Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis
- Universitas Padjadjaran, Indonesia
- Broad Institute, United States
- Oxford University Clinical Research Unit, Viet Nam
- Radboud University Nijmegen Medical Centre, Netherlands
- Universitas Indonesia, Indonesia
- Amsterdam University Medical Centers, Netherlands
- Pham Ngoc Thach Hospital for Tuberculosis and Lung Disease, Viet Nam
- 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
Valerie ACM Koeken
Arjan van Laarhoven
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.
Reviewing Editor
- Bavesh D Kana, University of the Witwatersrand, South Africa
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.
Version history
- Received: December 1, 2022
- Preprint posted: January 9, 2023 (view preprint)
- Accepted: May 1, 2023
- Accepted Manuscript published: May 9, 2023 (version 1)
- Version of Record published: May 12, 2023 (version 2)
- Version of Record updated: May 16, 2023 (version 3)
- Version of Record updated: July 7, 2023 (version 4)
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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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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