title: Deregulated tyrosine-phenylalanine metabolism in pulmonary tuberculosis patients.
abstract: Metabolic profiling of biofluids from tuberculosis (TB) patients would help us in understanding the disease pathophysiology and may also be useful for the development of novel diagnostics and host-directed therapy. In this pilot study we have compared the urine metabolic profiles of two groups of subjects having similar TB symptoms and categorized as active TB (ATB, n = 21) and non-TB (NTB, n = 21) based on GeneXpert test results. Silylation, gas chromatography mass spectrometry, and standard chemometric methods were employed to identify the important molecules and deregulated metabolic pathways. Eleven active TB patients were followed up on longitudinally for comparative urine metabolic profiling with healthy controls (n = 11). A set of 42 features qualified to have a variable importance parameter score of > 1.5 of a partial least-squares discriminate analysis model and fold change of > 1.5 at p value < 0.05 between ATB and NTB. Using these variables, a receiver operating characteristics curve was plotted and the area under the curve was calculated to be 0.85 (95% CI: 0.72-0.96). Several of these variables that represent norepinephrine, gentisic acid, 4-hydroxybenzoic acid, hydroquinone, and 4-hydroxyhippuric acid are part of the tyrosine-phenylalanine metabolic pathway. In the longitudinal study we observed a treatment-dependent trend in the urine metabolome of follow-up samples, and subjects declared as clinically cured showed similar metabolic profile as those of asymptomatic healthy subjects. The deregulated tyrosine-phenylalanine axis reveals a potential target for diagnostics and intervention in TB.
authors.affiliation: †Immunology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India.
authors.forename: Mrinal Kumar
authors.initials: MK
authors.lastname: Das
authors.affiliation: †Immunology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India.
authors.forename: Subasa Chandra
authors.initials: SC
authors.lastname: Bishwal
authors.affiliation: †Immunology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India.
authors.forename: Aleena
authors.initials: A
authors.lastname: Das
authors.affiliation: †Immunology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India.
authors.forename: Deepti
authors.initials: D
authors.lastname: Dabral
authors.affiliation: †Immunology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India.
authors.forename: Vinod Kumar
authors.initials: VK
authors.lastname: Badireddy
authors.affiliation: ‡National Institute of Biomedical Genomics, Kalyani, West Bengal 741251, India.
authors.forename: Bhaswati
authors.initials: B
authors.lastname: Pandit
authors.affiliation: §Department of Medicine, Christian Medical College, Vellore, Tamil Nadu 632004, India.
authors.forename: George M
authors.initials: GM
authors.lastname: Varghese
authors.affiliation: †Immunology Group, International Centre for Genetic Engineering and Biotechnology (ICGEB), Aruna Asaf Ali Road, New Delhi 110067, India.
authors.forename: Ranjan Kumar
authors.initials: RK
authors.lastname: Nanda
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D016002:Discriminant Analysis; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008137:Longitudinal Studies; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D055442:Metabolome / Q000502:physiology*; D010649:Phenylalanine / Q000378:metabolism* / Q000652:urine; D010865:Pilot Projects; D012372:ROC Curve; D014397:Tuberculosis, Pulmonary / Q000378:metabolism / Q000503:physiopathology*; D014443:Tyrosine / Q000378:metabolism* / Q000652:urine
chemical_list: D015415:Biomarkers; D014443:Tyrosine; D010649:Phenylalanine
keywords: GC−MS; metabolomics; silyalation; tuberculosis; tyrosine−phenylalanine metabolism; urine analysis