CONTRIBUTION OF TRYPTOPHAN AND TRIMETHYLAMINE N-OXIDE DYSREGULATION TO THE MOLECULAR MECHANISMS OF LONG COVID-19 DEVELOPMENT DEPENDING ON THE CT STAGE OF LUNG INVOLVEMENT

Relevance. COVID-19, caused by the SARS-CoV-2 virus, is characterized by a wide range of clinical manifestations, from asymptomatic to critical forms with multiple organ failure. One of the key prognostic factors of the severity of the disease is the degree of damage to the lung tissue according to CT data, reflecting the severity of the inflammatory and immune response. Patients retain symptoms after the acute period, including fatigue, cognitive impairment, and myalgia, the pathogenesis of which is not fully understood. Current data indicate a significant role of metabolic disorders in the development of Long COVID-19. It has been shown that in patients with severe COVID-19 and higher CT scores, there is a decrease in tryptophan levels, activation of its catabolism via the kynurenine pathway, as well as an increase in trimethylamine N-oxide (TMAO) levels, which have proinflammatory activity. Despite numerous studies, there is insufficient data on the role of tryptophan and trimethylamine N-oxide molecules in the pathogenesis of Long COVID-19 and their relationship to severity during acute COVID-19.

Aim. To study the relationship between the degree of lung damage in acute COVID-19 and tryptophan and TMAO levels in patients with Long COVID-19.

Materials and methods. The retrospective cohort study was conducted, which included 30 people. The concentration of tryptophan and TMAO in the patients' plasma was determined using the method of highly efficient liquid chromatography with mass-selective mass spectrometric detection (HPLC-MS/MS).

Results and discussion. As a result, the median tryptophan level in the moderate group was 9.62 [8.11; 10.50] mcmol/l, in the severe group was 4.68 [2.81; 5.05] mcmol/l, respectively. The median TMAO level in the moderate group was 0.57 [0.51; 0.81] mcmol/l, in the severe group 1.88 [1.07; 3.08] mcmol/l.

Conclusions. Statistically significant differences were found between tryptophan levels and the moderate and severe groups. The significance level when comparing tryptophan concentrations was p=0.000. Statistically significant differences were also found between the level of TMAO and the severity of patients, the significance level was p<0.001. 

1. Abdallah A.M., Doudin A., Sulaiman T.O. Metabolic predictors of COVID-19 mortality and severity: a survival analysis. Frontiers in Immunology. 2024; 15: 135.

2. Ahmed J.O., Ahmad S.A., Hassan M.N. Post COVID-19 neurological complications; a meta-analysis. Annals of Medicine and Surgery. 2022; 76: 1-6.

3. Aksoyalp Z.Ş., Erdoğan B.R., Aksun S. Trimethylamine N-oxide as a potential prognostic biomarker for mortality in patients with COVID-19 disease. Advances in Medical Sciences. 2025; 70 (1): 174-183.

4. Almulla A.F., Thipakorn Y., Vasupanrajit A. The tryptophan catabolite or kynurenine pathway in a major depressive episode with melancholia, psychotic features and suicidal behaviors: a systematic review and meta-analysis. Cells. 2022; 11: 1-19.

5. Cai Y., Kim D.J., Takahashi T. Kynurenic acid may underlie sex-specific immune responses to COVID-19. Science Signaling. 2021; 14: 1-11.

6. Chen P., Wu M., He Y. et al. Metabolic alterations upon SARS-CoV-2 infection and potential therapeutic targets against coronavirus infection. Signal Transduction and Targeted Therapy. 2023; 1: 237.

7. Costanzo M., Caterino M., Fedele R. COVIDomics: the proteomic and metabolomic signatures of COVID-19. International Journal of Molecular Sciences. 2022; 23: 24.

8. Cucinotta D., Vanelli M. WHO declares COVID-19 a pandemic. Acta Bio Medica: Atenei Parmensis. 2020; 91 (1): 157.

9. Furie B., Furie B.С. Mechanisms of thrombus formation. New England Journal of Medicine. 2008; 359 (9): 938-949.

10. Kanova M., Kohout P. Tryptophan: a unique role in the critically ill. International Journal of Molecular Sciences. 2021; 22: 1-21.

11. Karki R., Kanneganti T.D. Innate immunity, cytokine storm, and inflammatory cell death in COVID-19. Journal of Translational Medicine. 2022; 20 (1): 542.

12. Khan S., Siddique R., Bai Q. Coronaviruses disease 2019 (COVID-19): causative agent, mental health concerns, and potential management options. Journal of Infection and Public Health. 2020; 13 (12): 1840-1844.

13. Lionetto L., Ulivieri M., Capi M. Increased kynurenine-to-tryptophan ratio in the serum of patients infected with SARS-CoV2: An observational cohort study. Biochim. Biophys. Acta. Mol. Basis. Dis. 2021; 1867: 1-8.

14. McCabe J.J., Walsh C., Gorey S. C-reactive protein, interleukin-6, and vascular recurrence according to stroke subtype: an individual participant data meta-analysis. Neurology. 2024; 2.

15. National Institute for Health and Care Excellence (NICE). COVID-19 rapid guideline: managing the longterm effects of COVID-19 – 18 December 2020. https://www.nice.org.uk/guidance/ng188 (дата обращения: 24.05.2025)

16. Ottiger M., Nickler M., Steuer C. et al. Trimethylamine-N-oxide (TMAO) predicts fatal outcomes in community-acquired pneumonia patients without evident coronary artery disease. Eur. J. Intern. Med. 2016; 36: 67-73.

17. Pannone G., Caponio V.C.A., De Stefano I.S. et al. Lung histopathological findings in COVID-19 disease – a systematic review. Infectious Agents and Cancer. 2021; 16 (1): 34.

18. Seldin M.M., Meng Y., Qi H. Trimethylamine N-Oxide Promotes Vascular Inflammation Through Signaling of Mitogen-Activated Protein Kinase and Nuclear Factor-kappaB. J. Am. Heart. Assoc. 2016; 5 (2): 1-12.

19. Sun X., Jiao X., Ma Y. Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome. Biochemical and Biophysical Research Communications. 2016; 481 (1-2): 63-70.

20. Tay M.Z., Poh C.M., Rénia L. The trinity of COVID-19: immunity, inflammation and intervention. Nature Reviews Immunology. 2020; 20 (6): 363-374.

21. Valdés A., Moreno L.O., Rello S.R. Metabolomics study of COVID-19 patients in four different clinical stages. Scientific Reports. 2022; 12: 1-11.

22. World Health Organization. Report of the WHO-China Joint Mission on Coronavirus Disease 2019 (COVID-19), 28 февраля 2020. https://www.who.int/publications/i/item/report-of-the-who-china-joint-missionon-coronavirus-disease-2019-(covid-19) (дата обращения: 30.05.2025).

23. Zhu W., Gregory J.C., Org E. Gut Microbial Metabolite TMAO Enhances Platelet Hyperreactivity and Thrombosis Risk. Cell. 2016; 165 (1): 111-124.

24. Dolgopolov I.S., Mentkevich G.L., Rykov M.Ju. i dr. Nevrologicheskie narushenija u pacientov s long COVID sindromom i metody kletochnoj terapii dlja ih korrekcii: obzor literatury. Sechenovskij vestnik. 2021; 12 (3): 56-67.

25. Morozov S.P., Gombolevskij V.A., Chernina V.Ju. Prognozirovanie letal'nyh ishodov pri COVID-19 po dannym komp'juternoj tomografii organov grudnoj kletki. Tuberkulez i bolezni legkih. 2020; 98 (6): 7-14.

26. Hasanova D.R., Zhitkova Ju.V., Vaskaeva G.R. Postkovidnyj sindrom: obzor znanij o patogeneze, nejropsihiatricheskih projavlenijah i perspektivah lechenija. Nevrologija, nejropsihiatrija, psihosomatika. 2021; 13 (3): 93-98.