levels were significantly higher in LCHF group, in particular in participants with higher ketogenic ratio. Fatty acids intakes and intakes of cholesterol, dietary fibers and animal proteins explained 40% of variance in total cholesterol level, with saturated fatty acids being the strongest positive predictor and monounsaturated fatty acids a negative predictor.ConclusionNone of the self-advised diets provided all the necessary nutrients in optimal levels. Due to the detected increased levels of serum cholesterols, selection of healthy fat sources, higher intake of dietary fibers and partial replacing of animal sources with plant sources of foods should be recommended to the individuals selecting LCFH dietary pattern.Clinical Trial Registration: ClinicalTrials.gov, identifier NCT04347213.

Project description:ImportanceIncreasing evidence suggests that, compared with an omnivorous diet, a vegan diet confers potential cardiovascular benefits from improved diet quality (ie, higher consumption of vegetables, legumes, fruits, whole grains, nuts, and seeds).ObjectiveTo compare the effects of a healthy vegan vs healthy omnivorous diet on cardiometabolic measures during an 8-week intervention.Design, setting, and participantsThis single-center, population-based randomized clinical trial of 22 pairs of twins (N = 44) randomized participants to a vegan or omnivorous diet (1 twin per diet). Participant enrollment began March 28, 2022, and continued through May 5, 2022. The date of final follow-up data collection was July 20, 2022. This 8-week, open-label, parallel, dietary randomized clinical trial compared the health impact of a vegan diet vs an omnivorous diet in identical twins. Primary analysis included all available data.InterventionTwin pairs were randomized to follow a healthy vegan diet or a healthy omnivorous diet for 8 weeks. Diet-specific meals were provided via a meal delivery service from baseline through week 4, and from weeks 5 to 8 participants prepared their own diet-appropriate meals and snacks.Main outcomes and measuresThe primary outcome was difference in low-density lipoprotein cholesterol concentration from baseline to end point (week 8). Secondary outcome measures were changes in cardiometabolic factors (plasma lipids, glucose, and insulin levels and serum trimethylamine N-oxide level), plasma vitamin B12 level, and body weight. Exploratory measures were adherence to study diets, ease or difficulty in following the diets, participant energy levels, and sense of well-being.ResultsA total of 22 pairs (N = 44) of twins (34 [77.3%] female; mean [SD] age, 39.6 [12.7] years; mean [SD] body mass index, 25.9 [4.7]) were enrolled in the study. After 8 weeks, compared with twins randomized to an omnivorous diet, the twins randomized to the vegan diet experienced significant mean (SD) decreases in low-density lipoprotein cholesterol concentration (-13.9 [5.8] mg/dL; 95% CI, -25.3 to -2.4 mg/dL), fasting insulin level (-2.9 [1.3] μIU/mL; 95% CI, -5.3 to -0.4 μIU/mL), and body weight (-1.9 [0.7] kg; 95% CI, -3.3 to -0.6 kg).Conclusions and relevanceIn this randomized clinical trial of the cardiometabolic effects of omnivorous vs vegan diets in identical twins, the healthy vegan diet led to improved cardiometabolic outcomes compared with a healthy omnivorous diet. Clinicians can consider this dietary approach as a healthy alternative for their patients.Trial registrationClinicalTrials.gov Identifier: NCT05297825.

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L-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans.

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l-Carnitine in omnivorous diets induces an atherogenic gut microbial pathway in humans.

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