Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide

Mar 19, 2015mBio

Gut bacteria influence how dietary choline is used and the buildup of a heart disease–linked compound

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Abstract

Nine strains of gut bacteria were identified that can produce trimethylamine (TMA) from .

TMA is produced by gut bacteria from choline and is converted to (TMAO) in the liver.
TMAO levels in the blood correlate with the severity of atherosclerosis in humans and have been shown to worsen this condition in mice.
In gnotobiotic mice, only those colonized with TMA-producing bacteria had detectable levels of TMAO in their serum.
Low colonization levels of TMA-producing bacteria led to significantly reduced choline availability for the host, with greater reductions observed at higher bacterial abundances.
These findings suggest that the gut microbiota's ability to produce TMA may influence dietary choline requirements and strategies for managing cardiovascular disease.

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UNLABELLED: 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 (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.

IMPORTANCE: Cardiovascular 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.

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100-fold

Decrease in Serum Levels

Relative abundance of TMA-producing bacteria in gnotobiotic mice.

Nine Identified Bacterial Strains

Strains capable of converting to TMA in vitro.

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Intestinal Microbiota Composition Modulates Choline Bioavailability from Diet and Accumulation of the Proatherogenic Metabolite Trimethylamine-N-Oxide

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