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Buffa JA, Romano KA, Copeland MF, et al. The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism. Nat Microbiol. 2021;doi: 10.1038/s41564-021-01010-x.
Buffa, J. A., Romano, K. A., Copeland, M. F., Cody, D. B., Zhu, W., Galvez, R., Fu, X., Ward, K., Ferrell, M., Dai, H. J., Skye, S., Hu, P., Li, L., Parlov, M., McMillan, A., Wei, X., Nemet, I., Koeth, R. A., Li, X. S., Wang, Z., Sangwan, N., Hajjar, A. M., Dwidar, M., Weeks, T. L., Bergeron, N., Krauss, R. M., Tang, W. H. W., Rey, F. E., DiDonato, J. A., Gogonea, V., Gerberick, G. F., Garcia-Garcia, J. C., & Hazen, S. L. (2021). The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism. Nature microbiology, . https://doi.org/10.1038/s41564-021-01010-x
Buffa, Jennifer A, et al. "The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism." Nature microbiology vol. (2021). doi: https://doi.org/10.1038/s41564-021-01010-x
Buffa JA, Romano KA, Copeland MF, Cody DB, Zhu W, Galvez R, Fu X, Ward K, Ferrell M, Dai HJ, Skye S, Hu P, Li L, Parlov M, McMillan A, Wei X, Nemet I, Koeth RA, Li XS, Wang Z, Sangwan N, Hajjar AM, Dwidar M, Weeks TL, Bergeron N, Krauss RM, Tang WHW, Rey FE, DiDonato JA, Gogonea V, Gerberick GF, Garcia-Garcia JC, Hazen SL. The microbial gbu gene cluster links cardiovascular disease risk associated with red meat consumption to microbiota L-carnitine catabolism. Nat Microbiol. 2021 Dec 23; doi: 10.1038/s41564-021-01010-x. Epub 2021 Dec 23. PMID: 34949826.
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Nat Microbiol. 2021 Dec 23; doi: 10.1038/s41564-021-01010-x. Epub 2021 Dec 23.

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

Nature microbiology

Jennifer A Buffa, Kymberleigh A Romano, Matthew F Copeland, David B Cody, Weifei Zhu, Rachel Galvez, Xiaoming Fu, Kathryn Ward, Marc Ferrell, Hong J Dai, Sarah Skye, Ping Hu, Lin Li, Mirjana Parlov, Amy McMillan, Xingtao Wei, Ina Nemet, Robert A Koeth, Xinmin S Li, Zeneng Wang, Naseer Sangwan, Adeline M Hajjar, Mohammed Dwidar, Taylor L Weeks, Nathalie Bergeron, Ronald M Krauss, W H Wilson Tang, Federico E Rey, Joseph A DiDonato, Valentin Gogonea, G Frank Gerberick, Jose Carlos Garcia-Garcia, Stanley L Hazen

Affiliations

  1. Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
  2. Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH, USA.
  3. Life Sciences TPT and Global Biosciences, The Procter & Gamble Company, Cincinnati, OH, USA.
  4. Abbott Structural Heart, Santa Clara, CA, USA.
  5. Dose Biosystems Inc., Toronto, Ontario, Canada.
  6. Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA.
  7. Department of Biological and Pharmaceutical Sciences, College of Pharmacy, Touro University California, Vallejo, CA, USA.
  8. Departments of Pediatrics and Medicine, University of California, San Francisco, CA, USA.
  9. Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, USA.
  10. Department of Chemistry, Cleveland State University, Cleveland, OH, USA.
  11. Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA. [email protected].
  12. Center for Microbiome & Human Health, Cleveland Clinic, Cleveland, OH, USA. [email protected].
  13. Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH, USA. [email protected].

PMID: 34949826 DOI: 10.1038/s41564-021-01010-x

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.

© 2021. The Author(s), under exclusive licence to Springer Nature Limited.

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