Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis

  1. Edwin Ardiansyah
  2. Julian Avila Pacheco
  3. Nhat Thanh Hoang Le
  4. Sofiati Dian
  5. Dao Nguyen Vinh
  6. Hoang Thanh Hai
  7. Kevin Bullock
  8. Bachti Alisjahbana
  9. Mihai G Netea
  10. Riwanti Estiasari
  11. Trinh Thi Bich Tram
  12. Joseph Donovan
  13. Dorothee Heemskerk
  14. Tran Thi Hong Chau
  15. Nguyen Duc Bang
  16. Ahmad Rizal Ganiem
  17. Rovina Ruslami
  18. Valerie ACM Koeken
  19. Raph L Hamers
  20. Darma Imran
  21. Kartika Maharani
  22. Vinod Kumar
  23. Clary B Clish
  24. Reinout van Crevel
  25. Guy E Thwaites
  26. Arjan van Laarhoven  Is a corresponding author
  27. Nguyen TT Thuong
  1. Universitas Padjadjaran, Indonesia
  2. Broad Institute, United States
  3. Oxford University Clinical Research Unit, Viet Nam
  4. Radboud University Nijmegen Medical Centre, Netherlands
  5. Universitas Indonesia, Indonesia
  6. Amsterdam University Medical Centers, Netherlands
  7. Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Viet Nam
  8. Oxford University Clinical Research Unit, Indonesia

Abstract

Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism.

Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography mass-spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins.

Results: CSF tryptophan was associated with 60-day mortality from tuberculous meningitis (HR=1.16, 95%CI=1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and HIV-positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95%CI=1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis.

Conclusion: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy.

Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).

Data availability

The data generated or analysed during this study are included in the supporting file.

Article and author information

Author details

  1. Edwin Ardiansyah

    Research Center for Care and Control of Infectious Diseases, Universitas Padjadjaran, Bandung, Indonesia
    Competing interests
    No competing interests declared.
  2. Julian Avila Pacheco

    Broad Institute, Boston, United States
    Competing interests
    No competing interests declared.
  3. Nhat Thanh Hoang Le

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  4. Sofiati Dian

    Research Center for Care and Control of Infectious Diseases, Universitas Padjadjaran, Bandung, Indonesia
    Competing interests
    No competing interests declared.
  5. Dao Nguyen Vinh

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  6. Hoang Thanh Hai

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  7. Kevin Bullock

    Broad Institute, Boston, United States
    Competing interests
    No competing interests declared.
  8. Bachti Alisjahbana

    Research Center for Care and Control of Infectious Diseases, Universitas Padjadjaran, Bandung, Indonesia
    Competing interests
    No competing interests declared.
  9. Mihai G Netea

    Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    Competing interests
    Mihai G Netea, has received consulting fees from Scientific Board TTxD and is a scientific founder of TTxD, Lemba and BioTRIP. The author has no other competing interests to declare..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2421-6052
  10. Riwanti Estiasari

    Department of Neurology, Universitas Indonesia, Jakarta, Indonesia
    Competing interests
    No competing interests declared.
  11. Trinh Thi Bich Tram

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  12. Joseph Donovan

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  13. Dorothee Heemskerk

    Department of Medical Microbiology and Infection Prevention, Amsterdam University Medical Centers, Amsterdam, Netherlands
    Competing interests
    No competing interests declared.
  14. Tran Thi Hong Chau

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  15. Nguyen Duc Bang

    Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
  16. Ahmad Rizal Ganiem

    Research Center for Care and Control of Infectious Diseases, Universitas Padjadjaran, Bandung, Indonesia
    Competing interests
    No competing interests declared.
  17. Rovina Ruslami

    Research Center for Care and Control of Infectious Diseases, Universitas Padjadjaran, Bandung, Indonesia
    Competing interests
    No competing interests declared.
  18. Valerie ACM Koeken

    Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5783-9013
  19. Raph L Hamers

    Oxford University Clinical Research Unit, Jakarta, Indonesia
    Competing interests
    No competing interests declared.
  20. Darma Imran

    Department of Neurology, Universitas Indonesia, Jakarta, Indonesia
    Competing interests
    No competing interests declared.
  21. Kartika Maharani

    Department of Neurology, Universitas Indonesia, Jakarta, Indonesia
    Competing interests
    No competing interests declared.
  22. Vinod Kumar

    Department of Internal Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  23. Clary B Clish

    Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
  24. Reinout van Crevel

    Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    Competing interests
    No competing interests declared.
  25. Guy E Thwaites

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2858-2087
  26. Arjan van Laarhoven

    Department of Internal Medicine and Radboud Center of Infectious Diseases (RCI), Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands
    For correspondence
    Arjan.vanLaarhoven@radboudumc.nl
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6607-4075
  27. Nguyen TT Thuong

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
    Competing interests
    No competing interests declared.

Funding

National Institutes of Health (R01AI145781)

  • Edwin Ardiansyah
  • Julian Avila Pacheco
  • Nhat Thanh Hoang Le
  • Sofiati Dian
  • Dao Nguyen Vinh
  • Hoang Thanh Hai
  • Kevin Bullock
  • Bachti Alisjahbana
  • Mihai G Netea
  • Riwanti Estiasari
  • Trinh Thi Bich Tram
  • Joseph Donovan
  • Dorothee Heemskerk
  • Tran Thi Hong Chau
  • Nguyen Duc Bang
  • Ahmad Rizal Ganiem
  • Valerie ACM Koeken
  • Raph L Hamers
  • Darma Imran
  • Kartika Maharani
  • Vinod Kumar
  • Clary B Clish
  • Reinout van Crevel
  • Guy E Thwaites
  • Arjan van Laarhoven
  • Nguyen TT Thuong

Wellcome Trust

  • Nhat Thanh Hoang Le
  • Dao Nguyen Vinh
  • Hoang Thanh Hai
  • Trinh Thi Bich Tram
  • Joseph Donovan
  • Dorothee Heemskerk
  • Tran Thi Hong Chau
  • Nguyen Duc Bang
  • Guy E Thwaites
  • Nguyen TT Thuong

Direktorat Jendral Pendidikan Tinggi, Indonesia (BPPLN)

  • Sofiati Dian

Ministry of Research, Technology, and Higher Education, Indonesia (PKSLN)

  • Sofiati Dian
  • Rovina Ruslami

United States Agency for International Development (PEER Health)

  • Rovina Ruslami

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: Ethical approval was obtained from the Ethical Committee of Hasan Sadikin Hospital, Faculty of Medicine, Universitas Padjadjaran, Bandung, Indonesia and from the Oxford Tropical Research Ethics Committee in the United Kingdom, the Institutional Review Boards of the Hospital for Tropical Diseases and Pham Ngoc Thach Hospital in Vietnam. Written (Vietnam) or oral (Indonesia) consent to be included in the study, for storage of surplus sample, and to obtain follow-up data was obtained from patients or close relatives of patients who were unconscious.

Copyright

© 2023, Ardiansyah et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Edwin Ardiansyah
  2. Julian Avila Pacheco
  3. Nhat Thanh Hoang Le
  4. Sofiati Dian
  5. Dao Nguyen Vinh
  6. Hoang Thanh Hai
  7. Kevin Bullock
  8. Bachti Alisjahbana
  9. Mihai G Netea
  10. Riwanti Estiasari
  11. Trinh Thi Bich Tram
  12. Joseph Donovan
  13. Dorothee Heemskerk
  14. Tran Thi Hong Chau
  15. Nguyen Duc Bang
  16. Ahmad Rizal Ganiem
  17. Rovina Ruslami
  18. Valerie ACM Koeken
  19. Raph L Hamers
  20. Darma Imran
  21. Kartika Maharani
  22. Vinod Kumar
  23. Clary B Clish
  24. Reinout van Crevel
  25. Guy E Thwaites
  26. Arjan van Laarhoven
  27. Nguyen TT Thuong
(2023)
Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis
eLife 12:e85307.
https://doi.org/10.7554/eLife.85307

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https://doi.org/10.7554/eLife.85307

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