Yen Chin Koay1,2,3, Yung-Chih Chen4, Jibran A Wali2,5, Alison W S Luk2,5, Mengbo Li2,6, Hemavarni Doma4, Rosa Reimark4, Maria T K Zaldivia4, Habteab T Habtom7,8, Ashley E Franks7,8, Gabrielle Fusco-Allison1,2,3, Jean Yang2,6, Andrew Holmes2,5, Stephen J Simpson2,5, Karlheinz Peter4, John F O'Sullivan1,2,3,9. 1. Heart Research Institute, The University of Sydney, Sydney, NSW, Australia. 2. Charles Perkins Centre, The University of Sydney, Sydney, NSW, Australia. 3. Central Clinical School, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia. 4. Baker Heart & Diabetes Institute, Melbourne, VIC, Australia. 5. Faculty of Science, School of Life and Environmental Sciences, The University of Sydney, Sydney, NSW, Australia. 6. School of Mathematics and Statistics, The University of Sydney, Sydney, NSW, Australia. 7. Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC, Australia. 8. Centre for Future Landscapes, La Trobe University, Melbourne, VIC, Australia. 9. Department of Cardiology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
Abstract
AIMS: The microbiome-derived metabolite trimethylamine-N-oxide (TMAO) has attracted major interest and controversy both as a diagnostic biomarker and therapeutic target in atherothrombosis. METHODS AND RESULTS: Plasma TMAO increased in mice on 'unhealthy' high-choline diets and notably also on 'healthy' high-fibre diets. Interestingly, TMAO was found to be generated by direct oxidation in the gut in addition to oxidation by hepatic flavin-monooxygenases. Unexpectedly, two well-accepted mouse models of atherosclerosis, ApoE-/- and Ldlr-/- mice, which reflect the development of stable atherosclerosis, showed no association of TMAO with the extent of atherosclerosis. This finding was validated in the Framingham Heart Study showing no correlation between plasma TMAO and coronary artery calcium score or carotid intima-media thickness (IMT), as measures of atherosclerosis in human subjects. However, in the tandem-stenosis mouse model, which reflects plaque instability as typically seen in patients, TMAO levels correlated with several characteristics of plaque instability, such as markers of inflammation, platelet activation, and intraplaque haemorrhage. CONCLUSIONS: Dietary-induced changes in the microbiome, of both 'healthy' and 'unhealthy' diets, can cause an increase in the plasma level of TMAO. The gut itself is a site of significant oxidative production of TMAO. Most importantly, our findings reconcile contradictory data on TMAO. There was no direct association of plasma TMAO and the extent of atherosclerosis, both in mice and humans. However, using a mouse model of plaque instability we demonstrated an association of TMAO plasma levels with atherosclerotic plaque instability. The latter confirms TMAO as being a marker of cardiovascular risk. Published on behalf of the European Society of Cardiology. All rights reserved.
AIMS: The microbiome-derived metabolite trimethylamine-N-oxide (TMAO) has attracted major interest and controversy both as a diagnostic biomarker and therapeutic target in atherothrombosis. METHODS AND RESULTS: Plasma TMAO increased in mice on 'unhealthy' high-choline diets and notably also on 'healthy' high-fibre diets. Interestingly, TMAO was found to be generated by direct oxidation in the gut in addition to oxidation by hepatic flavin-monooxygenases. Unexpectedly, two well-accepted mouse models of atherosclerosis, ApoE-/- and Ldlr-/- mice, which reflect the development of stable atherosclerosis, showed no association of TMAO with the extent of atherosclerosis. This finding was validated in the Framingham Heart Study showing no correlation between plasma TMAO and coronary artery calcium score or carotid intima-media thickness (IMT), as measures of atherosclerosis in human subjects. However, in the tandem-stenosis mouse model, which reflects plaque instability as typically seen in patients, TMAO levels correlated with several characteristics of plaque instability, such as markers of inflammation, platelet activation, and intraplaque haemorrhage. CONCLUSIONS: Dietary-induced changes in the microbiome, of both 'healthy' and 'unhealthy' diets, can cause an increase in the plasma level of TMAO. The gut itself is a site of significant oxidative production of TMAO. Most importantly, our findings reconcile contradictory data on TMAO. There was no direct association of plasma TMAO and the extent of atherosclerosis, both in mice and humans. However, using a mouse model of plaque instability we demonstrated an association of TMAO plasma levels with atherosclerotic plaque instability. The latter confirms TMAO as being a marker of cardiovascular risk. Published on behalf of the European Society of Cardiology. All rights reserved.
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