Relationship of Serum Trimethylamine N-Oxide (TMAO) Levels with early Atherosclerosis in Humans
Open accessAbstract
Circulating trimethylamine N-Oxide (TMAO) levels predict cardiovascular disease (CVD), possibly by impacting on cholesterol metabolism and oxidative stress. Because hepatic TMAO production is regulated by insulin signalling and it is unclear whether and to what extent circulating TMAO levels associate with CVD risk, independently of insulin resistance and its important determinants fatty liver and visceral obesity, we have now addressed this question in 220 subjects who participated in the Tübingen Lifestyle Intervention Program. Visceral fat mass (r = 0.40, p < 0.0001), liver fat content (r = 0.23, p = 0.0005) and TMAO levels (r = 0.26, p < 0.0001) associated positively, and insulin sensitivity associated negatively (r = -0.18, p = 0.009) with carotid intima-media thickness (cIMT). Higher TMAO levels (std.-Beta 0.11, p = 0.03) predicted increased cIMT, independently of age, sex and visceral fat mass. While during the lifestyle intervention most cardiovascular risk parameters improved, mean TMAO levels did not change (p = 0.18). However, cIMT decreased significantly (p = 0.0056) only in subjects in the tertile with the largest decrease of TMAO levels (>20%). We provide novel information that increased serum TMAO levels associate with increased cIMT, independently of established cardiovascular risk markers, including insulin resistance, visceral obesity and fatty liver. Furthermore, the decrease of cIMT during a lifestyle intervention may be related to the decrease of TMAO levels.
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Higher levels of choline and trimethylamine N-oxide have been linked to metabolic disturbances that might increase colorectal cancer risk, including higher body mass index, greater visceral adiposity, insulin resistance, diabetes, and fatty liver.
“Higher levels of choline and TMAO have been linked to a spectrum of metabolic disturbances that might increase CRC risk, including higher BMI, greater visceral adiposity, insulin resistance, diabetes, and fatty liver.153, 154”
From Influence of the Gut Microbiome, Diet, and Environment on Risk of Colorectal Cancer (2020) · cites this paper as [153]
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Matthews, D. R., Hosker, J. P., Rudenski, A. S., Naylor, B. A., Treacher, D. F., & Turner, R. C. (1985) · Diabetologia · doi:10.1007/bf00280883 · Cited by 31,502 · see citing works
Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk
Tang, W. H. W., Wang, Z., Levison, B. S., Koeth, R. A., Britt, E. B., Fu, X., Wu, Y., & Hazen, S. L. (2013) · New England Journal of Medicine · doi:10.1056/nejmoa1109400 · Cited by 3,402 · see citing works
2013 AHA/ACC Guideline on Lifestyle Management to Reduce Cardiovascular Risk
Eckel, R. H., Jakicic, J. M., Ard, J. D., de Jesus, J. M., Houston Miller, N., Hubbard, V. S., Lee, I.-M., Lichtenstein, A. H., Loria, C. M., Millen, B. E., et al. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2013.11.003 · Cited by 1,160 · see citing works
Bennett, B. J., Vallim, T. Q. D. A., Wang, Z., Shih, D. M., Meng, Y., Gregory, J., Allayee, H., Lee, R., Graham, M., Crooke, R., et al. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2012.12.011 · Cited by 1,070 · see citing works
Artinian, N. T., Fletcher, G. F., Mozaffarian, D., Kris-Etherton, P., Van Horn, L., Lichtenstein, A. H., Kumanyika, S., Kraus, W. E., Fleg, J. L., Redeker, N. S., et al. (2010) · Circulation · doi:10.1161/cir.0b013e3181e8edf1 · Cited by 919 · see citing works
The role of hepatokines in metabolism
Stefan, N., & Häring, H.-U. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.258 · Cited by 500 · see citing works
Serum Trimethylamine-N-Oxide is Elevated in CKD and Correlates with Coronary Atherosclerosis Burden
Stubbs, J. R., House, J. A., Ocque, A. J., Zhang, S., Johnson, C., Kimber, C., Schmidt, K., Gupta, A., Wetmore, J. B., Nolin, T. D., et al. (2016) · Journal of the American Society of Nephrology · doi:10.1681/asn.2014111063 · Cited by 450 · see citing works
Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet
Gao, X., Liu, X., Xu, J., Xue, C., Xue, Y., & Wang, Y. (2014) · Journal of Bioscience and Bioengineering · doi:10.1016/j.jbiosc.2014.03.001 · Cited by 360 · see citing works
Shih, D. M., Wang, Z., Lee, R., Meng, Y., Che, N., Charugundla, S., Qi, H., Wu, J., Pan, C., Brown, J. M., et al. (2015) · Journal of Lipid Research · doi:10.1194/jlr.m051680 · Cited by 335 · see citing works
Mueller, D. M., Allenspach, M., Othman, A., Saely, C. H., Muendlein, A., Vonbank, A., Drexel, H., & von Eckardstein, A. (2015) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2015.10.091 · Cited by 217 · see citing works
Flagged first, then by citations
Research works printed but not linked: 30
- Loscalzo J. Gut microbiota, the genome, and diet in atherogenesis. N Engl J Med. 25(368), 1647– 1649 (2013). 23614591
- Wang Z.. Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57– 63 (2011). 21475195 PMC3086762
- Koeth R. A.. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med. 19, 576– 585 (2013). 23563705 PMC3650111
- Koeth R. A.. γ-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab. 20, 799– 812 (2014). 25440057 PMC4255476
- Kaysen G. A.. Associations of Trimethylamine N-Oxide With Nutritional and Inflammatory Biomarkers and Cardiovascular Outcomes in Patients New to Dialysis. J Ren Nutr. 25, 351– 356 (2015). 25802017 PMC4469547
- Warrier M.. The TMAO-Generating Enzyme Flavin Monooxygenase 3 Is a Central Regulator of Cholesterol Balance. Cell Rep. pii: S2211-1247(14)01065-1. (2015). PMC4501903 25600868
- Schugar R. C. & Brown J. M. Emerging roles of flavin monooxygenase 3 in cholesterol metabolism and atherosclerosis. Curr Opin Lipidol. 26, 426– 431 (2015). 26218418 PMC4666514
- Miao J.. Flavin-containing monooxygenase 3 as a potential player in diabetes-associated atherosclerosis. Nat Commun. 6, 6498 (2015). 25849138 PMC4391288
- Li G.. Cardiovascular mortality, all-cause mortality, and diabetes incidence after lifestyle intervention for people with impaired glucose tolerance in the Da Qing Diabetes Prevention Study: a 23-year follow-up study. Lancet Diabetes Endocrinol. 2, 474– 480 (2014). 24731674
- Lehmann R.. Circulating lysophosphatidylcholines are markers of a metabolically benign nonalcoholic fatty liver. Diabetes Care 36, 2331– 2338 (2013). 23514731 PMC3714475
- Stefan N.. A high-risk phenotype associates with reduced improvement in glycaemia during a lifestyle intervention in prediabetes. Diabetologia 58, 2877– 84 (2015). 26404062
- Chalasani N.. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 55, 2005– 2023 (2012). 22488764
- Peter A.. PNPLA3 variant I148M is associated with altered hepatic lipid composition in humans. Diabetologia 57, 2103– 2107 (2014). 24972532
- Baecke J. A., Burema J. & Frijters J. E. A short questionnaire for the measurement of habitual physical activity in epidemiological studies. Am J Clin Nutr. 36, 936– 942 (1982). 7137077
- Stefan N.. Inhibition of 11β-HSD1 with RO5093151 for non-alcoholic fatty liver disease: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2, 406– 416 (2014). 24795254
- Szczepaniak L. S.. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab. 288, E462– 468 (2005). 15339742
- Matsuda M. & DeFronzo R. A. Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp. Diabetes Care 22, 1462– 1470 (1999). 10480510
- Balletshofer B. M.. Early carotid atherosclerosis in overweight non-diabetic individuals is associated with subclinical chronic inflammation independent of underlying insulin resistance. Horm Metab Res. 37, 331– 335 (2005). 15971158
- Levey A. S.. Expressing the modification of diet in renal disease study equation for estimating glomerular filtration rate with standardized serum creatinine values, Clin. Chem. 53, 766– 772 (2007). 17332152
- Wang Z.. Measurement of trimethylamine-N-oxide by stable isotope dilution liquid chromatography tandem mass spectrometry. Anal Biochem. 455, 35– 40 (2014). 24704102 PMC4167037
- Mozaffarian D.. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2015 update: a report from the American Heart Association. Circulation 131, e29– 322 (2015). 25520374
- Tang W. H. & Hazen S. L. The contributory role of gut microbiota in cardiovascular disease. J Clin Invest. 124, 4204– 4211 (2014). 25271725 PMC4215189
- Ufnal M., Zadlo A. & Ostaszewski R. TMAO: A small molecule of great expectations. Nutrition. 31, 1317– 1323 (2015). 26283574
- Saltiel A.R. & Kahn C.R. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414, 799– 806 (2001). 11742412
- Semple R. K. EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons. Eur J Endocrinol. 174, R209– 223 (2016). 26865583
- Boutagy N. E.. Short-term high-fat diet increases postprandial trimethylamine-N-oxide in humans. Nutr Res. 35, 858– 864 (2015). 26265295
- Boutagy N. E.. Probiotic supplementation and trimethylamine-N-oxide production following a high-fat diet. Obesity (Silver Spring). 23, 2357– 2363 (2015). 26465927
- Wang Z.. Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis. Cell 163, 1585– 95 (2015). 26687352 PMC4871610
- Buscemi S.. Long-term effects of a multidisciplinary treatment of uncomplicated obesity on carotid intima-media thickness. Obesity (Silver Spring) 19, 1187– 1192 (2011). 21183931
- Dogan S., Kastelein J. J., Grobbee D. E. & Bots M. L. Mean common or mean maximum carotid intima-media thickness as primary outcome in lipid-modifying intervention studies. J Atheroscler Thromb. 18, 946– 957 (2011). 21844660
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Crimarco, A., Springfield, S., Petlura, C., Streaty, T., Cunanan, K., Lee, J., Fielding-Singh, P., Carter, M. M., Topf, M. A., Wastyk, H. C., et al. (2020) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/nqaa203 · Cited by 286 · see citing works
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Kriaa, A., Bourgin, M., Potiron, A., Mkaouar, H., Jablaoui, A., Gérard, P., Maguin, E., & Rhimi, M. (2019) · Journal of Lipid Research · doi:10.1194/jlr.r088989 · Cited by 264 · see citing works
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Kurilshikov, A., van den Munckhof, I. C. L., Chen, L., Bonder, M. J., Schraa, K., Rutten, J. H. W., Riksen, N. P., de Graaf, J., Oosting, M., Sanna, S., et al. (2019) · Circulation Research · doi:10.1161/circresaha.118.314642 · Cited by 178 · see citing works
Pastori, D., Carnevale, R., Nocella, C., Novo, M., Santulli, M., Cammisotto, V., Menichelli, D., Pignatelli, P., & Violi, F. (2017) · Journal of the American Heart Association · doi:10.1161/jaha.117.005784 · Cited by 182 · see citing works
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Subramaniam, S., & Fletcher, C. (2018) · British Journal of Pharmacology · doi:10.1111/bph.13959 · Cited by 171 · see citing works
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The Impact of Intratumoral and Gastrointestinal Microbiota on Systemic Cancer Therapy
Cogdill, A. P., Gaudreau, P. O., Arora, R., Gopalakrishnan, V., & Wargo, J. A. (2018) · Trends in Immunology · doi:10.1016/j.it.2018.09.007 · Cited by 98 · see citing works
- Authors
- Randrianarisoa, E., Lehn-Stefan, A., Wang, X., Hoene, M., Peter, A., Heinzmann, S. S., Zhao, X., Königsrainer, I., Königsrainer, A., Balletshofer, B., Machann, J., Schick, F., Fritsche, A., Häring, H.-U., Xu, G., Lehmann, R., & Stefan, N.
- Affiliations
- Helmholtz Munich (DE)
- Dalian Institute of Chemical Physics (CN)
- University of Tübingen (DE)
- Corresponding author
- Stefan, Norbert
- ORCID
- Venue
- Scientific Reports
- Published
- 2016-05-27
- Volume
- 6
- Issue
- 1
- Pages
- 26745-26745
- ISSN
- 2045-2322 (ISSN-L)
- PMC
- PMC4882652
- OpenAlex
- W2407875089
- Cited by
- 296
- References
- 10
- Citations by year
- 2026: 13 · 2025: 23 · 2024: 27 · 2023: 28 · 2022: 33 · 2021: 47 · 2020: 37 · 2019: 34 · 2018: 31 · 2017: 18 · 2016: 5
- FWCI
- 29.44
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Scientific Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Dalian Institute of Chemical Physics, CAS Institutional Repository (submittedVersion)
- Site cant be reached (submittedVersion, cc-by)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (STE 1096/1-3, KFO 114)
- National Natural Science Foundation of China (21321064, 21435006)
- Bundesministerium für Bildung und Forschung (21435006, 21321064)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Keywords
- trimethylamine N-oxide, carotid intima-media thickness, early atherosclerosis, cardiovascular risk, insulin resistance, visceral obesity, hepatic steatosis, liver fat, lifestyle intervention, serum biomarkers
- MeSH terms
- Adult, Female, Humans, Insulin Resistance, Male, Methylamines, Middle Aged, Oxidative Stress, Intra-Abdominal Fat, Adiposity, Atherosclerosis
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