Abstract
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.
Highlights
The global burden of tuberculosis (TB) is vast, with an estimated 8.6 million new TB cases and 1.3 million deaths due to the disease in 2012 [1,2]
Our study demonstrates that discovery-based metabolomics profiling method can differentiate adults with pulmonary TB
A unique feature of our study compared to previous metabolomics studies in human TB is our use of liquid chromatography high-resolution mass spectrometry (LC-MS) metabolomics to profile .23,000 metabolites in plasma from humans with TB disease and concomitantly, their asymptomatic household contacts
Summary
The global burden of tuberculosis (TB) is vast, with an estimated 8.6 million new TB cases and 1.3 million deaths due to the disease in 2012 [1,2]. There are no well-validated or specific biomarkers that can predict transition from latent TB to active TB disease or are useful to monitor efficacy of anti-TB drugs [4,5]. Metabolomics analysis incorporates nuclear magnetic resonance (NMR) spectroscopy-based or mass spectrometry (MS)-based technologies to identify hundreds to thousands of small-molecule metabolites in biofluids or tissues, coupled with biostatistics and bioinformatics to identify potential regulated biomarkers and metabolic pathways associated with disease [6,7,8]. Targeted or untargeted NMR- or MS-based metabolomics methods have recently been shown to distinguish the presence of specific infectious diseases, to predict therapeutic responses to antimicrobial agents, and to explore host-pathogen metabolic interactions, including in malaria [9,10], chronic Pseudomonas aeruginosa pulmonary infection [11], HIV [12], and sepsis [13]
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