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Urinary metabolite markers characterizing tuberculosis treatment failure

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Abstract

Background

Considering that approximately 15% of the nine million new tuberculosis (TB) cases reported per annum are not treated successfully, new, distinctive and specific biomarkers are needed to better characterize the biological basis of a poor treatment outcome.

Methods

Urine samples from 41 active pulmonary TB patients were collected at baseline (time of diagnosis), during treatment (weeks 1, 2 and 4) and 2 weeks after treatment completion (week 26). These samples were divided into successful (cured) and unsuccessful (failed) treatment outcome groups and analyzed using a GCxGC-TOFMS metabolomics research approach.

Results

The metabolite data collected showed clear differentiation of the cured and failed treatment outcome groups using the samples collected at the time of diagnosis, i.e. before any treatment was administered.

Conclusions

The treatment failure group was characterized by an imbalanced gut microbiome, in addition to elevated levels of metabolites associated with abnormalities in the long-chain fatty acid β-oxidation pathway, accompanied by reduced l-carnitine and short-chain fatty acids, indicative of a mitochondrial trifunctional protein defect in particular. Furthermore, an altered amino acid metabolism was also observed in these patients, which confirms previous findings and associations to increased interferon gamma due to the host’s immune response to M. tuberculosis and a compromised insulin secretion.

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Authors and Affiliations

  1. School for Physical and Chemical Sciences, Human Metabolomics, North-West University, Potchefstroom Campus, Building F3: Biochemistry, 11 Hoffman Street, Private Bag x6001, Box 269, Potchefstroom, 2531, South Africa

    Laneke Luies, Japie Mienie, Christinah Motshwane & Du Toit Loots

  2. DST/NRF Centre of Excellence for Biomedical Tuberculosis Research/MRC Centre for Molecular and Cellular Biology, Division of Molecular Biology and Human Genetics, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, 7505, South Africa

    Katharina Ronacher & Gerhard Walzl

  3. Mater Medical Research Institute, The University of Queensland, Brisbane, Australia

    Katharina Ronacher

Authors
  1. Laneke Luies
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  2. Japie Mienie
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  3. Christinah Motshwane
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  4. Katharina Ronacher
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  5. Gerhard Walzl
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  6. Du Toit Loots
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Contributions

DTL conceptualized the study design; KR and GW provided all urine samples. LL performed the GC data acquisition/analysis and CM the UPLC data acquisition/analysis. LL, JM and DTL interpreted the data and drafted the article. All authors approved the final version to be submitted.

Corresponding authors

Correspondence to Laneke Luies or Du Toit Loots.

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Conflict of interest

The authors declare that there are no conflicts of interest, and that this manuscript, and the work described therein, is unpublished and has not been submitted for publication elsewhere.

Ethical approval

Ethical approval for this investigation, conducted according to the Declaration of Helsinki and International Conference on Harmonization Guidelines, was obtained from the Ethics Committee of the North-West University, South Africa (reference number NWU-00127-11-A1), as well as from Stellenbosch University Health Research Ethics Committee (reference number 99/039) and Cape Town City Health. All participants gave written informed consent for study participation and HIV testing.

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11306_2017_1261_MOESM1_ESM.jpg

Supplementary Figure: Principal components analysis (PCA) scores plots of principal component 1 versus principal component 2 of the successful and unsuccessful treatment outcome groups, at (a) time of diagnosis, (b) week 1, (c) week 2, (d) week 4 of treatment and (e) two weeks after treatment completion (week 26), subsequent to an organic acid extraction and GCxGC-TOFMS analyses. The explained variances are indicated in parenthesis. (JPG 1267 KB)

Supplementary material 2 (CSV 118 KB)

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Luies, L., Mienie, J., Motshwane, C. et al. Urinary metabolite markers characterizing tuberculosis treatment failure. Metabolomics 13, 124 (2017). https://doi.org/10.1007/s11306-017-1261-4

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