title: 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.
authors.affiliation: Nutrition and Health Sciences, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, Georgia, United States of America; Center for Clinical and Molecular Nutrition, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Frediani
authors.affiliation: Nutrition and Health Sciences, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, Georgia, United States of America; Center for Clinical and Molecular Nutrition, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Dean P
authors.initials: DP
authors.lastname: Jones
authors.affiliation: National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia.
authors.forename: Nestan
authors.initials: N
authors.lastname: Tukvadze
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Karan
authors.initials: K
authors.lastname: Uppal
authors.affiliation: National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia.
authors.forename: Eka
authors.initials: E
authors.lastname: Sanikidze
authors.affiliation: National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia.
authors.forename: Maia
authors.initials: M
authors.lastname: Kipiani
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: ViLinh T
authors.initials: VT
authors.lastname: Tran
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Gautam
authors.initials: G
authors.lastname: Hebbar
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Civil and Environmental Engineering, Tufts University, Medford, Massachusetts, United States of America.
authors.forename: Douglas I
authors.initials: DI
authors.lastname: Walker
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Kempker
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Shaheen S
authors.initials: SS
authors.lastname: Kurani
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: Nutrition and Health Sciences, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, Georgia, United States of America; Center for Clinical and Molecular Nutrition, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America; Atlanta Veterans Affairs Medical Center, Decatur, Georgia, United States of America.
authors.forename: Vin
authors.initials: V
authors.lastname: Tangpricha
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Harvard Medical School, Boston, Massachusetts, United States of America.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America; National Center for Tuberculosis and Lung Disease, Tbilisi, Georgia; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Henry M
authors.initials: HM
authors.lastname: Blumberg
authors.affiliation: Nutrition and Health Sciences, Graduate Division of Biological and Biomedical Sciences, Laney Graduate School, Emory University, Atlanta, Georgia, United States of America; Center for Clinical and Molecular Nutrition, Emory University School of Medicine, Atlanta, Georgia, United States of America; Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Ziegler
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000097:blood / Q000627:therapeutic use; D019295:Computational Biology; D005260:Female; D006801:Humans; D008658:Inactivation, Metabolic; D008297:Male; D055432:Metabolomics; D009169:Mycobacterium tuberculosis / Q000378:metabolism* / Q000472:pathogenicity; D010865:Pilot Projects; D013183:Sputum / Q000378:metabolism / Q000382:microbiology; D053719:Tandem Mass Spectrometry; D014397:Tuberculosis, Pulmonary / Q000097:blood* / Q000188:drug therapy* / Q000382:microbiology; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents