nnpNeurology, Neuropsychiatry, PsychosomaticsНеврология, нейропсихиатрия, психосоматика2074-27112310-1342"IMA-Press", LLC10.14412/2074-2711-20234-100-104nnp-2066Research ArticleREVIEWSОБЗОРЫThe role of trimethylamine-N-oxide in the development of cerebrovascular disease (brief review)Роль триметиламин-N-оксида в развитии цереброваскулярных заболеваний (краткий обзор)https://orcid.org/0000-0003-1001-2024КутлубаевМ. А.KutlubaevM. A.

Мансур Амирович Кутлубаев

450008, Уфа, ул. Ленина, 3

Mansur Amirovich Kutlubaev

3, Lenina St., Ufa 450008

mansur.kutlubaev@yahoo.comhttps://orcid.org/0000-0002-8342-3943РахматуллинА. Р.RakhmatullinA. R.

450008, Уфа, ул. Ленина, 3

3, Lenina St., Ufa 450008

https://orcid.org/0000-0002-4671-9040КутлубаеваР. Ф.KutlubaevaR. F.

450008, Уфа, ул. Ленина, 3

3, Lenina St., Ufa 450008

ФГБОУ ВО «Башкирский государственный медицинский университет» Минздрава РоссииРоссияBashkir State Medical University, Ministry of Health of RussiaRussian Federation202315082023154100104Copyright © Kutlubaev M.A., Rakhmatullin A.R., Kutlubaeva R.F., 20232023Кутлубаев М.А., Рахматуллин А.Р., Кутлубаева Р.Ф.Kutlubaev M.A., Rakhmatullin A.R., Kutlubaeva R.F.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://nnp.ima-press.net/nnp/article/view/2066

Trimethylamine-N-oxide (TMO) is one of the best studied metabolites of the gut microbiota. It increases the risk of stroke and dyscirculatory encephalopathy, independent of traditional cardiovascular risk factors. The mechanisms of the negative effects of TMO on the cardiovascular system are related to the acceleration of atherosclerosis progression, platelet activation, and the development of aseptic inflammation. Currently, elevated TMO levels are an indication for a strict diet with restriction of foods rich in TMO precursors. Future research should clarify the role of TMO in the development of cerebrovascular disease (CVD). It is necessary to continue the investigation of new compounds that can reduce TMO levels in patients at high risk for developing CVD.

Триметиламин-N-оксид (ТМО) является одним из наиболее изученных метаболитов кишечной микрофлоры. Он повышает риск развития инсульта и дисциркуляторной энцефалопатии вне зависимости от традиционных факторов сердечно-сосудистого риска. Механизмы негативного влияния ТМО на сердечно-сосудистую систему связаны с увеличением скорости прогрессирования атеросклероза, активацией тромбоцитов и развитием асептического воспаления. В настоящее время повышение уровня ТМО является показанием для соблюдения строгой диеты с ограничением продуктов, богатых предшественниками ТМО. Будущие исследования должны уточнить роль ТМО в развитии цереброваскулярного заболевания (ЦВЗ). Необходимо продолжить изучение новых соединений для снижения уровня ТМО у пациентов с высоким риском развития ЦВЗ.

триметиламин-N-оксидинсульткишечная микробиотаметаболитыатеросклерозtrimethylamine-N-oxidestrokegut microbiotametabolitesatherosclerosisReferencesMitrea L, Nemes SA, Szabo K, et al. Guts Imbalance Imbalances the Brain: A Review of Gut Microbiota Association With Neurological and Psychiatric Disorders. Front Med (Lausanne). 2022 Mar 31;9:813204. doi: 10.3389/fmed.2022.813204Mitrea L, Nemes SA, Szabo K, et al. Guts Imbalance Imbalances the Brain: A Review of Gut Microbiota Association With Neurological and Psychiatric Disorders. Front Med (Lausanne). 2022 Mar 31;9:813204. doi: 10.3389/fmed.2022.813204Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ. 2018 Jun 13;361:k2179. doi: 10.1136/bmj.k2179Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ. 2018 Jun 13;361:k2179. doi: 10.1136/bmj.k2179Peh A, O’Donnell JA, Broughton BRS, Marques FZ. Gut Microbiota and Their Metabolites in Stroke: A Double-Edged Sword. Stroke. 2022 May;53(5):1788-801. doi: 10.1161/STROKEAHA.121.036800. Epub 2022 Feb 9.Peh A, O’Donnell JA, Broughton BRS, Marques FZ. Gut Microbiota and Their Metabolites in Stroke: A Double-Edged Sword. Stroke. 2022 May;53(5):1788-801. doi: 10.1161/STROKEAHA.121.036800. Epub 2022 Feb 9.Konieczny RA, Kuliczkowski W. Trimethylamine N-oxide in cardiovascular disease. Adv Clin Exp Med. 2022 Aug;31(8):913- 25. doi: 10.17219/acem/147666Konieczny RA, Kuliczkowski W. Trimethylamine N-oxide in cardiovascular disease. Adv Clin Exp Med. 2022 Aug;31(8):913- 25. doi: 10.17219/acem/147666Obeid R, Awwad HM, Rabagny Y, et al. Plasma trimethylamine N-oxide concentration is associated with choline, phospholipids, and methyl metabolism. Am J Clin Nutr. 2016 Mar;103(3):703-11. doi: 10.3945/ajcn.115.121269. Epub 2016 Feb 10.Obeid R, Awwad HM, Rabagny Y, et al. Plasma trimethylamine N-oxide concentration is associated with choline, phospholipids, and methyl metabolism. Am J Clin Nutr. 2016 Mar;103(3):703-11. doi: 10.3945/ajcn.115.121269. Epub 2016 Feb 10.Gatarek P, Kaluzna-Czaplinska J. Trimethylamine N-oxide (TMAO) in human health. EXCLI J. 2021 Feb 11;20:301-19. doi: 10.17179/excli2020-3239Gatarek P, Kaluzna-Czaplinska J. Trimethylamine N-oxide (TMAO) in human health. EXCLI J. 2021 Feb 11;20:301-19. doi: 10.17179/excli2020-3239Bennett BJ, de Aguiar Vallim TQ, Wang Z, et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013 Jan 8;17(1):49-60. doi: 10.1016/j.cmet.2012.12.011Bennett BJ, de Aguiar Vallim TQ, Wang Z, et al. Trimethylamine-N-oxide, a metabolite associated with atherosclerosis, exhibits complex genetic and dietary regulation. Cell Metab. 2013 Jan 8;17(1):49-60. doi: 10.1016/j.cmet.2012.12.011Mendelsohn AR, Larrick JW. Dietary modification of the microbiome affects risk for cardiovascular disease. Rejuvenation Res. 2013 Jun;16(3):241-4. doi: 10.1089/rej.2013.1447Mendelsohn AR, Larrick JW. Dietary modification of the microbiome affects risk for cardiovascular disease. Rejuvenation Res. 2013 Jun;16(3):241-4. doi: 10.1089/rej.2013.1447Canyelles M, Tondo M, Cedo L, et al. Trimethylamine N-Oxide: A Link among Diet, Gut Microbiota, Gene Regulation of Liver and Intestine Cholesterol Homeostasis and HDL Function. Int J Mol Sci. 2018 Oct 19;19(10):3228. doi: 10.3390/ijms19103228Canyelles M, Tondo M, Cedo L, et al. Trimethylamine N-Oxide: A Link among Diet, Gut Microbiota, Gene Regulation of Liver and Intestine Cholesterol Homeostasis and HDL Function. Int J Mol Sci. 2018 Oct 19;19(10):3228. doi: 10.3390/ijms19103228Zhu W, Gregory JC, Org E, et al. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell. 2016 Mar 24;165(1):111-24. doi: 10.1016/j.cell.2016.02.011. Epub 2016 Mar 10.Zhu W, Gregory JC, Org E, et al. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell. 2016 Mar 24;165(1):111-24. doi: 10.1016/j.cell.2016.02.011. Epub 2016 Mar 10.Sun X, Jiao X, Ma Y, et al. Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome. Biochem Biophys Res Commun. 2016 Dec 2;481(1-2):63-70. doi: 10.1016/j.bbrc.2016.11.017. Epub 2016 Nov 8.Sun X, Jiao X, Ma Y, et al. Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome. Biochem Biophys Res Commun. 2016 Dec 2;481(1-2):63-70. doi: 10.1016/j.bbrc.2016.11.017. Epub 2016 Nov 8.Singh GB, Zhang Y, Boini KM, Koka S. HighMobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction. Int J Mol Sci. 2019 Jul 22;20(14):3570. doi: 10.3390/ijms20143570Singh GB, Zhang Y, Boini KM, Koka S. HighMobility Group Box 1 Mediates TMAO-Induced Endothelial Dysfunction. Int J Mol Sci. 2019 Jul 22;20(14):3570. doi: 10.3390/ijms20143570Komaroff AL. The Microbiome and Risk for Atherosclerosis. JAMA. 2018 Jun 19;319(23):2381-2. doi: 10.1001/jama.2018.5240Komaroff AL. The Microbiome and Risk for Atherosclerosis. JAMA. 2018 Jun 19;319(23):2381-2. doi: 10.1001/jama.2018.5240Skye SM, Zhu W, Romano KA, et al. Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential. Circ Res. 2018 Oct 26;123(10):1164-76. doi: 10.1161/CIRCRESA-HA.118.313142Skye SM, Zhu W, Romano KA, et al. Microbial Transplantation With Human Gut Commensals Containing CutC Is Sufficient to Transmit Enhanced Platelet Reactivity and Thrombosis Potential. Circ Res. 2018 Oct 26;123(10):1164-76. doi: 10.1161/CIRCRESA-HA.118.313142Zhu W, Romano KA, Li L, et al. Gutmicrobes impact stroke severity via the trimethylamine N-oxide pathway. Cell Host Microbe. 2021 Jul 14;29(7):1199-208.e5. doi: 10.1016/j.chom.2021.05.002. Epub 2021 Jun 16.Zhu W, Romano KA, Li L, et al. Gutmicrobes impact stroke severity via the trimethylamine N-oxide pathway. Cell Host Microbe. 2021 Jul 14;29(7):1199-208.e5. doi: 10.1016/j.chom.2021.05.002. Epub 2021 Jun 16.Swanepoel I, Roberts A, Brauns C, et al.Trimethylamine N-oxide (TMAO): a new attractive target to decrease cardiovascular risk. Postgrad Med J. 2022 Sep;98(1163):723-7. doi: 10.1136/postgradmedj-2021-139839. Epub 2021 Mar 31.Swanepoel I, Roberts A, Brauns C, et al.Trimethylamine N-oxide (TMAO): a new attractive target to decrease cardiovascular risk. Postgrad Med J. 2022 Sep;98(1163):723-7. doi: 10.1136/postgradmedj-2021-139839. Epub 2021 Mar 31.Nie J, Xie L, Zhao BX, et al. Serum Trimethylamine N-Oxide Concentration Is Positively Associated With First Stroke in Hypertensive Patients. Stroke. 2018 Sep;49(9):2021-8. doi: 10.1161/STROKEAHA.118.021997. Erratum in: Stroke. 2019 Jun;50(6):e175.Nie J, Xie L, Zhao BX, et al. Serum Trimethylamine N-Oxide Concentration Is Positively Associated With First Stroke in Hypertensive Patients. Stroke. 2018 Sep;49(9):2021-8. doi: 10.1161/STROKEAHA.118.021997. Erratum in: Stroke. 2019 Jun;50(6):e175.Tang WH, Wang Z, Li XS, et al. Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus. Clin Chem. 2017 Jan;63(1):297-306. doi: 10.1373/clinchem.2016.263640. Epub 2016 Nov 18.Tang WH, Wang Z, Li XS, et al. Increased Trimethylamine N-Oxide Portends High Mortality Risk Independent of Glycemic Control in Patients with Type 2 Diabetes Mellitus. Clin Chem. 2017 Jan;63(1):297-306. doi: 10.1373/clinchem.2016.263640. Epub 2016 Nov 18.Xu D, Zhao W, Song J, et al. The Relationship of Large-Artery Atherothrombotic Stroke with Plasma Trimethylamine N-Oxide Level and Blood Lipid-Related Indices: A Cross-Sectional Comparative Study. Biomed Res Int. 2021 Apr 22;2021:5549796. doi: 10.1155/2021/5549796Xu D, Zhao W, Song J, et al. The Relationship of Large-Artery Atherothrombotic Stroke with Plasma Trimethylamine N-Oxide Level and Blood Lipid-Related Indices: A Cross-Sectional Comparative Study. Biomed Res Int. 2021 Apr 22;2021:5549796. doi: 10.1155/2021/5549796Farhangi MA, Vajdi M, Asghari-Jafarabadi M.Gut microbiota-associated metabolite trimethylamine N-oxide and the risk of stroke: a systematic review and dose-response metaanalysis. Nutr J. 2020 Jul 30;19(1):76. doi: 10.1186/s12937-020-00592-2Farhangi MA, Vajdi M, Asghari-Jafarabadi M.Gut microbiota-associated metabolite trimethylamine N-oxide and the risk of stroke: a systematic review and dose-response metaanalysis. Nutr J. 2020 Jul 30;19(1):76. doi: 10.1186/s12937-020-00592-2Li Z, Hui J, Li S, et al. Trimethylamine N-oxide predicts stroke severity in diabetic patients with acute ischaemic stroke and is related to glycemic variability. Eur J Neurol. 2022 Jan 12. doi: 10.1111/ene.15249. Epub ahead of print.Li Z, Hui J, Li S, et al. Trimethylamine N-oxide predicts stroke severity in diabetic patients with acute ischaemic stroke and is related to glycemic variability. Eur J Neurol. 2022 Jan 12. doi: 10.1111/ene.15249. Epub ahead of print.Xia F, Wen LP, Ge BC, et al. Gut microbiota as a target for prevention and treatment of type 2 diabetes: Mechanisms and dietary natural products. World J Diabetes. 2021 Aug 15;12(8):1146-63. doi: 10.4239/wjd.v12.i8.1146Xia F, Wen LP, Ge BC, et al. Gut microbiota as a target for prevention and treatment of type 2 diabetes: Mechanisms and dietary natural products. World J Diabetes. 2021 Aug 15;12(8):1146-63. doi: 10.4239/wjd.v12.i8.1146Xu J, Cheng A, Song B, et al. TrimethylamineN-Oxide and Stroke Recurrence Depends on Ischemic Stroke Subtypes. Stroke. 2022 Apr;53(4):1207-15. doi: 10.1161/STROKEAHA.120.031443. Epub 2021 Nov 19.Xu J, Cheng A, Song B, et al. TrimethylamineN-Oxide and Stroke Recurrence Depends on Ischemic Stroke Subtypes. Stroke. 2022 Apr;53(4):1207-15. doi: 10.1161/STROKEAHA.120.031443. Epub 2021 Nov 19.Chen Y, Xu J, Pan Y, et al. Association of Trimethylamine N-Oxide and Its Precursor With Cerebral Small Vessel Imaging Markers. Front Neurol. 2021 Apr 1;12:648702. doi: 10.3389/fneur.2021.648702Chen Y, Xu J, Pan Y, et al. Association of Trimethylamine N-Oxide and Its Precursor With Cerebral Small Vessel Imaging Markers. Front Neurol. 2021 Apr 1;12:648702. doi: 10.3389/fneur.2021.648702Li X, Fan Z, Cui J, et al. TrimethylamineN-Oxide in Heart Failure: A Meta-Analysis of Prognostic Value. Front Cardiovasc Med. 2022 Feb 16;9:817396. doi: 10.3389/fcvm.2022.817396Li X, Fan Z, Cui J, et al. TrimethylamineN-Oxide in Heart Failure: A Meta-Analysis of Prognostic Value. Front Cardiovasc Med. 2022 Feb 16;9:817396. doi: 10.3389/fcvm.2022.817396Koszewicz M, Jaroch J, Brzecka A, et al.Dysbiosis is one of the risk factor for stroke and cognitive impairment and potential target for treatment. Pharmacol Res. 2021 Feb;164:105277. doi: 10.1016/j.phrs.2020.105277. Epub 2020 Nov 7.Koszewicz M, Jaroch J, Brzecka A, et al.Dysbiosis is one of the risk factor for stroke and cognitive impairment and potential target for treatment. Pharmacol Res. 2021 Feb;164:105277. doi: 10.1016/j.phrs.2020.105277. Epub 2020 Nov 7.Roberts AB, Gu X, Buffa JA, et al.Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med. 2018 Sep;24(9):1407-17. doi: 10.1038/s41591-018-0128-1. Epub 2018 Aug 6.Roberts AB, Gu X, Buffa JA, et al.Development of a gut microbe-targeted nonlethal therapeutic to inhibit thrombosis potential. Nat Med. 2018 Sep;24(9):1407-17. doi: 10.1038/s41591-018-0128-1. Epub 2018 Aug 6.Wang Z, Roberts AB, Buffa JA, et al. Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis. Cell. 2015 Dec 17;163(7):1585-95. doi: 10.1016/j.cell.2015.11.055Wang Z, Roberts AB, Buffa JA, et al. Non-lethal Inhibition of Gut Microbial Trimethylamine Production for the Treatment of Atherosclerosis. Cell. 2015 Dec 17;163(7):1585-95. doi: 10.1016/j.cell.2015.11.055Nam HS. Gut Microbiota and Ischemic Stroke: The Role of Trimethylamine N-Oxide. J Stroke. 2019 May;21(2):151-9. doi: 10.5853/jos.2019.00472. Epub 2019 May 31.Nam HS. Gut Microbiota and Ischemic Stroke: The Role of Trimethylamine N-Oxide. J Stroke. 2019 May;21(2):151-9. doi: 10.5853/jos.2019.00472. Epub 2019 May 31.Konop M, Radkowski M, Grochowska M, et al. Enalapril decreases rat plasma concentration of TMAO, a gut bacteria-derived cardiovascular marker. Biomarkers. 2018 May-Jun;23(4):380-5. doi: 10.1080/1354750X.2018.1432689. Epub 2018 Feb 7.Konop M, Radkowski M, Grochowska M, et al. Enalapril decreases rat plasma concentration of TMAO, a gut bacteria-derived cardiovascular marker. Biomarkers. 2018 May-Jun;23(4):380-5. doi: 10.1080/1354750X.2018.1432689. Epub 2018 Feb 7.Chen ML, Yi L, Zhang Y, et al. Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)- Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota. mBio. 2016 Apr 5;7(2):e02210-15. doi: 10.1128/mBio.02210-15Chen ML, Yi L, Zhang Y, et al. Resveratrol Attenuates Trimethylamine-N-Oxide (TMAO)- Induced Atherosclerosis by Regulating TMAO Synthesis and Bile Acid Metabolism via Remodeling of the Gut Microbiota. mBio. 2016 Apr 5;7(2):e02210-15. doi: 10.1128/mBio.02210-15Dambrova M, Skapare-Makarova E,Konrade I, et al. Meldonium decreases the dietincreased plasma levels of trimethylamine N-oxide, a metabolite associated with atherosclerosis. J Clin Pharmacol. 2013 Oct;53(10):1095-8. doi: 10.1002/jcph.135. Epub 2013 Jul 25.Dambrova M, Skapare-Makarova E,Konrade I, et al. Meldonium decreases the dietincreased plasma levels of trimethylamine N-oxide, a metabolite associated with atherosclerosis. J Clin Pharmacol. 2013 Oct;53(10):1095-8. doi: 10.1002/jcph.135. Epub 2013 Jul 25.McEntyre CJ, Lever M, Chambers ST, et al.Variation of betaine, N,N-dimethylglycine, choline, glycerophosphorylcholine, taurine and trimethylamine-N-oxide in the plasma and urine of overweight people with type 2 diabetes over a two-year period. Ann Clin Biochem. 2015 May;52(Pt 3):352-60. doi: 10.1177/0004563214545346. Epub 2014 Jul 10.McEntyre CJ, Lever M, Chambers ST, et al.Variation of betaine, N,N-dimethylglycine, choline, glycerophosphorylcholine, taurine and trimethylamine-N-oxide in the plasma and urine of overweight people with type 2 diabetes over a two-year period. Ann Clin Biochem. 2015 May;52(Pt 3):352-60. doi: 10.1177/0004563214545346. Epub 2014 Jul 10.Кашух ЕА, Полуэктова ЕА, Кудрявцева АВи др. Влияние рифаксимина и мультиштаммового пробиотика на кишечный микробиом и показатели сердечно-сосудистого риска у пациентов с ишемической болезнью сердца. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2019;29(4):3849. doi: 10.22416/1382-4376-2019-29-4-38-49Kashukh EA, Poluektova EA, Kudryavtseva AV, et al. Effect of Rifaximin and a Multi-Strain Probiotic on the Intestinal Microbiome and Cardiovascular Risk Indicators in Patients with Coronary Heart Disease. Rossiyskiy zhurnal gastroenterologii, gepatologii, koloproktologii = Russian Journal of Gastroenterology, Hepatology, Coloproctology. 2019;29(4):38-49. doi: 10.22416/1382-4376-2019-29-4-38-49 (In Russ.)].Zhang H, Meng J, Yu H. Trimethylamine N-oxide Supplementation Abolishes the Cardioprotective Effects of Voluntary Exercise in Mice Fed a Western Diet. Front Physiol. 2017 Nov 23;8:944. doi: 10.3389/fphys.2017.00944Zhang H, Meng J, Yu H. Trimethylamine N-oxide Supplementation Abolishes the Cardioprotective Effects of Voluntary Exercise in Mice Fed a Western Diet. Front Physiol. 2017 Nov 23;8:944. doi: 10.3389/fphys.2017.00944

The authors declare that there are no conflicts of interest present.