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Preliminary Communication

Predicting tuberculosis treatment outcome using metabolomics

    Laneke Luies

    School for Physical & Chemical Sciences, Human Metabolomics, North-West University (Potchefstroom Campus), Private Bag x6001, Box 269, Potchefstroom 2531, South Africa

    ,
    Mari van Reenen

    School for Physical & Chemical Sciences, Human Metabolomics, North-West University (Potchefstroom Campus), Private Bag x6001, Box 269, Potchefstroom 2531, South Africa

    ,
    Katharina Ronacher

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

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

    ,
    Gerhard Walzl

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

    &
    Du Toit Loots

    *Author for correspondence: Tel.: +27 18 299 1818; Fax: +27 18 299 1823;

    E-mail Address: dutoit.loots@nwu.ac.za

    School for Physical & Chemical Sciences, Human Metabolomics, North-West University (Potchefstroom Campus), Private Bag x6001, Box 269, Potchefstroom 2531, South Africa

    Published Online:https://doi.org/10.2217/bmm-2017-0133

    Aim: Predicting a poor treatment outcome would offer significant benefits for patient care and for new drug development. Materials, methods & results: Urine samples from tuberculosis-positive patients with a successful and unsuccessful treatment outcome were collected at baseline and analyzed. The identified metabolites were used in a forward logistic regression model, which achieved a receiver operating characteristic area under the curve of 0.94 (95% CI: 0.84–1) and cross-validated well in a leave-one-out context, with an area under the curve of 0.89 (95% CI: 0.7–1). Two possible predictors were identified, which are associated with a gut microbiota imbalance. Discussion & conclusion: Our findings show the capacity of metabolomics to predict treatment failure at the time of diagnosis, which potentially offers significant benefits for the use in new drug development clinical trials and individualized patient care.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 World Health Organization. Global Tuberculosis Report 2015 (2015). http://apps.who.int/iris/bitstream/10665/191102/1/9789241565059_eng.pdf.
    • 2 Olivier I, Loots DT. An overview of tuberculosis treatments and diagnostics. What role could metabolomics play. J. Cell Tiss. Res. 11(1), 2655–2671 (2011).
    • 3 Mukherjee JS, Rich ML, Socci AR et al. Programmes and principles in treatment of multidrug-resistant tuberculosis. Lancet 363(9407), 474–481 (2004).
    • 4 Alobu I, Oshi DC, Oshi SN, Ukwaja KN. Profile and determinants of treatment failure among smear-positive pulmonary tuberculosis patients in Ebonyi, southeastern Nigeria. Int. J. Mycobacteriol. 3(2), 127–131 (2014).
    • 5 Krapp F, Veliz JC, Cornejo E, Gotuzzo E, Seas C. Bodyweight gain to predict treatment outcome in patients with pulmonary tuberculosis in Peru. Int. J. Tuberc. Lung Dis. 12(10), 1153–1159 (2008).
    • 6 de Albuquerque Mde F, Ximenes RA, Lucena-Silva N et al. Factors associated with treatment failure, dropout, and death in a cohort of tuberculosis patients in Recife, Pernambuco State, Brazil. Cad. Saude Publica 23(7), 1573–1582 (2007).
    • 7 Walzl G, Ronacher K, Djoba Siawaya JF, Dockrell HM. Biomarkers for TB treatment response: challenges and future strategies. J. Infect. 57(2), 103–109 (2008).
    • 8 Lawn SD, Kerkhoff AD, Vogt M, Wood R. Diagnostic accuracy of a low-cost, urine antigen, point-of-care screening assay for HIV-associated pulmonary tuberculosis before antiretroviral therapy: a descriptive study. Lancet Infect. Dis. 12(3), 201–209 (2012).
    • 9 Lawn SD, Kerkhoff AD, Burton R et al. Diagnostic accuracy, incremental yield and prognostic value of Determine TB-LAM for routine diagnostic testing for tuberculosis in HIV-infected patients requiring acute hospital admission in South Africa: a prospective cohort. BMC Med. 15(1), 67 (2017). • Determines the diagnostic yield, accuracy and prognostic value of urine-lipoarabinomannan (LAM) testing. They reported that the diagnostic yield of urine-LAM was unrelated to respiratory symptoms, and that a positive urine-LAM status was strongly associated with a poor prognosis.
    • 10 Cannas A, Calvo L, Chiacchio T et al. IP-10 detection in urine is associated with lung diseases. BMC Infect. Dis. 10(1), 333 (2010).
    • 11 Petrone L, Cannas A, Aloi F et al. Blood or urine IP-10 cannot discriminate between active tuberculosis and respiratory diseases different from tuberculosis in children. Biomed. Res. Int. 2015, 589471 (2015).
    • 12 Petrone L, Cannas A, Vanini V et al. Blood and urine inducible protein 10 as potential markers of disease activity. Int. J. Tuberc. Lung Dis. 20(11), 1554–1561 (2016).
    • 13 Horne DJ, Royce SE, Gooze L et al. Sputum monitoring during tuberculosis treatment for predicting outcome: systematic review and meta-analysis. Lancet Infect. Dis. 10(6), 387–394 (2010).
    • 14 Baumann R, Kaempfer S, Chegou NN et al. Serodiagnostic markers for the prediction of the outcome of intensive phase tuberculosis therapy. Tuberculosis (Edinb.) 93(2), 239–245 (2013).
    • 15 Siawaya JFD, Bapela NB, Ronacher K et al. Immune parameters as markers of tuberculosis extent of disease and early prediction of anti-tuberculosis chemotherapy response. J. Infect. 56(5), 340–347 (2008).
    • 16 Namukwaya E, Nakwagala FN, Mulekya F, Mayanja-Kizza H, Mugerwa R. Predictors of treatment failure among pulmonary tuberculosis patients in Mulago hospital, Uganda. Afr. Health Sci. 11(3), S105–S111 (2011).
    • 17 Dunn WB, Wilson ID, Nicholls AW, Broadhurst D. The importance of experimental design and QC samples in large-scale and MS-driven untargeted metabolomic studies of humans. Bioanalysis 4(18), 2249–2264 (2012). • Provides an understanding/importance of receiver operating characteristic (AUC) and odds ratios, as well as how to interpret these, which forms an important part of this manuscript.
    • 18 De Villiers L, Loots DT. Using metabolomics for elucidating the mechanisms related to tuberculosis treatment failure. Curr. Metabol. 1(4), 306–317 (2013).
    • 19 Olivier I, Loots DT. A comparison of two extraction methods for differentiating and characterising various Mycobacterium species and Pseudomonas aeruginosa using GC-MS metabolomics. Afr. J. Microbiol. Res. 6(13), 3159–3172 (2012).
    • 20 Che NY, Cheng JH, Li HJ et al. Decreased serum 5-oxoproline in TB patients is associated with pathological damage of the lung. Clin. Chim. Acta 423, 5–9 (2013).
    • 21 Hesseling AC, Walzl G, Enarson DA et al. Baseline sputum time to detection predicts month two culture conversion and relapse in non-HIV-infected patients. Int. J. Tuberc. Lung Dis. 14(5), 560–570 (2010).
    • 22 Luies L, Loots D. Tuberculosis metabolomics reveals adaptations of man and microbe in order to outcompete and survive (vol 12, 40, 2016). Metabolomics. 12(3), 1–9 (2016).
    • 23 Van Den Berg RA, Hoefsloot HC, Westerhuis JA, Smilde AK, Van Der Werf MJ. Centering, scaling, and transformations: improving the biological information content of metabolomics data. BMC Genomics 7(1), 142 (2006).
    • 24 Smuts I, Van Der Westhuizen FH, Louw R et al. Disclosure of a putative biosignature for respiratory chain disorders through a metabolomics approach. Metabolomics 9(2), 379–391 (2013).
    • 25 Wang X, Zhang A, Sun H. Urine metabolomics. Clin. Chim. Acta 414, 65–69 (2012).
    • 26 Du Preez I, Loots DT. New sputum metabolite markers implicating adaptations of the host to Mycobacterium tuberculosis, and vice versa. Tuberculosis (Edinb.) 93(3), 330–337 (2013).
    • 27 Pallant J. Manual SPSS Survival: a step by step guide to data analysis using SPSS. 302 (2001). www.mheducation.co.uk/openup/chapters/0335208908.pdf.
    • 28 Ellis SM, Steyn HS. Practical significance (effect sizes) versus or in combination with statistical significance (p-values): research note. Manage. Dynamics 12(4), 51–53 (2003).
    • 29 Field A. Discovering Statistics Using SPSS Statistics (3rd Edition). Sage Publications Ltd, London, UK (2013).
    • 30 MathWorks. notBoxPlot. www.mathworks.com/matlabcentral/fileexchange/26508-raacampbell13-notboxplot.
    • 31 Liu C, Kuei C, Zhu J et al. 3,5-Dihydroxybenzoic acid, a specific agonist for hydroxycarboxylic acid 1, inhibits lipolysis in adipocytes. J. Pharmacol. Exp. Ther. 341(3), 794–801 (2012).
    • 32 Rechner AR, Spencer JP, Kuhnle G, Hahn U, Rice-Evans CA. Novel biomarkers of the metabolism of caffeic acid derivatives in vivo. Free Radic. Biol. Med. 30(11), 1213–1222 (2001).
    • 33 Singh VV, Toskes PP. Small bowel bacterial overgrowth: presentation, diagnosis, and treatment. Curr. Treat. Options Gastroenterol. 7(1), 19–28 (2004).
    • 34 Estudante M, Morais JG, Soveral G, Benet LZ. Intestinal drug transporters: an overview. Adv. Drug Del. Rev. 65(10), 1340–1356 (2013).
    • 35 Luies L, Mienie J, Motshwane C, Ronacher K, Walzl G, Loots DT. Urinary metabolite markers characterizing tuberculosis treatment failure. Metabolomics 13(10), 124 (2017).
    • 36 Clemente JC, Ursell LK, Parfrey LW, Knight R. The impact of the gut microbiota on human health: an integrative view. Cell 148(6), 1258–1270 (2012).
    • 37 Gonzalez A, Stombaugh J, Lozupone C, Turnbaugh PJ, Gordon JI, Knight R. The mind-body-microbial continuum. Dialogues Clin. Neurosci. 13(1), 55–62 (2011).
    • 38 Warren G, Houslay M, Metcalfe J. Cholesterol is excluded from the phospholipid annulus surrounding an active calcium transport protein. Nature 255, 684–687 (1975).
    • 39 Vasiliou V, Vasiliou K, Nebert DW. Human ATP-binding cassette (ABC) transporter family. Hum. Genomics 3(3), 281–290 (2009).
    • 40 Louw GE, Warren RM, Gey Van Pittius NC, Mcevoy CR, Van Helden PD, Victor TC. A balancing act: efflux/influx in mycobacterial drug resistance. Antimicrob. Agents Chemother. 53(8), 3181–3189 (2009). • Describes ATP-binding cassette type multidrug transporters in the context of Mycobacterium tuberculosis and drug delivery.
    • 41 Mercado-Lubo R, Mccormick BA. The interaction of gut microbes with host ABC transporters. Gut Microbes 1(5), 301–306 (2010).
    • 42 Zhang Y, Yew WW. Mechanisms of drug resistance in Mycobacterium tuberculosis: update 2015. Int. J. Tuberc. Lung Dis. 19(11), 1276–1289 (2015).