JCI insightMar 23, 2018

Metabolite analysis finds trimethyllysine, a nutrient linked to TMAO, predicts future heart disease risk

Circadian Biology Weekly Brief ↗PubMed ↗DOI ↗

Updated Apr 1, 2026

Abstract

Plasma levels of N6,N6,N6-trimethyl-L-lysine (TML) are associated with a 2.4 times higher risk of major adverse cardiovascular events within three years.

TML levels are independently associated with a 2.9 times higher risk of mortality within five years.
Genome-wide association studies suggest several loci for TML levels, but none reached genome-wide significance.
TML can serve as a nutrient precursor for gut bacteria to produce trimethylamine (TMA) and trimethylamine N-oxide (TMAO), which are linked to cardiovascular disease.
Both plant- and animal-derived foods contain abundant TML, but its conversion to TMA is slow in fecal cultures from both omnivores and vegans.
TML supplementation in mice does not increase plasma TMAO levels or enhance thrombosis potential.

Simplified

Using an untargeted metabolomics approach in initial (N = 99 subjects) and replication cohorts (N = 1,162), we discovered and structurally identified a plasma metabolite associated with cardiovascular disease (CVD) risks, N6,N6,N6-trimethyl-L-lysine (trimethyllysine, TML). Stable-isotope-dilution tandem mass spectrometry analyses of an independent validation cohort (N = 2,140) confirmed TML levels are independently associated with incident (3-year) major adverse cardiovascular event risks (hazards ratio [HR], 2.4; 95% CI, 1.7-3.4) and incident (5-year) mortality risk (HR, 2.9; 95% CI, 2.0-4.2). Genome-wide association studies identified several suggestive loci for TML levels, but none reached genome-wide significance; and d9(trimethyl)-TML isotope tracer studies confirmed TML can serve as a nutrient precursor for gut microbiota-dependent generation of trimethylamine (TMA) and the atherogenic metabolite trimethylamine N-oxide (TMAO). Although TML was shown to be abundant in both plant- and animal-derived foods, mouse and human fecal cultures (omnivores and vegans) showed slow conversion of TML to TMA. Furthermore, unlike chronic dietary choline, TML supplementation in mice failed to elevate plasma TMAO or heighten thrombosis potential in vivo. Thus, TML is identified as a strong predictor of incident CVD risks in subjects and to serve as a dietary precursor for gut microbiota-dependent generation of TMAO; however, TML does not appear to be a major microbial source for TMAO generation in vivo.

Full Text

Full text is available at the source.

View Full Text ↗

Funding

Competing interests

Conflict of interest: SLH and ZW are named as coinventors on patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. SLH and ZW report being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab and Procter & Gamble (P&G). SLH is a paid consultant for P&G, and has received research funds from P&G, Pfizer Inc., Roche Diagnostics, and Takeda.

PubMed

Metabolite analysis finds trimethyllysine, a nutrient linked to TMAO, predicts future heart disease risk

Abstract

Full Text

Funding

Competing interests

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the circadian biology brief

Abstract

Full Text

Funding

Competing interests

Related papers

You found one interesting study. We’ll send the next 7.

What Lands in Your Inbox Each Week:

Recent issues from the circadian biology brief