Elevated Circulating Trimethylamine N-Oxide Levels Contribute to Endothelial Dysfunction in Aged Rats through Vascular Inflammation and Oxidative Stress
Open accessAbstract
Vascular endothelial dysfunction, a characteristic of the aging process, is an important risk factor for cardiovascular disease in aging. Although vascular inflammation and oxidative stress are major contributors to endothelial dysfunction in aging, the underlying mechanisms during the aging process are not fully understood. Accumulating evidence reveals that gut microbiota-dependent metabolite trimethylamine-N-oxide (TMAO) is implicated in the pathogenesis of many cardiovascular diseases. We tested the hypothesis that aging increases circulating TMAO levels, which induce vascular inflammation and oxidative stress, resulting in age-associated endothelial dysfunction. Old (22-mo-old) and young (4-mo-old) Fischer-344 rats were treated without (control) or with 1.0 % 3,3-Dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) in drinking water for 8 weeks. Compared with young control group, old control group had markedly higher plasma TMAO levels, which were reduced by DMB treatment. Endothelium-dependent relaxation of aorta in response to acetylcholine was impaired in old control group compared with young control group as indicated by decreased maximal relaxation (Emax) and reduced area under the curve (AUC). Emax and AUC were both normalized in old rats treated with DMB. No difference in endothelial-independent relaxation in response to sodium nitroprusside was observed among groups. Molecular studies revealed that old control group exhibits increased expression of proinflammatory cytokines and superoxide production, and decreased expression of endothelial nitric-oxide synthase (eNOS) in the aorta, all of which were restored by DMB treatment. These results suggest that aging increases circulating TMAO levels, which may impair eNOS-derived NO bioavailability by increasing vascular inflammation and oxidative stress, contributing to aging-associated endothelial dysfunction.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
DMB cannot avoid complete TMAO synthesis because it cannot inhibit the conversion of GBB to TMA.
“Although it inhibits the transformation of choline, carnitine and crotonobetaine into TMA in mice and rats, DMB is not able to avoid the complete TMAO synthesis as it cannot inhibit the conversion of GBB to TMA [8,17,32,38].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [32]
DMB inhibits the transformation of choline, carnitine and crotonobetaine into TMA in mice and rats.
“Although it inhibits the transformation of choline, carnitine and crotonobetaine into TMA in mice and rats, DMB is not able to avoid the complete TMAO synthesis as it cannot inhibit the conversion of GBB to TMA [8,17,32,38].”
From Implication of Trimethylamine N-Oxide (TMAO) in Disease: Potential Biomarker or New Therapeutic Target (2018) · cites this paper as [32]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
Wang, Z., Klipfell, E., Bennett, B. J., Koeth, R., Levison, B. S., DuGar, B., Feldstein, A. E., Britt, E. B., Fu, X., Chung, Y.-M., et al. (2011) · Nature · doi:10.1038/nature09922 · Cited by 5,597 · see citing works
Intestinal microbiota metabolism of l-carnitine, a nutrient in red meat, promotes atherosclerosis
Koeth, R. A., Wang, Z., Levison, B. S., Buffa, J. A., Org, E., Sheehy, B. T., Britt, E. B., Fu, X., Wu, Y., Li, L., et al. (2013) · Nature Medicine · doi:10.1038/nm.3145 · Cited by 4,386 · see citing works
Lakatta, E. G., & Levy, D. (2003) · Circulation · doi:10.1161/01.cir.0000048892.83521.58 · Cited by 2,244 · see citing works
Wang, Z., Roberts, A. B., Buffa, J. A., Levison, B. S., Zhu, W., Org, E., Gu, X., Huang, Y., Zamanian-Daryoush, M., Culley, M. K., et al. (2015) · Cell · doi:10.1016/j.cell.2015.11.055 · Cited by 1,317 · see citing works
Marques, F. Z., Nelson, E., Chu, P.-Y., Horlock, D., Fiedler, A., Ziemann, M., Tan, J. K., Kuruppu, S., Rajapakse, N. W., El-Osta, A., et al. (2017) · Circulation · doi:10.1161/circulationaha.116.024545 · Cited by 1,065 · see citing works
Seldin, M. M., Meng, Y., Qi, H., Zhu, W., Wang, Z., Hazen, S. L., Lusis, A. J., & Shih, D. M. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.115.002767 · Cited by 911 · see citing works
Yoshizumi, M., Perrella, M. A., Burnett, J. C., & Lee, M. E. (1993) · Circulation Research · doi:10.1161/01.res.73.1.205 · Cited by 771 · cited 1× · see citing works
“Increased proinflammatory cytokines, a hallmark of aging, have been shown to downregulate eNOS activity in endothelial cells (Yoshizumi et al., 1993; Heeringa et al., 2002; Herrera et al., 2010) and cause vascular oxidative stress, leading to vascular damage in aging (Csiszar et al., 2007; Zhang et…”
BackgroundChen, M.-L., Yi, L., Zhang, Y., Zhou, X., Ran, L., Yang, J., Zhu, J.-D., Zhang, Q.-Y., & Mi, M.-T. (2016) · mBio · doi:10.1128/mbio.02210-15 · Cited by 754 · cited 3× · see citing works
“…that TMAO promotes vascular inflammation and oxidative stress, inhibits eNOS expression and activity and reduces NO production, which are associated with endothelial dysfunction and atherosclerosis (Wang et al., 2011; Hu et al., 2015; Chen et al., 2016; Seldin et al., 2016; Sun et al., 2016).”
BackgroundAging and vascular endothelial function in humans
Seals, D. R., Jablonski, K. L., & Donato, A. J. (2011) · Clinical Science · doi:10.1042/cs20100476 · Cited by 725 · see citing works
Role of TNF-α in vascular dysfunction
Zhang, H., Park, Y., Wu, J., Chen, X. P., Lee, S., Yang, J., Dellsperger, K. C., & Zhang, C. (2009) · Clinical Science · doi:10.1042/cs20080196 · Cited by 683 · see citing works
The contributory role of gut microbiota in cardiovascular disease
Tang, W. H. W., & Hazen, S. L. (2014) · Journal of Clinical Investigation · doi:10.1172/jci72331 · Cited by 641 · see citing works
Aging-Induced Phenotypic Changes and Oxidative Stress Impair Coronary Arteriolar Function
Csiszár, A., Ungvari, Z. I., Edwards, J. G., Kaminski, P. M., Wolin, M. S., Koller, Á., & Kaley, G. (2002) · Circulation Research · doi:10.1161/01.res.0000020401.61826.ea · Cited by 565 · see citing works
Cellular and molecular biology of aging endothelial cells
Donato, A. J., Morgan, R. G., Walker, A. E., & Lesniewski, L. A. (2015) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2015.01.021 · Cited by 538 · see citing works
Sun, X., Jiao, X., Ma, Y., Liu, Y., Zhang, L., He, Y., & Chen, Y. (2016) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2016.11.017 · Cited by 507 · see citing works
Self-citationTransmission of Atherosclerosis Susceptibility with Gut Microbial Transplantation
Gregory, J. C., Buffa, J. A., Org, E., Wang, Z., Levison, B. S., Zhu, W., Wagner, M. A., Bennett, B. J., Li, L., DiDonato, J. A., et al. (2015) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.618249 · Cited by 486 · see citing works
Li, X. S., Obeid, S., Klingenberg, R., Gencer, B., Mach, F., Räber, L., Windecker, S., Rodondi, N., Nanchen, D., Muller, O., et al. (2017) · European Heart Journal · doi:10.1093/eurheartj/ehw582 · Cited by 479 · see citing works
Self-citationGut microbiota: A player in aging and a target for anti-aging intervention
Vaiserman, A. M., Koliada, A. K., & Marotta, F. (2017) · Ageing Research Reviews · doi:10.1016/j.arr.2017.01.001 · Cited by 465 · see citing works
Organ, C. L., Otsuka, H., Bhushan, S., Wang, Z., Bradley, J., Trivedi, R., Polhemus, D. J., Tang, W. H. W., Wu, Y., Hazen, S. L., et al. (2016) · Circulation: Heart Failure · doi:10.1161/circheartfailure.115.002314 · Cited by 382 · see citing works
Alterations in the gut microbiota can elicit hypertension in rats
Adnan, S., Nelson, J. W., Ajami, N. J., Venna, V. R., Petrosino, J. F., Bryan, R. M., & Durgan, D. J. (2016) · Physiological Genomics · doi:10.1152/physiolgenomics.00081.2016 · Cited by 380 · see citing works
Tang, W. H. W., Wang, Z., Shrestha, K., Borowski, A. G., Wu, Y., Troughton, R. W., Klein, A. L., & Hazen, S. L. (2015) · Journal of Cardiac Failure · doi:10.1016/j.cardfail.2014.11.006 · Cited by 325 · see citing works
Endothelial dysfunction and aging: An update
Herrera, M. D., Mingorance, C., Rodríguez‐Rodríguez, R., & de Sotomayor, M. Á. (2009) · Ageing Research Reviews · doi:10.1016/j.arr.2009.07.002 · Cited by 322 · see citing works
Endothelial Function and Oxidant Stress
Harrison, D. G. (1997) · Clinical Cardiology · doi:10.1002/j.1932-8737.1997.tb00007.x · Cited by 302 · see citing works
Proinflammatory Profile Within the Grossly Normal Aged Human Aortic Wall
Wang, M., Zhang, J., Jiang, L.-Q., Spinetti, G., Pintus, G., Monticone, R. E., Kolodgie, F. D., Virmani, R., & Lakatta, E. G. (2007) · Hypertension · doi:10.1161/hypertensionaha.107.089409 · Cited by 269 · see citing works
Effect of age on kinetics of nitric oxide release in rat aorta and pulmonary artery.
Tschudi, M. R., Barton, M., Bersinger, N. A., Moreau, P. R., Cosentino, F., Noll, G., Maliñski, T., & Lüscher, T. F. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118872 · Cited by 260 · see citing works
Mechanisms Involved in the Aging-Induced Vascular Dysfunction
Fuente, M. E. A. D. L., Angulo, J., Fernán, S. E., Peiró, C., Sánchez‐Ferrer, C. F., & Rodríguez‐Mañas, L. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00132 · Cited by 226 · see citing works
Anatomic Heterogeneity of Vascular Aging
Barton, M., Cosentino, F., Brandes, R. P., Moreau, P. R., Shaw, S., & Lüscher, T. F. (1997) · Hypertension · doi:10.1161/01.hyp.30.4.817 · Cited by 222 · see citing works
Vasculoprotective Effects of Anti-Tumor Necrosis Factor-α Treatment in Aging
Csiszár, A., Labinskyy, N., Smith, K. E., Rivera, A., Orosz, Z. Z., & Ungvari, Z. I. (2007) · American Journal Of Pathology · doi:10.2353/ajpath.2007.060708 · Cited by 214 · see citing works
Ufnal, M., Jazwiec, R., Dadlez, M., Drapala, A., Sikora, M., & Skrzypecki, J. (2014) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2014.09.010 · Cited by 205 · see citing works
Trimethylamine <i>N</i> ‐Oxide and Mortality Risk in Patients With Peripheral Artery Disease
Senthong, V., Wang, Z., Fan, Y., Wu, Y., Hazen, S. L., & Tang, W. H. W. (2016) · Journal of the American Heart Association · doi:10.1161/jaha.116.004237 · Cited by 175 · see citing works
Microbiome, trimethylamine N-oxide, and cardiometabolic disease
Tang, W. H. W., & Hazen, S. L. (2017) · Translational Research · doi:10.1016/j.trsl.2016.07.007 · Cited by 160 · see citing works
Vascular Smooth Muscle and Endothelial Functions in Aging
Yıldız, O. (2007) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1395.038 · Cited by 152 · see citing works
Aerobic exercise reverses arterial inflammation with aging in mice
Lesniewski, L. A., Durrant, J., Connell, M. L., Henson, G. D., Black, A. D., Donato, A. J., & Seals, D. R. (2011) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.01276.2010 · Cited by 144 · see citing works
Soucy, K. G., Ryoo, S., Benjo, A., Lim, H. K., Gupta, G., Sohi, J. S., Elser, J., Aon, M. A., Nyhan, D., Shoukas, A. A., et al. (2006) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00138.2006 · Cited by 135 · see citing works
Contribution of oxidative stress to endothelial dysfunction in hypertension
Silva, B. R., Pernomian, L., & Bendhack, L. M. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00441 · Cited by 133 · see citing works
Positive crosstalk between arginase‐II and S6K1 in vascular endothelial inflammation and aging
Yepuri, G., Velagapudi, S., Xiong, Y., Rajapakse, A. G., Montani, J., Ming, X., & Yang, Z. (2012) · Aging Cell · doi:10.1111/acel.12001 · Cited by 129 · see citing works
Exercise training improves ageing‐induced decrease in eNOS expression of the aorta
Tanabe, T., Maeda, S., Miyauchi, T., Iemitsu, M., Takanashi, M., Irukayama‐Tomobe, Y., Yokota, T., Ohmori, H., & Matsuda, M. (2003) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2003.01100.x · Cited by 122 · see citing works
Differential Modulation of Nitric Oxide Synthases in Aging: Therapeutic Opportunities
Cáu, S. B. D. A., Carneiro, F. S., & Tostes, R. C. (2012) · Frontiers in Physiology · doi:10.3389/fphys.2012.00218 · Cited by 121 · see citing works
Exploring the Microbiome in Heart Failure
Kitai, T., Kirsop, J., & Tang, W. H. W. (2016) · Current Heart Failure Reports · doi:10.1007/s11897-016-0285-9 · Cited by 76 · see citing works
Hezel, M. P., Peleli, M., Liu, M. R., Zollbrecht, C., Jensen, B. L., Checa, A., Giulietti, A., Wheelock, C. E., Lundberg, J. O., Weitzberg, E., et al. (2016) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2016.07.025 · Cited by 73 · see citing works
The Influence of the Gut Microbiota on Host Physiology: In Pursuit of Mechanisms.
Jones, R. M. (2016) · PubMed Central · Cited by 70 · see citing works
Hu, Y., Zhao, Y., Yuan, L., & Yang, X. (2015) · Food & Function · doi:10.1039/c5fo00581g · Cited by 68 · see citing works
Redox Control of Vascular Nitric Oxide Bioavailability
Price, D. T., Vita, J. A., & Keaney, J. F. (2000) · Antioxidants and Redox Signaling · doi:10.1089/ars.2000.2.4-919 · Cited by 44 · see citing works
A protective role for endothelial nitric oxide synthase in glomerulonephritis
Heeringa, P., Steenbergen, E., & van Goor, H. (2002) · Kidney International · doi:10.1046/j.1523-1755.2002.00227.x · Cited by 37 · see citing works
Gut Microbiota in Vascular Disease: Therapeutic Target?
Anbazhagan, A. N., Priyamvada, S., & Priyadarshini, M. (2017) · Current Vascular Pharmacology · doi:10.2174/1570161115666170105095834 · Cited by 23 · see citing works
Martens, C. R., Kuczmarski, J. M., Kim, J., Guers, J. J., Harris, M. B., Lennon, S. L., & Edwards, D. G. (2014) · American Journal of Physiology-Renal Physiology · doi:10.1152/ajprenal.00014.2014 · Cited by 20 · see citing works
Intermittent parathyroid hormone administration attenuates endothelial dysfunction in old rats
Guers, J. J., Prisby, R. D., Edwards, D. G., & Lennon, S. L. (2016) · Journal of Applied Physiology · doi:10.1152/japplphysiol.00348.2016 · Cited by 9 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Janeiro, M., Ramírez, M., Milagro, F., Martínez, J., & Solas, M. (2018) · Nutrients · doi:10.3390/nu10101398 · Cited by 631 · see citing works
Development of a gut microbe–targeted nonlethal therapeutic to inhibit thrombosis potential
Roberts, A. B., Gu, X., Buffa, J. A., Hurd, A. G., Wang, Z., Zhu, W., Gupta, N., Skye, S. M., Cody, D. B., Levison, B. S., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0128-1 · Cited by 552 · see citing works
Yang, S., Li, X., Yang, F., Zhao, R., Pan, X., Liang, J., Tian, L., Li, X., Liu, L., Xing, Y., et al. (2019) · Frontiers in Pharmacology · doi:10.3389/fphar.2019.01360 · Cited by 347 · see citing works
Self-citationTrimethylamine‐<i>N</i>‐oxide promotes brain aging and cognitive impairment in mice
Li, D., Ke, Y., Zhan, R., Liu, C., Zhao, M., Zeng, A., Shi, X., Ji, L., Cheng, S., Pan, B., et al. (2018) · Aging Cell · doi:10.1111/acel.12768 · Cited by 304 · see citing works
Zhang, X., Li, Y., Yang, P., Liu, X., Lu, L., Chen, Y., Zhong, X., Li, Z., Liu, H., Ou, C., et al. (2020) · Arteriosclerosis, Thrombosis, and Vascular Biology · doi:10.1161/atvbaha.119.313414 · Cited by 291 · see citing works
Self-citationKe, Y., Li, D., Zhao, M., Liu, C., Liu, J., Zeng, A., Shi, X., Cheng, S., Pan, B., Zheng, L., et al. (2018) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2018.01.007 · Cited by 285 · see citing works
Brunt, V. E., Gioscia‐Ryan, R. A., Casso, A. G., VanDongen, N. S., Ziemba, B. P., Sapinsley, Z. J., Richey, J. J., Zigler, M. C., Neilson, A. P., Davy, K. P., et al. (2020) · Hypertension · doi:10.1161/hypertensionaha.120.14759 · Cited by 285 · see citing works
The gut microbial metabolite trimethylamine N-oxide and cardiovascular diseases
Zhen, J., Zhou, Z., He, M., Han, H.-X., Lv, E., Wen, P., Liu, X., Wang, Y., Cai, X., Tian, J., et al. (2023) · Frontiers in Endocrinology · doi:10.3389/fendo.2023.1085041 · Cited by 240 · see citing works
Liu, Y., & Dai, M. (2020) · Mediators of Inflammation · doi:10.1155/2020/4634172 · Cited by 231 · see citing works
Resveratrol and endothelial function: A literature review
Parsamanesh, N., Asghari, A., Sardari, S., Tasbandi, A., Jamialahmadi, T., Xu, S., & Sahebkar, A. (2021) · Pharmacological Research · doi:10.1016/j.phrs.2021.105725 · Cited by 210 · see citing works
Gut Microbiota-Derived TMAO: A Causal Factor Promoting Atherosclerotic Cardiovascular Disease?
Canyelles, M., Borràs, C., Rotllán, N., Tondo, M., Escolá‐Gil, J. C., & Blanco‐Vaca, F. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24031940 · Cited by 211 · see citing works
Brunt, V. E., LaRocca, T. J., Bazzoni, A. E., Sapinsley, Z. J., Miyamoto-Ditmon, J., Gioscia-Ryan, R. A., Neilson, A. P., Link, C. D., & Seals, D. R. (2021) · GeroScience · doi:10.1007/s11357-020-00257-2 · Cited by 197 · see citing works
Lyu, M., Wang, Y., Fan, G., Wang, X., Xu, S.-Y., & Zhu, Y. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.02146 · Cited by 193 · see citing works
Brunt, V. E., Gioscia‐Ryan, R. A., Richey, J. J., Zigler, M. C., Cuevas, L. M., Gonzalez, A., Vázquez‐Baeza, Y., Battson, M. L., Smithson, A. T., Gilley, A. D., et al. (2019) · The Journal of Physiology · doi:10.1113/jp277336 · Cited by 182 · see citing works
The gut microbiota as a novel regulator of cardiovascular function and disease
Battson, M. L., Lee, D. M., Weir, T. L., & Gentile, C. L. (2017) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2017.12.010 · Cited by 185 · see citing works
Benson, T. W., Conrad, K. A., Li, X. S., Wang, Z., Helsley, R. N., Schugar, R. C., Coughlin, T. M., Wadding-Lee, C., Fleifil, S., Russell, H., et al. (2023) · Circulation · doi:10.1161/circulationaha.122.060573 · Cited by 165 · see citing works
Self-citationTrimethylamine N-Oxide in Relation to Cardiometabolic Health—Cause or Effect?
Papandreou, C., Moré, M. I., & Bellamine, A. (2020) · Nutrients · doi:10.3390/nu12051330 · Cited by 150 · see citing works
Chou, R., Chen, C., Chen, I., Huang, H.-L., Lu, Y., Kuo, C., Chang, C., Huang, P., Chen, J., & Lin, S. (2019) · Scientific Reports · doi:10.1038/s41598-019-40638-y · Cited by 135 · see citing works
Wang, Q., Shen, Y., Wang, X., Fu, S., Zhang, X., Zhang, Y., & Wang, R. (2020) · Aging · doi:10.18632/aging.102645 · Cited by 129 · see citing works
Li, L., Chen, B., Zhu, R., Li, R., Tian, Y., Liu, C., Jia, Q., Wang, L., Tang, J., Zhao, D., et al. (2019) · Aging · doi:10.18632/aging.102376 · Cited by 128 · see citing works
Gut Microbiota-Derived Metabolites in Colorectal Cancer: The Bad and the Challenges
Zhang, W., An, Y., Qin, X., Wu, X., Wang, X., Hou, H., Song, X., Liu, T., Wang, B., Huang, X., et al. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.739648 · Cited by 119 · see citing works
Witkowski, M., Witkowski, M., Friebel, J., Buffa, J. A., Li, X. S., Wang, Z., Sangwan, N., Li, L., DiDonato, J. A., Tizian, C., et al. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab263 · Cited by 116 · see citing works
Self-citationPraveenraj, S. S., Sonali, S., Anand, N., Hediyal, T. A., Vichitra, C., Kalyan, M., Kanna, P. V., Chandana, K. A., Paneyala, S., Mahalakshmi, A. M., et al. (2022) · Molecular Neurobiology · doi:10.1007/s12035-022-02990-5 · Cited by 111 · see citing works
Du, D., Tang, W., Zhou, C., Sun, X., Wei, Z., Zhong, J., & Huang, Z. (2021) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2021/5816837 · Cited by 103 · see citing works
Uraemic solutes as therapeutic targets in CKD-associated cardiovascular disease
Ravid, J. D., Kamel, M. H., & Chitalia, V. C. (2021) · Nature Reviews Nephrology · doi:10.1038/s41581-021-00408-4 · Cited by 102 · see citing works
3,3-Dimethyl-1-butanol attenuates cardiac remodeling in pressure-overload-induced heart failure mice
Wang, G., Kong, B., Shuai, W., Fu, H., Jiang, X., & Huang, H. (2020) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2020.108341 · Cited by 100 · see citing works
Can Meat and Meat-Products Induce Oxidative Stress?
Macho‐González, A., Garcimartín, A., López‐Oliva, M. E., Bastida, S., Benedı́, J., Ros, G., Nieto, G., & Sánchez-Muniz, F. J. (2020) · Antioxidants · doi:10.3390/antiox9070638 · Cited by 106 · see citing works
High Mobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction
Singh, G. B., Zhang, Y., Boini, K. M., & Koka, S. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20143570 · Cited by 102 · see citing works
Chan, C. W. H., Law, B. M. H., Waye, M. M. Y., Chan, J. Y., So, W. K. W., & Chow, K. M. (2019) · Journal of Cancer · doi:10.7150/jca.31737 · Cited by 96 · see citing works
Mosterd, C. M., Kanbay, M., van den Born, B. H., van Raalte, D. H., & Rampanelli, E. (2021) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2021.101484 · Cited by 94 · see citing works
Contribution of Trimethylamine N-Oxide (TMAO) to Chronic Inflammatory and Degenerative Diseases
Constantino-Jonapa, L. A., Espinoza-Palacios, Y., Escalona‐Montaño, A. R., Hernández-Ruiz, P., Amezcua-Guerra, L. M., Amedei, A., & Aguirre‐García, M. M. (2023) · Biomedicines · doi:10.3390/biomedicines11020431 · Cited by 97 · see citing works
Shanmugham, M., Bellanger, S., & Leo, C. H. (2023) · Pharmaceuticals · doi:10.3390/ph16040504 · Cited by 96 · see citing works
Li, T., Gua, C., Wu, B., & Chen, Y. (2017) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2017.12.069 · Cited by 86 · see citing works
Self-citationTrimethylamine-N-Oxide (TMAO) as a Rising-Star Metabolite: Implications for Human Health
Caradonna, E., Abate, F., Schiano, E., Paparella, F., Ferrara, F., Vanoli, E., Difruscolo, R., Goffredo, V. M., Amato, B., Setacci, C., et al. (2025) · Metabolites · doi:10.3390/metabo15040220 · Cited by 88 · see citing works
Oktaviono, Y. H., Lamara, A. D., Saputra, P. B. T., Arnindita, J. N., Pasahari, D., Saputra, M. E., & Suasti, N. M. A. (2023) · Biomolecules and Biomedicine · doi:10.17305/bb.2023.8893 · Cited by 87 · see citing works
Cai, C., Zhang, Z., Morales, M., Wang, Y., Khafipour, E., & Friel, J. K. (2019) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2019.02.032 · Cited by 76 · see citing works
Trimethylamine N -oxide: heart of the microbiota–CVD nexus?
Naghipour, S., Cox, A. J., Peart, J. N., Toit, E. F. D., & Headrick, J. P. (2020) · Nutrition Research Reviews · doi:10.1017/s0954422420000177 · Cited by 75 · see citing works
Probiotics: Protecting Our Health from the Gut
Varela-Trinidad, G. U., Domínguez-Díaz, C., Solórzano-Castanedo, K., Íñiguez-Gutiérrez, L., Hernández-Flores, T. D. J., & Fafutis‐Morris, M. (2022) · Microorganisms · doi:10.3390/microorganisms10071428 · Cited by 78 · see citing works
Chen, H., Li, J., Li, N., Liu, H., & Tang, J. (2019) · Hypertension in Pregnancy · doi:10.1080/10641955.2019.1584630 · Cited by 72 · see citing works
Resveratrol: Molecular Mechanisms, Health Benefits, and Potential Adverse Effects
Ren, Z., Zheng, S., Sun, Z., Luo, Y., Wang, Y., Yi, P., Li, Y., Huang, C., & Xiao, W. (2025) · MedComm · doi:10.1002/mco2.70252 · Cited by 71 · see citing works
Chan, M. M.-Y., Yang, X., Wang, H., Saaoud, F., Sun, Y., & Fong, D. (2019) · Nutrients · doi:10.3390/nu11081821 · Cited by 68 · see citing works
Zou, X., Wang, L., Xiao, L., Wang, S., & Zhang, L. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.975921 · Cited by 70 · see citing works
Bruyne, T. D., Steenput, B., Roth, L., Meyer, G. R. Y. D., dos Santos, C. N., Valentová, K., Dambrova, M., & Hermans, N. (2019) · Nutrients · doi:10.3390/nu11030578 · Cited by 68 · see citing works
Meng, F., Li, N., Li, D., Song, B., & Li, L. (2019) · Behavioural Brain Research · doi:10.1016/j.bbr.2019.111902 · Cited by 67 · see citing works
Wu, S., Luo, T., Wang, S., Zhou, J., Ni, Y., Fu, Z., & Jin, Y. (2018) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2018.06.084 · Cited by 62 · see citing works
Ageing mechanisms that contribute to tissue remodeling in lung disease
Schuliga, M. J., Read, J. M., & Knight, D. A. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101405 · Cited by 62 · see citing works
Tacconi, E., Palma, G., Biase, D. D., Luciano, A., Barbieri, M., de Nigris, F., & Bruzzese, F. (2023) · Nutrients · doi:10.3390/nu15030563 · Cited by 62 · see citing works
Zhang, H., Meng, J., & Yu, H. (2017) · Frontiers in Physiology · doi:10.3389/fphys.2017.00944 · Cited by 59 · see citing works
Microbial Metabolite Dysbiosis and Colorectal Cancer
Niekamp, P., & Kim, C. H. (2023) · Gut and Liver · doi:10.5009/gnl220260 · Cited by 56 · see citing works
Kuka, J., Ozola, M., Makrecka‐Kuka, M., Liepinsh, E., Grı̄nberga, S., Sevostjanovs, E., Vilks, K., Liepinsh, E., & Dambrova, M. (2020) · Scientific Reports · doi:10.1038/s41598-020-71470-4 · Cited by 52 · see citing works
He, W., Luo, Y., Liu, J., Sun, N. L., Guo, D., Cui, L.-L., Zheng, P., Yao, S.-M., Yang, J.-F., & Wang, H. (2020) · Clinical Interventions in Aging · doi:10.2147/cia.s270887 · Cited by 52 · see citing works
Godos, J., Romano, G. L., Gozzo, L., Laudani, S., Paladino, N., Azpíroz, I. D., López, N. M. M., Giampieri, F., Quiles, J. L., Battino, M. A., et al. (2024) · Frontiers in Pharmacology · doi:10.3389/fphar.2024.1368949 · Cited by 51 · see citing works
Ozola, M., Vilšķe̅rsts, R., Korzh, S., Cirule, H., Sevostjanovs, E., Dambrova, M., & Makrecka‐Kuka, M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.622741 · Cited by 50 · see citing works
Stroke and Vascular Cognitive Impairment: The Role of Intestinal Microbiota Metabolite TMAO
Tu, R., & Xia, J. (2024) · CNS & Neurological Disorders - Drug Targets · doi:10.2174/1871527322666230203140805 · Cited by 47 · see citing works
Gut microbiota metabolites, redox status, and the related regulatory effects of probiotics
Zhao, J.-S., Zhao, F., Yuan, J., Liu, H., & Wang, Y. (2023) · Heliyon · doi:10.1016/j.heliyon.2023.e21431 · Cited by 47 · see citing works
Farhangi, M. A., & Vajdi, M. (2020) · Nutrition Reviews · doi:10.1093/nutrit/nuaa111 · Cited by 46 · see citing works
Wiese, G. N., Biruete, A., Moorthi, R. N., Moe, S. M., Lindemann, S. R., & Gallant, K. M. H. (2020) · Journal of Renal Nutrition · doi:10.1053/j.jrn.2020.04.007 · Cited by 46 · see citing works
Therapeutic potential of natural products against atherosclerosis: Targeting on gut microbiota
Zhao, X., Oduro, P. K., Tong, W., Wang, Y., Gao, X., & Wang, Q. (2020) · Pharmacological Research · doi:10.1016/j.phrs.2020.105362 · Cited by 47 · see citing works
Thenappan, T., Khoruts, A., Chen, Y., & Weir, Ε. K. (2019) · American Journal of Physiology-Heart and Circulatory Physiology · doi:10.1152/ajpheart.00416.2019 · Cited by 45 · see citing works
Self-citationZhao, L., Zhang, C., Cao, G., Dong, X., Li, D., & Jiang, L. (2019) · Neurochemical Research · doi:10.1007/s11064-019-02868-4 · Cited by 46 · see citing works
Quan, L., Yi, J., Zhao, Y., Zhang, F., Shi, X.-T., Feng, Z., & Miller, H. L. (2020) · NeuroToxicology · doi:10.1016/j.neuro.2019.10.012 · Cited by 44 · see citing works
Li, T., Chen, Y., Gua, C., & Wu, B. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.00840 · Cited by 44 · see citing works
Self-citationGut microbial metabolite TMAO portends prognosis in acute ischemic stroke
Zhang, J., Wang, L., Cai, J., Lei, A., Liu, C., Lin, R., Li, J., & Fu, Y. (2021) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2021.577526 · Cited by 44 · see citing works
Gut Microbiome Interactions with Oxidative Stress: Mechanisms and Consequences for Health
Semenova, N. V., Евгеньевна, Г. Н., Kolesnikov, S. I., Darenskaya, M. A., & Kolesnikova, L. (2024) · Pathophysiology · doi:10.3390/pathophysiology31030023 · Cited by 43 · see citing works
Contribution of Gut Microbiota-Derived Uremic Toxins to the Cardiovascular System Mineralization
Filipska, I., Winiarska, A., Knysak, M., & Stompór, T. P. (2021) · Toxins · doi:10.3390/toxins13040274 · Cited by 42 · see citing works
Pathogenic Mechanisms of Trimethylamine N-Oxide-induced Atherosclerosis and Cardiomyopathy
Zheng, Y., & He, J. (2021) · Current Vascular Pharmacology · doi:10.2174/1570161119666210812152802 · Cited by 44 · see citing works
Liu, G., Cheng, J., Zhang, T., Shao, Y., Chen, X., Han, L., Zhou, R., & Wu, B. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.856914 · Cited by 42 · see citing works
Use of dietary phytochemicals for inhibition of trimethylamine N-oxide formation
Iglesias‐Carres, L., Hughes, M. D., Steele, C. N., Ponder, M. A., Davy, K. P., & Neilson, A. P. (2021) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2021.108600 · Cited by 42 · see citing works
Krueger, E. S., Lloyd, T. S., & Tessem, J. S. (2021) · Nutrients · doi:10.3390/nu13082873 · Cited by 40 · see citing works
Trimethylamine-N-oxide and cerebral stroke risk: A review
Dolkar, P., Deyang, T., Anand, N., Rathipriya, A. G., Hediyal, T. A., Vichitra, C., Krishnamoorthy, N. K., Gorantla, V. R., Bishir, M., Rashan, L. J., et al. (2024) · Neurobiology of Disease · doi:10.1016/j.nbd.2024.106423 · Cited by 43 · see citing works
Mitchell, S. M., Milan, A. M., Mitchell, C. J., Gillies, N. A., D’Souza, R. F., Zeng, N., Ramzan, F., Sharma, P., Knowles, S. O., Roy, N. C., et al. (2019) · Nutrients · doi:10.3390/nu11092207 · Cited by 40 · see citing works
Gut Microbiota-Derived Metabolites in Atherosclerosis: Pathways, Biomarkers, and Targets
Tonch-Cerbu, A.-K., Boicean, A., Stoia, O., & Teodoru, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26178488 · Cited by 40 · see citing works
Vascular Cognitive Impairment and the Gut Microbiota
Li, S., Shao, Y., Li, K., HuangFu, C., Wang, W., Liu, Z., Cai, Z., & Zhao, B. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-171103 · Cited by 38 · see citing works
Role of S-Equol, Indoxyl Sulfate, and Trimethylamine N-Oxide on Vascular Function
Matsumoto, T., Kojima, M., Takayanagi, K., Taguchi, K., & Kobayashi, T. (2020) · American Journal of Hypertension · doi:10.1093/ajh/hpaa053 · Cited by 37 · see citing works
Resveratrol and the Interaction between Gut Microbiota and Arterial Remodelling
Man, A. W. C., Li, H., & Xia, N. (2020) · Nutrients · doi:10.3390/nu12010119 · Cited by 34 · see citing works
Bacterial-Induced Blood Pressure Reduction: Mechanisms for the Treatment of Hypertension via the Gut
Cookson, T. A. (2021) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2021.721393 · Cited by 34 · see citing works
Trimethylamine oxide: a potential target for heart failure therapy
Lv, S., Wang, Y., Zhang, W., & Shang, H. (2021) · Heart · doi:10.1136/heartjnl-2021-320054 · Cited by 35 · see citing works
Liu, X., Shao, Y., Tu, J., Sun, J., Li, L., Tao, J., Chen, J., & Chen, J. (2021) · Annals of Translational Medicine · doi:10.21037/atm-21-5043 · Cited by 34 · see citing works
Mödinger, Y., Schön, C., Wilhelm, M. G., & Hals, P. (2019) · Nutrients · doi:10.3390/nu11102548 · Cited by 34 · see citing works
Querio, G., Antoniotti, S., Levi, R. C., & Gallo, M. P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20123045 · Cited by 33 · see citing works
Matsumoto, T., Kojima, M., Takayanagi, K., Taguchi, K., & Kobayashi, T. (2020) · Biological and Pharmaceutical Bulletin · doi:10.1248/bpb.b19-00957 · Cited by 33 · see citing works
Wang, H., Luo, Q., Ding, X., Chen, L., & Zhang, Z. (2022) · Frontiers in Cardiovascular Medicine · doi:10.3389/fcvm.2022.922441 · Cited by 33 · see citing works
Food Peptides, Gut Microbiota Modulation, and Antihypertensive Effects
Tsafack, P. B., Li, C., & Tsopmo, A. (2022) · Molecules · doi:10.3390/molecules27248806 · Cited by 34 · see citing works
Xie, H., Jiang, J., Cao, S., Xu, X., Zhou, J., Zhang, R., Huang, B., Lu, P., Peng, L., & Liu, M. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26031373 · Cited by 33 · see citing works
Thrombolome and Its Emerging Role in Chronic Kidney Diseases
Fryc, J., & Naumnik, B. (2021) · Toxins · doi:10.3390/toxins13030223 · Cited by 34 · see citing works
Casso, A. G., VanDongen, N. S., Gioscia‐Ryan, R. A., Clayton, Z. S., Greenberg, N., Ziemba, B. P., Hutton, D. A., Neilson, A. P., Davy, K. P., Seals, D. R., et al. (2022) · The Journal of Physiology · doi:10.1113/jp283581 · Cited by 31 · see citing works
The association between the gut microbiota metabolite trimethylamine N-oxide and heart failure
Jarmukhanov, Z., Mukhanbetzhanov, N., Kozhakhmetov, S., Nurgaziyev, M., Sailybayeva, A., Bekbossynova, M. S., & Kushugulova, A. R. (2024) · Frontiers in Microbiology · doi:10.3389/fmicb.2024.1440241 · Cited by 34 · see citing works
microRNA-146a-5p association with the cardiometabolic disease risk factor TMAO
Coffey, A. R., Kanke, M., Smallwood, T., Albright, J., Pitman, W. A., Gharaibeh, R. Z., Hua, K., Gertz, E., Biddinger, S. B., Temel, R. E., et al. (2019) · Physiological Genomics · doi:10.1152/physiolgenomics.00079.2018 · Cited by 30 · see citing works
Gut Microbiota and Coronary Artery Disease: Current Therapeutic Perspectives
Katsimichas, T., Theofilis, P., Tsioufis, K. P., & Tousoulis, D. (2023) · Metabolites · doi:10.3390/metabo13020256 · Cited by 31 · see citing works
Botchway, B. O., Okoye, F. C., Chen, Y., Arthur, W. E., & Fang, M. (2022) · Aging and disease · doi:10.14336/ad.2021.0616 · Cited by 32 · see citing works
Self-citationLi, X., Sun, Y., Zhang, X., & Wang, J. (2019) · Molecular Medicine Reports · doi:10.3892/mmr.2019.10297 · Cited by 29 · see citing works
Self-citationYang, Y., Yang, B., Li, X., Xue, L., Liu, B., Liang, Y., Zhao, Z., Luo, Q., Liu, Z., Zeng, Q., et al. (2022) · Respiratory Research · doi:10.1186/s12931-022-02282-5 · Cited by 29 · see citing works
Self-citationTrimethylamine N-Oxide in Aquatic Foods
Li, X., Wang, C., Yanagita, T., Xue, C., Zhang, T., & Wang, Y. (2024) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.4c01974 · Cited by 28 · see citing works
Self-citationGao, X., Sun, G., Randell, E. W., Tian, Y., & Zhou, H. (2020) · Food & Function · doi:10.1039/d0fo01743d · Cited by 27 · see citing works
He, J., Li, H., Jia, J., Liu, Y., Zhang, N., Wang, R., Qu, W., Liu, Y., & Jia, L. (2023) · Molecular Biomedicine · doi:10.1186/s43556-023-00157-9 · Cited by 28 · see citing works
Olek, R. A., Samulak, J. J., Sawicka, A. K., Hartmane, D., Grı̄nberga, S., Pugovičs, O., & Łysiak−Szydłowska, W. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/6247169 · Cited by 27 · see citing works
Trimethylamine N-oxide—a marker for atherosclerotic vascular disease
Xie, G., An, Y., Lin, P., Wang, Y., & Guo, L. (2021) · Reviews in Cardiovascular Medicine · doi:10.31083/j.rcm2203085 · Cited by 27 · see citing works
Enterobacter aerogenes ZDY01 inhibits choline-induced atherosclerosis through CDCA-FXR-FGF15 axis
Tang, J., Qin, M., Tang, L. M., Shan, D., Zhang, C., Zhang, Y., Wei, H., Qiu, L., & Yu, J. (2021) · Food & Function · doi:10.1039/d1fo02021h · Cited by 26 · see citing works
Yun, B., King, M. T., Draz, M. S., Kline, T. R., & Rodriguez‐Palacios, A. (2021) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2021.11.009 · Cited by 25 · see citing works
Baranyi, A., Enko, D., von Lewinski, D., Rothenhäusler, H., Amouzadeh-Ghadikolai, O., Harpf, H. H., Harpf, L., Traninger, H., Obermayer-Pietsch, B. M., Schweinzer, M., et al. (2021) · European Journal of Psychotraumatology · doi:10.1080/20008198.2021.1920201 · Cited by 24 · see citing works
- Authors
- Li, T., Chen, Y., Gua, C., & Li, X.
- Affiliations
- Sheng Jing Hospital (CN)
- Corresponding author
- Li, Tiejun
- Venue
- Frontiers in Physiology
- Publisher
- Frontiers Media SA
- Published
- 2017-05-30
- Volume
- 8
- Pages
- 350-350
- ISSN
- 1664-042X (ISSN-L)
- PMC
- PMC5447752
- OpenAlex
- W2617058021
- Cited by
- 216
- References
- 46
- Citations by year
- 2026: 18 · 2025: 20 · 2024: 28 · 2023: 30 · 2022: 28 · 2021: 31 · 2020: 22 · 2019: 24 · 2018: 11 · 2017: 4
- FWCI
- 12.34
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Frontiers in Physiology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- China Medical University
- Topics
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Health and Disease Prevention
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- trimethylamine N-oxide, endothelial dysfunction, aging, vascular inflammation, oxidative stress, gut microbiota metabolites, 3,3-dimethyl-1-butanol, endothelial nitric oxide synthase, nitric oxide bioavailability, inflammatory cytokines, superoxide production, aortic relaxation, acetylcholine, F344 rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
