Journal Article

Plasma Metabolomics in Human Pulmonary Tuberculosis Disease: A Pilot Study

Uppal, Karan, Kempker, Russell R., Kipiani, Maia, Dalli, Jesmond, Kurani, Shaheen S., Tran, ViLinh T., Blumberg, Henry M., Jones, Dean P., Sanikidze, Eka, Tangpricha, Vin, Frediani, Jennifer K., Serhan, Charles N., Tukvadze, Nestan, Ziegler, Thomas R., Walker, Douglas I., Colas, Romain A., Hebbar, Gautam

2014

Overview

We aimed to characterize metabolites during tuberculosis (TB) disease and identify new pathophysiologic pathways involved in infection as well as biomarkers of TB onset, progression and resolution. Such data may inform development of new anti-tuberculosis drugs. Plasma samples from adults with newly diagnosed pulmonary TB disease and their matched, asymptomatic, sputum culture-negative household contacts were analyzed using liquid chromatography high-resolution mass spectrometry (LC-MS) to identify metabolites. Statistical and bioinformatics methods were used to select accurate mass/charge (m/z) ions that were significantly different between the two groups at a false discovery rate (FDR) of q<0.05. Two-way hierarchical cluster analysis (HCA) was used to identify clusters of ions contributing to separation of cases and controls, and metabolomics databases were used to match these ions to known metabolites. Identity of specific D-series resolvins, glutamate and Mycobacterium tuberculosis (Mtb)-derived trehalose-6-mycolate was confirmed using LC-MS/MS analysis. Over 23,000 metabolites were detected in untargeted metabolomic analysis and 61 metabolites were significantly different between the two groups. HCA revealed 8 metabolite clusters containing metabolites largely upregulated in patients with TB disease, including anti-TB drugs, glutamate, choline derivatives, Mycobacterium tuberculosis-derived cell wall glycolipids (trehalose-6-mycolate and phosphatidylinositol) and pro-resolving lipid mediators of inflammation, known to stimulate resolution, efferocytosis and microbial killing. The resolvins were confirmed to be RvD1, aspirin-triggered RvD1, and RvD2. This study shows that high-resolution metabolomic analysis can differentiate patients with active TB disease from their asymptomatic household contacts. Specific metabolites upregulated in the plasma of patients with active TB disease, including Mtb-derived glycolipids and resolvins, have potential as biomarkers and may reveal pathways involved in TB disease pathogenesis and resolution.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Adults / Analysis / Antitubercular Agents - blood / Antitubercular Agents - therapeutic use / Aspirin / Bioinformatics / Biology / Biology and Life Sciences / Biomarkers / Cell culture / Cell walls / Choline / Chromatography / Cluster analysis / Computational Biology / Drug development / Drug therapy / Drugs / Fatty acids / Female / Glutamate / Glycolipids / Health aspects / Health sciences / High resolution / HIV / Human immunodeficiency virus / Humans / Identification methods / Inactivation, Metabolic / Infections / Ion charge / Ions / Laboratories / Liquid chromatography / Lung diseases / Male / Mass spectrometry / Mass spectroscopy / Medical research / Medicine / Medicine and Health Sciences / Membrane lipids / Metabolism / Metabolites / Metabolomics / Microorganisms / Mycobacterium tuberculosis / Mycobacterium tuberculosis - metabolism / Mycobacterium tuberculosis - pathogenicity / NMR / Nuclear magnetic resonance / Nutrition / Pathogenesis / Patients / Phosphatidylinositol / Pilot Projects / Plant lipids / Public health / Sepsis / Sputum / Sputum - metabolism / Sputum - microbiology / Statistical analysis / Statistical methods / Tandem Mass Spectrometry / Trehalose / Tuberculosis / Tuberculosis, Pulmonary - blood / Tuberculosis, Pulmonary - drug therapy / Tuberculosis, Pulmonary - microbiology / Young Adult