Dataset Information

Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.

ABSTRACT: Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine--choline, trimethylamine N-oxide (TMAO) and betaine--were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease.

SUBMITTER: Wang Z

PROVIDER: S-EPMC3086762 | biostudies-other | 2011 Apr

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.

Wang Zeneng Z Klipfell Elizabeth E Bennett Brian J BJ Koeth Robert R Levison Bruce S BS Dugar Brandon B Feldstein Ariel E AE Britt Earl B EB Fu Xiaoming X Chung Yoon-Mi YM Wu Yuping Y Schauer Phil P Smith Jonathan D JD Allayee Hooman H Tang W H Wilson WH DiDonato Joseph A JA Lusis Aldons J AJ Hazen Stanley L SL

Nature 20110401 7341

Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine--choline, trimethylamine N-oxide (TMAO) and betaine--were identified and then shown to predict risk for CVD in an independent l ...[more]

PMID: 21475195

Similar Datasets

Project description:Recent studies in animals have shown a mechanistic link between intestinal microbial metabolism of the choline moiety in dietary phosphatidylcholine (lecithin) and coronary artery disease through the production of a proatherosclerotic metabolite, trimethylamine-N-oxide (TMAO). We investigated the relationship among intestinal microbiota-dependent metabolism of dietary phosphatidylcholine, TMAO levels, and adverse cardiovascular events in humans.We quantified plasma and urinary levels of TMAO and plasma choline and betaine levels by means of liquid chromatography and online tandem mass spectrometry after a phosphatidylcholine challenge (ingestion of two hard-boiled eggs and deuterium [d9]-labeled phosphatidylcholine) in healthy participants before and after the suppression of intestinal microbiota with oral broad-spectrum antibiotics. We further examined the relationship between fasting plasma levels of TMAO and incident major adverse cardiovascular events (death, myocardial infarction, or stroke) during 3 years of follow-up in 4007 patients undergoing elective coronary angiography.Time-dependent increases in levels of both TMAO and its d9 isotopologue, as well as other choline metabolites, were detected after the phosphatidylcholine challenge. Plasma levels of TMAO were markedly suppressed after the administration of antibiotics and then reappeared after withdrawal of antibiotics. Increased plasma levels of TMAO were associated with an increased risk of a major adverse cardiovascular event (hazard ratio for highest vs. lowest TMAO quartile, 2.54; 95% confidence interval, 1.96 to 3.28; P<0.001). An elevated TMAO level predicted an increased risk of major adverse cardiovascular events after adjustment for traditional risk factors (P<0.001), as well as in lower-risk subgroups.The production of TMAO from dietary phosphatidylcholine is dependent on metabolism by the intestinal microbiota. Increased TMAO levels are associated with an increased risk of incident major adverse cardiovascular events. (Funded by the National Institutes of Health and others.).

Project description:1. [(14)C]Cyclamate was not metabolized when incubated with the liver, spleen, kidney or blood of rats of rabbits kept on a cyclamate-containing diet, and that had become converters of cyclamate into cyclohexylamine. 2. [(14)C]Cyclamate was converted into cyclohexylamine when incubated under anaerobic conditions with the contents of the caecum, colon or rectum or with the faeces of cyclamate-pretreated rats. Similar results were obtained with cyclamate-pretreated rabbits. With cyclamate-pretreated guinea pigs, which did not readily convert cyclamate into cyclohexylamine, the colon contents showed only low activity in this respect. 3. The faeces of a human converter of [(14)C]cyclamate into cyclohexylamine were also very active, but became less active when cyclamate was removed from his diet. 4. On subculturing the organisms from the contents of the colon and rectum of rats, the ability to convert cyclamate into cyclohexylamine was lost during three subcultures, but the loss of the activity was considerably decreased by subculturing in the presence of cyclamate. 5. Incubation of rat faeces in broths containing cyclamate increased their ability to metabolize cyclamate, but similar treatment of rabbit and human faeces suppressed this activity. 6. When rats are kept on a cyclamate diet the number of clostridia in the faeces increased considerably. In human dietary cyclamate did not appear to alter the counts of various faecal micro-organisms. 7. The gut organisms that appear to develop the ability to convert cyclamate into cyclohexylamine are clostridia in rats, enterobacteria in rabbits and enterococci in man. 8. [(14)C]Cyclohexylamine injected into the caecum or colon of rats is readily absorbed and excreted in the urine. 9. It appears that on continued intake of cyclamate the gut flora develop the ability to convert cyclamate into cyclohexylamine, which is then absorbed and excreted mainly in the urine, although a small proportion is metabolized to other compounds.

Project description:The substitution of high-level soy meals for fish meal (FM) generally leads to fish enteritis, accompanied by significant variations in gut flora. Relevant studies have pointed out a close relationship between tryptophan metabolism mediated by gut flora and vertebrate inflammatory bowel disease. Present study examines the role of tryptophan metabolism and gut flora profile in fish enteritis caused by different soybean meals. The 960 groupers were randomly assigned into 4 groups (n = 4), which including: (1) FM (the control group, fed with 50% FM feed), (2) SBM40 (replacing 40% FM with soybean meal), (3) SPC40 (replacing 40% FM with soybean protein concentrate), and (4) FSBM40 (replacing 40% FM with fermented soybean meal). Under average temperature and natural light, the groupers were cultivated with feeds of iso-nitrogen and iso-lipid for 10 weeks. The results showed that soybean meal feeds at all experimental levels had negative effects on fish gut physiology and growth performance. Typical enteritis features and fluctuations of immune system occur, which can be observed in the enzyme activities of total superoxide dismutase and lysozyme and in the contents of immunoglobulin M, complement 3 and complement 4. 16SrDNA high-throughput sequencing indicated that it greatly influenced the gut flora with the abundance of maleficent bacteria, like Vibrio, amplified with increasing dietary soybean meals. According to the "3 + 2" full-length transcriptome sequencing, soy meals at the three experimental levels inhibited the key gene expressions of tryptophan metabolic pathway in fish gut, however, there are some differences in the types of key genes that are inhibited. The canonical correlation analysis showed that the changes in key gene expressions in tryptophan metabolic pathway had a positive correlation with the expressions of pro-inflammatory genes (P < 0.05) and negatively correlated with the expression of anti-inflammatory genes (P < 0.05). It is speculated from this study that tryptophan metabolism is closely related to fish soy meal-related enteritis, and the abnormal tryptophan metabolism caused by intestinal flora imbalance may play an important role. In the future research, we can further study the tolerance of fish to soy meals feed from two aspects of tryptophan metabolism and intestinal flora changes.

Dataset Information

Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.

Publications

Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets