Nature microbiologyDec 24, 2021

A gut bacterial gene cluster connects red meat-related heart disease risk to microbiome breakdown of L-carnitine

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Mar 28, 2026

Abstract

Plasma γ-butyrobetaine (γBB) levels in a clinical cohort of 2,918 individuals are strongly associated with incident cardiovascular disease (CVD) event risks.

The gut microbe Emergencia timonensis can metabolize γBB into trimethylamine (TMA), completing the transformation from carnitine to TMAO.
Introduction of E. timonensis in microbial transplantation studies enhances thrombosis potential after arterial injury.
A six-gene cluster, named the γBB utilization (gbu) gene cluster, is upregulated in response to γBB and is associated with the conversion of γBB to TMA.
Four specific genes (gbuA, gbuB, gbuC, and gbuE) are necessary and sufficient for the conversion of γBB to TMA when expressed together.
In a randomized diet intervention study, higher abundance of faecal gbuA correlates with increased plasma TMAO levels in individuals consuming a red meat-rich diet.

Simplified

The heightened cardiovascular disease (CVD) risk observed among omnivores is thought to be linked, in part, to gut microbiota-dependent generation of trimethylamine-N-oxide (TMAO) from L-carnitine, a nutrient abundant in red meat. Gut microbial transformation of L-carnitine into trimethylamine (TMA), the precursor of TMAO, occurs via the intermediate γ-butyrobetaine (γBB). However, the interrelationship of γBB, red meat ingestion and CVD risks, as well as the gut microbial genes responsible for the transformation of γBB to TMA, are unclear. In the present study, we show that plasma γBB levels in individuals from a clinical cohort (n = 2,918) are strongly associated with incident CVD event risks. Culture of human faecal samples and microbial transplantation studies in gnotobiotic mice with defined synthetic communities showed that the introduction of Emergencia timonensis, a human gut microbe that can metabolize γBB into TMA, is sufficient to complete the carnitine → γBB → TMA transformation, elevate TMAO levels and enhance thrombosis potential in recipients after arterial injury. RNA-sequencing analyses of E. timonensis identified a six-gene cluster, herein named the γBB utilization (gbu) gene cluster, which is upregulated in response to γBB. Combinatorial cloning and functional studies identified four genes (gbuA, gbuB, gbuC and gbuE) that are necessary and sufficient to recapitulate the conversion of γBB to TMA when coexpressed in Escherichia coli. Finally, reanalysis of samples (n = 113) from a clinical, randomized diet, intervention study showed that the abundance of faecal gbuA correlates with plasma TMAO and a red meat-rich diet. Our findings reveal a microbial gene cluster that is critical to dietary carnitine → γBB → TMA → TMAO transformation in hosts and contributes to CVD risk.

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Funding

Competing interests

Competing interests - Drs Hazen and Wang report being named as co-inventors on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics. Drs Hazen and Wang report having received royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland Heart Lab, a fully owned subsidiary of Quest Diagnostics, and Procter & Gamble. Dr. Hazen is a paid consultant for Procter & Gamble, and Zehna Therapeutics, and has received research funds from Procter & Gamble, Pfizer Inc., Roche Diagnostics and Zehna Therapeutics. Jennifer Buffa reports having received royalty payments from Procter & Gamble. GFG, MFC, DBC, KLW, BRLG, HJD, PH and JCGG are employees of Procter & Gamble. Dr. Tang reports being a consultant for Sequana Medical A.G., Owkin Inc, Relypsa Inc, and PreCardiac Inc, having received honorarium from Springer Nature for authorship/editorship and American Board of Internal Medicine for exam writing committee participation - all unrelated to the subject and contents of this paper. The other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

PubMed

A gut bacterial gene cluster connects red meat-related heart disease risk to microbiome breakdown of L-carnitine

Abstract

Full Text

Funding

Competing interests

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