Dataset Information

Plasma metabolomics in human pulmonary tuberculosis disease: a pilot study.

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.

SUBMITTER: Frediani JK

PROVIDER: S-EPMC4198093 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Plasma metabolomics in human pulmonary tuberculosis disease: a pilot study.

Frediani Jennifer K JK Jones Dean P DP Tukvadze Nestan N Uppal Karan K Sanikidze Eka E Kipiani Maia M Tran ViLinh T VT Hebbar Gautam G Walker Douglas I DI Kempker Russell R RR Kurani Shaheen S SS Colas Romain A RA Dalli Jesmond J Tangpricha Vin V Serhan Charles N CN Blumberg Henry M HM Ziegler Thomas R TR

PloS one 20141015 10

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 ident ...[more]

PMID: 25329995

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Project description:Novel biomarkers to identify infectious patients transmitting Mycobacterium tuberculosis are urgently needed to control the global tuberculosis (TB) pandemic. We hypothesized that proteins released into the plasma in active pulmonary TB are clinically useful biomarkers to distinguish TB cases from healthy individuals and patients with other respiratory infections. We applied a highly sensitive non-depletion tandem mass spectrometry discovery approach to investigate plasma protein expression in pulmonary TB cases compared to healthy controls in South African and Peruvian cohorts. . Plasma samples were analysed from 11 untreated male patients with active pulmonary TB and 10 male healthy control samples. Each plasma sample was initially separated into four segments by size exclusion chromatography, and each segment was processed individually. Analyses of plasma segments were performed in twelve iTRAQ (isobaric tags for relative and absolute quantification) 8-plex experimental sets in a block randomised design comprising three experimental sets. Each iTRAQ experiment contained a bridging master-pool plasma sample run in every experiment. Healthy controls were matched to TB samples by age, ethnicity, and smoking status within each iTRAQ set. Protein abundances from the plasma segments and multi-consensus reports were combined and adjusted for experimental batch effects. Protein abundances from the remaining combined plasma segment proteomes between experimental sets and the combined multi-consensus proteomes were analysed by complementary bioinformatic approaches to identify candidate diagnostic protein biomarkers. In total, 4,696 protein identifications were made across all iTRAQ experiments, at 5% FDR (false discovery rate). This comprised 2,332 unique host-derived proteins and 22 Mtb-derived proteins. Of these, 594 host proteins had a quantification result for every sample analysed and therefore comprised the complete quantified proteome. Subsequent bioinformatic analysis identified 118 differentially expressed proteins by three complementary bioinformatic pipelines and were taken forward in subsequent validation work as strong candidate biomarkers of pulmonary TB.

Project description:BackgroundCystic fibrosis (CF) is a chronic catabolic disease often requiring hospitalization for acute episodes of worsening pulmonary exacerbations. Limited data suggest that vitamin D may have beneficial clinical effects, but the impact of vitamin D on systemic metabolism in this setting is unknown.ObjectiveWe used high-resolution metabolomics (HRM) to assess the impact of baseline vitamin D status and high-dose vitamin D3 administration on systemic metabolism in adults with CF with an acute pulmonary exacerbation.DesignTwenty-five hospitalized adults with CF were enrolled in a randomized trial of high-dose vitamin D3 (250,000IU vitamin D3 bolus) versus placebo. Age-matched healthy subjects served as a reference group for baseline comparisons. Plasma was analyzed with liquid chromatography/ultra-high resolution mass spectrometry. Using recent HRM bioinformatics and metabolic pathway enrichment methods, we examined associations with baseline vitamin D status (sufficient vs. deficient per serum 25-hydroxyvitamin D concentrations) and the 7-day response to vitamin D3 supplementation.ResultsSeveral amino acids and lipid metabolites differed between CF and healthy control subjects, indicative of an overall catabolic state. In CF subjects, 343 metabolites differed (P<0.05) by baseline vitamin D status and were enriched within 7 metabolic pathways including fatty acid, amino acid, and carbohydrate metabolism. A total of 316 metabolites, which showed enrichment for 15 metabolic pathways-predominantly representing amino acid pathways-differed between the vitamin D3- and placebo-treated CF subjects over time (P<0.05). In the placebo group, several tricarboxylic acid cycle intermediates increased while several amino acid-related metabolites decreased; in contrast, little change in these metabolites occurred with vitamin D3 treatment.ConclusionsNumerous metabolic pathways detected by HRM varied in association with vitamin D status and high-dose vitamin D3 supplementation in adults with CF experiencing a pulmonary exacerbation. Overall, these pilot data suggest an anti-catabolic effect of high-dose vitamin D3 in this clinical setting.

Dataset Information

Plasma metabolomics in human pulmonary tuberculosis disease: a pilot study.

Publications

Plasma metabolomics in human pulmonary tuberculosis disease: a pilot study.

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