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Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients.

ABSTRACT: Although tuberculosis (TB) causes more deaths than any other pathogen, most infected individuals harbor the pathogen without signs of disease. We explored the metabolome of >400 small molecules in serum of uninfected individuals, latently infected healthy individuals and patients with active TB. We identified changes in amino acid, lipid and nucleotide metabolism pathways, providing evidence for anti-inflammatory metabolomic changes in TB. Metabolic profiles indicate increased activity of indoleamine 2,3 dioxygenase 1 (IDO1), decreased phospholipase activity, increased abundance of adenosine metabolism products, as well as indicators of fibrotic lesions in active disease as compared to latent infection. Consistent with our predictions, we experimentally demonstrate TB-induced IDO1 activity. Furthermore, we demonstrate a link between metabolic profiles and cytokine signaling. Finally, we show that 20 metabolites are sufficient for robust discrimination of TB patients from healthy individuals. Our results provide specific insights into the biology of TB and pave the way for the rational development of metabolic biomarkers for TB.

SUBMITTER: Weiner J

PROVIDER: S-EPMC3402490 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients.

Weiner January J Parida Shreemanta K SK Maertzdorf Jeroen J Black Gillian F GF Repsilber Dirk D Telaar Anna A Mohney Robert P RP Arndt-Sullivan Cordelia C Ganoza Christian A CA Faé Kellen C KC Walzl Gerhard G Kaufmann Stefan H E SH

PloS one 20120723 7

Although tuberculosis (TB) causes more deaths than any other pathogen, most infected individuals harbor the pathogen without signs of disease. We explored the metabolome of >400 small molecules in serum of uninfected individuals, latently infected healthy individuals and patients with active TB. We identified changes in amino acid, lipid and nucleotide metabolism pathways, providing evidence for anti-inflammatory metabolomic changes in TB. Metabolic profiles indicate increased activity of indole ...[more]

PMID: 22844400

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Project description:Obesity has reached epidemic proportions worldwide. Several animal models of obesity exist, but studies are lacking that compare traditional lard-based high fat diets (HFD) to "Cafeteria diets" (CAF) consisting of nutrient poor human junk food. Our previous work demonstrated the rapid and severe obesogenic and inflammatory consequences of CAF compared to HFD including rapid weight gain, markers of Metabolic Syndrome, multi-tissue lipid accumulation, and dramatic inflammation. To identify potential mediators of CAF-induced obesity and Metabolic Syndrome, we used metabolomic analysis to profile serum, muscle, and white adipose from rats fed CAF, HFD, or standard control diets. Principle component analysis identified elevations in clusters of fatty acids and acylcarnitines. These increases in metabolites were associated with systemic mitochondrial dysfunction that paralleled weight gain, physiologic measures of Metabolic Syndrome, and tissue inflammation in CAF-fed rats. Spearman pairwise correlations between metabolites, physiologic, and histologic findings revealed strong correlations between elevated markers of inflammation in CAF-fed animals, measured as crown like structures in adipose, and specifically the pro-inflammatory saturated fatty acids and oxidation intermediates laurate and lauroyl carnitine. Treatment of bone marrow-derived macrophages with lauroyl carnitine polarized macrophages towards the M1 pro-inflammatory phenotype through downregulation of AMPK and secretion of pro-inflammatory cytokines. Results presented herein demonstrate that compared to a traditional HFD model, the CAF diet provides a robust model for diet-induced human obesity, which models Metabolic Syndrome-related mitochondrial dysfunction in serum, muscle, and adipose, along with pro-inflammatory metabolite alterations. These data also suggest that modifying the availability or metabolism of saturated fatty acids may limit the inflammation associated with obesity leading to Metabolic Syndrome.

Project description:Tuberculosis (TB) is a serious infectious disease in that 90% of those latently infected with Mycobacterium tuberculosis present no symptoms, but possess a 10% lifetime chance of developing active TB. To prevent the spread of the disease, early diagnosis is crucial. However, current methods of detection require improvement in sensitivity, efficiency or specificity. In the present study, we conducted a microarray experiment, comparing the gene expression profiles in the peripheral blood mononuclear cells among individuals with active TB, latent infection, and healthy conditions in a Taiwanese population.Bioinformatics analysis revealed that most of the differentially expressed genes belonged to immune responses, inflammation pathways, and cell cycle control. Subsequent RT-PCR validation identified four differentially expressed genes, NEMF, ASUN, DHX29, and PTPRC, as potential biomarkers for the detection of active and latent TB infections. Receiver operating characteristic analysis showed that the expression level of PTPRC may discriminate active TB patients from healthy individuals, while ASUN could differentiate between the latent state of TB infection and healthy condidtion. In contrast, DHX29 may be used to identify latently infected individuals among active TB patients or healthy individuals. To test the concept of using these biomarkers as diagnostic support, we constructed classification models using these candidate biomarkers and found the Naïve Bayes-based model built with ASUN, DHX29, and PTPRC to yield the best performance.Our study demonstrated that gene expression profiles in the blood can be used to identify not only active TB patients, but also to differentiate latently infected patients from their healthy counterparts. Validation of the constructed computational model in a larger sample size would confirm the reliability of the biomarkers and facilitate the development of a cost-effective and sensitive molecular diagnostic platform for TB.

Dataset Information

Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients.

Publications

Biomarkers of inflammation, immunosuppression and stress with active disease are revealed by metabolomic profiling of tuberculosis patients.

Similar Datasets

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