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Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine.

ABSTRACT: Elevated levels of plasma trimethylamine N-oxide (TMAO), the product of gut microbiome and hepatic-mediated metabolism of dietary choline and L-carnitine, have recently been identified as a novel risk factor for the development of atherosclerosis in mice and humans. The goal of this study was to identify the genetic factors associated with plasma TMAO levels.We used comparative genome-wide association study approaches to discover loci for plasma TMAO levels in mice and humans. A genome-wide association study in the hybrid mouse diversity panel identified a locus for TMAO levels on chromosome 3 (P=2.37 × 10(-6)) that colocalized with a highly significant (P=1.07 × 10(-20)) cis-expression quantitative trait locus for solute carrier family 30 member 7. This zinc transporter could thus represent 1 positional candidate gene responsible for the association signal at this locus in mice. A genome-wide association study for plasma TMAO levels in 1973 humans identified 2 loci with suggestive evidence of association (P=3.0 × 10(-7)) on chromosomes 1q23.3 and 2p12. However, genotyping of the lead variants at these loci in 1892 additional subjects failed to replicate their association with plasma TMAO levels.The results of these limited observational studies indicate that, at least in humans, genes play a marginal role in determining TMAO levels and that any genetic effects are relatively weak and complex. Variation in diet or the repertoire of gut microbiota may be more important determinants of plasma TMAO levels in mice and humans, which should be investigated in future studies.

SUBMITTER: Hartiala J

PROVIDER: S-EPMC4035110 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine.

Hartiala Jaana J Bennett Brian J BJ Tang W H Wilson WH Wang Zeneng Z Stewart Alexandre F R AF Roberts Robert R McPherson Ruth R Lusis Aldons J AJ Hazen Stanley L SL Allayee Hooman H

Arteriosclerosis, thrombosis, and vascular biology 20140327 6

<h4>Objective</h4>Elevated levels of plasma trimethylamine N-oxide (TMAO), the product of gut microbiome and hepatic-mediated metabolism of dietary choline and L-carnitine, have recently been identified as a novel risk factor for the development of atherosclerosis in mice and humans. The goal of this study was to identify the genetic factors associated with plasma TMAO levels.<h4>Approach and results</h4>We used comparative genome-wide association study approaches to discover loci for plasma TMA ...[more]

PMID: 24675659

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Project description:UnlabelledCholine is a water-soluble nutrient essential for human life. Gut microbial metabolism of choline results in the production of trimethylamine (TMA), which upon absorption by the host is converted in the liver to trimethylamine-N-oxide (TMAO). Recent studies revealed that TMAO exacerbates atherosclerosis in mice and positively correlates with the severity of this disease in humans. However, which microbes contribute to TMA production in the human gut, the extent to which host factors (e.g., genotype) and diet affect TMA production and colonization of these microbes, and the effects TMA-producing microbes have on the bioavailability of dietary choline remain largely unknown. We screened a collection of 79 sequenced human intestinal isolates encompassing the major phyla found in the human gut and identified nine strains capable of producing TMA from choline in vitro. Gnotobiotic mouse studies showed that TMAO accumulates in the serum of animals colonized with TMA-producing species, but not in the serum of animals colonized with intestinal isolates that do not generate TMA from choline in vitro. Remarkably, low levels of colonization by TMA-producing bacteria significantly reduced choline levels available to the host. This effect was more pronounced as the abundance of TMA-producing bacteria increased. Our findings provide a framework for designing strategies aimed at changing the representation or activity of TMA-producing bacteria in the human gut and suggest that the TMA-producing status of the gut microbiota should be considered when making recommendations about choline intake requirements for humans.ImportanceCardiovascular disease (CVD) is the leading cause of death and disability worldwide, and increased trimethylamine N-oxide (TMAO) levels have been causally linked with CVD development. This work identifies members of the human gut microbiota responsible for both the accumulation of trimethylamine (TMA), the precursor of the proatherogenic compound TMAO, and subsequent decreased choline bioavailability to the host. Understanding how to manipulate the representation and function of choline-consuming, TMA-producing species in the intestinal microbiota could potentially lead to novel means for preventing or treating atherosclerosis and choline deficiency-associated diseases.

Project description:BACKGROUND:Intestinal microbiota have been found to be linked to cardiovascular disease via conversion of the dietary compounds choline and carnitine to the atherogenic metabolite TMAO (trimethylamine-N-oxide). Specifically, a vegan diet was associated with decreased plasma TMAO levels and nearly absent TMAO production on carnitine challenge. METHODS AND RESULTS:We performed a double-blind randomized controlled pilot study in which 20 male metabolic syndrome patients were randomized to single lean vegan-donor or autologous fecal microbiota transplantation. At baseline and 2 weeks thereafter, we determined the ability to produce TMAO from d6-choline and d3-carnitine (eg, labeled and unlabeled TMAO in plasma and 24-hour urine after oral ingestion of 250 mg of both isotope-labeled precursor nutrients), and fecal samples were collected for analysis of microbiota composition. 18F-fluorodeoxyglucose positron emission tomography/computed tomography scans of the abdominal aorta, as well as ex vivo peripheral blood mononuclear cell cytokine production assays, were performed. At baseline, fecal microbiota composition differed significantly between vegans and metabolic syndrome patients. With vegan-donor fecal microbiota transplantation, intestinal microbiota composition in metabolic syndrome patients, as monitored by global fecal microbial community structure, changed toward a vegan profile in some of the patients; however, no functional effects from vegan-donor fecal microbiota transplantation were seen on TMAO production, abdominal aortic 18F-fluorodeoxyglucose uptake, or ex vivo cytokine production from peripheral blood mononuclear cells. CONCLUSIONS:Single lean vegan-donor fecal microbiota transplantation in metabolic syndrome patients resulted in detectable changes in intestinal microbiota composition but failed to elicit changes in TMAO production capacity or parameters related to vascular inflammation. CLINICAL TRIAL REGISTRATION:URL: http://www.trialregister.nl. Unique identifier: NTR 4338.

Dataset Information

Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine.

Publications

Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine.

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