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Serum trimethylamine N-oxide and long-term mortality risk in rural northern China: a family-based cohort study
Published online by Cambridge University Press: 03 September 2025
Abstract
The current study aims to assess associations between trimethylamine N-oxide (TMAO) levels and mortality and to investigate modification effects of genetics. A total of 500 participants from a family-based cohort study were enrolled from 2005 to 2017 and followed up until 2020 in Fangshan District, Beijing, China. Serum TMAO levels were measured using the ELISA kit. The primary outcomes were all-cause mortality and deaths from CVD and stroke. During a median follow-up time of 7·38 years, thirty-eight deaths were recorded, including twenty deaths due to CVD and nineteen deaths due to stroke. Compared with the lowest TMAO quartile group, the HR for all-cause mortality was 1·35 (95 % CI: 0·44, 4·15), 1·65 (95 % CI: 0·58, 4·64) and 2·45 (95 % CI: 0·91, 6·57), respectively, in higher groups. No association was observed between TMAO and CVD mortality. However, compared with the lowest TMAO concentration group, the HR for stroke mortality was 1·93 (95 % CI: 0·40, 9·39), 1·91 (95 % CI: 0·41, 8·96) and 4·16 (95 % CI: 0·94, 18·52), respectively, in higher groups (Pfor trend = 0·046). Furthermore, polygenic risk score (PRS) for longevity modified the association of TMAO with all-cause mortality (Pfor interaction = 0·008). The risk of mortality (HR = 2·20, 95 % CI: 1·06, 4·57) was higher among participants with lower PRS compared with higher PRS (HR = 1·00, 95 % CI: 0·71, 1·40). The study indicates that elevated serum TMAO levels are potentially associated with long-term mortality risk in rural areas of northern China, especially for stroke deaths. Additionally, it provides novel evidence that genetic variations might modify the association.
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- © The Author(s), 2025. Published by Cambridge University Press on behalf of the Nutrition Society
Footnotes
Mengying Wang and Hexiang Peng contributed equally to the article.
References
Tang, WHW, Backhed, F, Landmesser, U, et al. (2019) Intestinal microbiota in cardiovascular health and disease: JACC state-of-the-art review. J Am Coll Cardiol 73, 2089–2105.10.1016/j.jacc.2019.03.024CrossRefGoogle ScholarPubMed
de Vos, WM, Tilg, H, Van Hul, M, et al. (2022) Gut microbiome and health: mechanistic insights. Gut 71, 1020–1032.10.1136/gutjnl-2021-326789CrossRefGoogle ScholarPubMed
Witkowski, M, Weeks, TL & Hazen, SL (2020) Gut microbiota and cardiovascular disease. Circ Res 127, 553–570.CrossRefGoogle ScholarPubMed
Wang, Z, Klipfell, E, Bennett, BJ, et al. (2011) Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease. Nature 472, 57–63.10.1038/nature09922CrossRefGoogle ScholarPubMed
Koeth, RA, Wang, Z, Levison, BS, et al. (2013) Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19, 576–585.CrossRefGoogle ScholarPubMed
Tang, WH, Wang, Z, Levison, BS, et al. (2013) Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. N Engl J Med 368, 1575–1584.10.1056/NEJMoa1109400CrossRefGoogle ScholarPubMed
Abbasi, J (2019) TMAO and heart disease: the new red meat risk? JAMA 321, 2149–2151.10.1001/jama.2019.3910CrossRefGoogle ScholarPubMed
Zhu, W, Gregory, JC, Org, E, et al. (2016) Gut microbial metabolite TMAO enhances platelet hyperreactivity and thrombosis risk. Cell 165, 111–124.10.1016/j.cell.2016.02.011CrossRefGoogle ScholarPubMed
Tang, WH, Wang, Z, Kennedy, DJ, et al. (2015) Gut microbiota-dependent trimethylamine N-oxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res 116, 448–455.10.1161/CIRCRESAHA.116.305360CrossRefGoogle ScholarPubMed
Chen, S, Henderson, A, Petriello, MC, et al. (2019) Trimethylamine N-Oxide binds and activates PERK to promote metabolic dysfunction. Cell Metab 30, 1141–1151 e5.10.1016/j.cmet.2019.08.021CrossRefGoogle ScholarPubMed
Chan, CWH, Law, BMH, Waye, MMY, et al. (2019) Trimethylamine-N-oxide as one hypothetical link for the relationship between intestinal microbiota and cancer – where we are and where shall we go? J Cancer 10, 5874–5882.10.7150/jca.31737CrossRefGoogle ScholarPubMed
Wang, M, Li, XS, Wang, Z, et al. (2023) Trimethylamine N-oxide is associated with long-term mortality risk: the multi-ethnic study of atherosclerosis. Eur Heart J 44, 1608–1618.10.1093/eurheartj/ehad089CrossRefGoogle Scholar
Schiattarella, GG, Sannino, A, Toscano, E, et al. (2017) Gut microbe-generated metabolite trimethylamine-N-oxide as cardiovascular risk biomarker: a systematic review and dose-response meta-analysis. Eur Heart J 38, 2948–2956.10.1093/eurheartj/ehx342CrossRefGoogle ScholarPubMed
Heianza, Y, Ma, W, Manson, JE, et al. (2017) Gut microbiota metabolites and risk of major adverse cardiovascular disease events and death: a systematic review and meta-analysis of prospective studies. J Am Heart Assoc 6, e004947.10.1161/JAHA.116.004947CrossRefGoogle Scholar
Qi, J, You, T, Li, J, et al. (2018) Circulating trimethylamine N-oxide and the risk of cardiovascular diseases: a systematic review and meta-analysis of 11 prospective cohort studies. J Cell Mol Med 22, 185–194.10.1111/jcmm.13307CrossRefGoogle ScholarPubMed
Farhangi, MA (2020) Gut microbiota-dependent trimethylamine N-oxide and all-cause mortality: findings from an updated systematic review and meta-analysis. Nutrition 78, 110856.10.1016/j.nut.2020.110856CrossRefGoogle ScholarPubMed
Li, X & Qi, L (2019) Gene–environment interactions on body fat distribution. Int J Mol Sci 20, 3690.10.3390/ijms20153690CrossRefGoogle ScholarPubMed
Virolainen, SJ, VonHandorf, A, Viel, K, et al. (2023) Gene–environment interactions and their impact on human health. Genes Immun 24, 1–11.10.1038/s41435-022-00192-6CrossRefGoogle ScholarPubMed
Liu, X, Song, Z, Li, Y, et al. (2021) Integrated genetic analyses revealed novel human longevity loci and reduced risks of multiple diseases in a cohort study of 15 651 Chinese individuals. Aging Cell 20, e13323.10.1111/acel.13323CrossRefGoogle Scholar
Rhee, EP, Ho, JE, Chen, MH, et al. (2013) A genome-wide association study of the human metabolome in a community-based cohort. Cell Metab 18, 130–143.10.1016/j.cmet.2013.06.013CrossRefGoogle Scholar
Jia, J, Dou, P, Gao, M, et al. (2019) Assessment of causal direction between gut microbiota-dependent metabolites and cardiometabolic health: a bidirectional Mendelian randomization analysis. Diabetes 68, 1747–1755.10.2337/db19-0153CrossRefGoogle Scholar
Tang, X, Hu, Y, Chen, D, et al. (2007) The Fangshan/family-based ischemic stroke study in China (FISSIC) protocol. BMC Med Genet 8, 60.10.1186/1471-2350-8-60CrossRefGoogle Scholar
Wu, N, Tang, X, Wu, Y, et al. (2014) Cohort profile: the Fangshan Cohort Study of cardiovascular epidemiology in Beijing, China. J Epidemiol 24, 84–93.10.2188/jea.JE20120230CrossRefGoogle ScholarPubMed
Liu, Z, Zhang, Y, Graham, S, et al. (2020) Causal relationships between NAFLD, T2D and obesity have implications for disease subphenotyping. J Hepatol 73, 263–276.10.1016/j.jhep.2020.03.006CrossRefGoogle ScholarPubMed
Nagata, C, Wada, K, Tamura, T, et al. (2015) Choline and betaine intakes are not associated with cardiovascular disease mortality risk in Japanese men and women. J Nutr 145, 1787–1792.10.3945/jn.114.209296CrossRefGoogle Scholar
Nam, HS (2019) Gut Microbiota and ischemic stroke: the role of trimethylamine N-oxide. J Stroke 21, 151–159.10.5853/jos.2019.00472CrossRefGoogle ScholarPubMed
Haghikia, A, Li, XS, Liman, TG, et al. (2018) Gut microbiota-dependent trimethylamine N-oxide predicts risk of cardiovascular events in patients with stroke and is related to proinflammatory monocytes. Arterioscler Thromb Vasc Biol 38, 2225–2235.10.1161/ATVBAHA.118.311023CrossRefGoogle ScholarPubMed
Tang, WHW, Wang, ZE, Levison, BS, et al. (2013) Intestinal microbial metabolism of phosphatidylcholine and cardiovascular risk. New Engl J Med 368, 1575–1584.10.1056/NEJMoa1109400CrossRefGoogle ScholarPubMed
Wang, Z, Bergeron, N, Levison, BS, et al. (2019) Impact of chronic dietary red meat, white meat, or non-meat protein on trimethylamine N-oxide metabolism and renal excretion in healthy men and women. Eur Heart J 40, 583–594.10.1093/eurheartj/ehy799CrossRefGoogle ScholarPubMed
Meyer, KA & Shea, JW (2017) Dietary choline and betaine and risk of CVD: a systematic review and meta-analysis of prospective studies. Nutrients 9, 711.10.3390/nu9070711CrossRefGoogle ScholarPubMed
Zhen, J, Zhou, Z, He, M, et al. (2023) The gut microbial metabolite trimethylamine N-oxide and cardiovascular diseases. Front Endocrinol (Lausanne) 14, 1085041.10.3389/fendo.2023.1085041CrossRefGoogle ScholarPubMed
Brunt, VE, Gioscia-Ryan, RA, Casso, AG, et al. (2020) Trimethylamine-N-oxide promotes age-related vascular oxidative stress and endothelial dysfunction in mice and healthy humans. Hypertension 76, 101–112.10.1161/HYPERTENSIONAHA.120.14759CrossRefGoogle ScholarPubMed
Zhang, X, Li, Y, Yang, P, et al. (2020) Trimethylamine-N-oxide promotes vascular calcification through activation of NLRP3 (nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3) inflammasome and NF-kappaB (nuclear factor kappaB) signals. Arterioscler Thromb Vasc Biol 40, 751–765.10.1161/ATVBAHA.119.313414CrossRefGoogle ScholarPubMed
Seldin, MM, Meng, Y, Qi, H, et al. (2016) Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-kappaB. J Am Heart Assoc 5, e002767.10.1161/JAHA.115.002767CrossRefGoogle ScholarPubMed
Gao, X, Liu, X, Xu, J, et al. (2014) Dietary trimethylamine N-oxide exacerbates impaired glucose tolerance in mice fed a high fat diet. J Biosci Bioeng 118, 476–481.10.1016/j.jbiosc.2014.03.001CrossRefGoogle ScholarPubMed
Dumas, ME, Rothwell, AR, Hoyles, L, et al. (2017) Microbial-host co-metabolites are prodromal markers predicting phenotypic heterogeneity in behavior, obesity, and impaired glucose tolerance. Cell Rep 20, 136–148.10.1016/j.celrep.2017.06.039CrossRefGoogle ScholarPubMed
Gupta, N, Buffa, JA, Roberts, AB, et al. (2020) Targeted inhibition of gut microbial trimethylamine N-oxide production reduces renal tubulointerstitial fibrosis and functional impairment in a murine model of chronic kidney disease. Arterioscler Thromb Vasc Biol 40, 1239–1255.10.1161/ATVBAHA.120.314139CrossRefGoogle Scholar
Li, D, Ke, Y, Zhan, R, et al. (2018) Trimethylamine-N-oxide promotes brain aging and cognitive impairment in mice. Aging Cell 17, e12768.10.1111/acel.12768CrossRefGoogle ScholarPubMed
Brunt, VE, LaRocca, TJ, Bazzoni, AE, et al. (2021) The gut microbiome-derived metabolite trimethylamine N-oxide modulates neuroinflammation and cognitive function with aging. Geroscience 43, 377–394.10.1007/s11357-020-00257-2CrossRefGoogle ScholarPubMed
Heianza, Y & Qi, L (2019) Impact of genes and environment on obesity and cardiovascular disease. Endocrinology 160, 81–100.10.1210/en.2018-00591CrossRefGoogle ScholarPubMed
Qi, Q, Chu, AY, Kang, JH, et al. (2012) Sugar-sweetened beverages and genetic risk of obesity. N Engl J Med 367, 1387–1396.10.1056/NEJMoa1203039CrossRefGoogle ScholarPubMed
Wang, T, Heianza, Y, Sun, D, et al. (2018) Improving adherence to healthy dietary patterns, genetic risk, and long term weight gain: gene–diet interaction analysis in two prospective cohort studies. BMJ 360, j5644.10.1136/bmj.j5644CrossRefGoogle Scholar
Wang et al. supplementary material
Wang et al. supplementary material
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