Dataset Information

The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism.

ABSTRACT: 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.

SUBMITTER: Buffa JA

PROVIDER: S-EPMC8732312 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism.

Buffa Jennifer A JA Romano Kymberleigh A KA Copeland Matthew F MF Cody David B DB Zhu Weifei W Galvez Rachel R Fu Xiaoming X Ward Kathryn K Ferrell Marc M Dai Hong J HJ Skye Sarah S Hu Ping P Li Lin L Parlov Mirjana M McMillan Amy A Wei Xingtao X Nemet Ina I Koeth Robert A RA Li Xinmin S XS Wang Zeneng Z Sangwan Naseer N Hajjar Adeline M AM Dwidar Mohammed M Weeks Taylor L TL Bergeron Nathalie N Krauss Ronald M RM Tang W H Wilson WHW Rey Federico E FE DiDonato Joseph A JA Gogonea Valentin V Gerberick G Frank GF Garcia-Garcia Jose Carlos JC Hazen Stanley L SL

Nature microbiology 20211223 1

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 ...[more]

PMID: 34949826

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Project description:BackgroundCardiovascular risk (CVR) underlies aging process and longevity. Previous work points to genetic and environmental factors associated with this risk.ObjectivesThe aim of this research is to look for any CVR gene-gene and gene-multifactorial/lifestyle interactions that may impact health and disease and underlie exceptional longevity.MethodsA case-control study involving 521 both gender individuals, 253 centenarians (100.26 ± 1.98 years), and 268 controls (67.51 ± 3.25 years), low (LCR, n = 107) and high (HCR, n = 161) CVR. Hypertension, diabetes, obesity (BMI, kg·m-2), and impaired kidney function were defined according to standard criteria. CVR was calculated using Q risk®. DNA was genotyping (ACE-rs4646994, AGT-rs4762, AGR1-rs5182, GRK4-rs2960306, GRK4-rs1024323, NOS3-rs1799983, and SLC12A3-rs13306673) through iPlex-MassARRAY®, read by MALDI-TOF mass spectrometry, and analyzed by EARTDECODE®.ResultsAntilongevity factors consisted (OR 95% CI, p < 0.05) BMI 1.558 (1.445-1.680), hypertension 2.358 (1.565-3.553), smoking habits 4.528 (2.579-7.949), diabetes 5.553 (2.889-10.675), hypercholesterolemia 1.016 (1.010-1.022), and regular consumption of red meat 22.363 (13.987-35.755). Genetic aspects particularly for HCR individuals ACE II (OR: 3.96 (1.83-8.56), p < 0.0001) and NOS3 TT (OR: 3.11 (1.70-5.70), p < 0.0001) genotypes were also risk associate. Obesity, smoking, hypercholesterolemia, and frequent consumption of red meat have an additive action to hypertension in the longevity process. There was a synergistic interaction between the endothelial NOS3 genotypes and the severity of arterial hypertension. An epistatic interaction between functional genetic variants of GRK4 and angiotensinogen was also observed.ConclusionsCardiovascular risk-related genetic and multifactorial or predominantly lifestyle aspects and its interactions might influence the aging process and contribute to exceptional longevity in Portuguese centenarians. Besides lifestyle, the activity of nitrite oxide synthase may be one of the main physiologic regulators of cardiovascular protection in the path of longevity.

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Dataset Information

The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism.

Publications

The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism.

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