High-resolution plasma metabolomics analysis to detect Mycobacterium tuberculosis-associated metabolites that distinguish active pulmonary tuberculosis in humans.

ABSTRACT

INTRODUCTION: Pulmonary tuberculosis (TB) is a major worldwide health problem that lacks robust blood-based biomarkers for detection of active disease. High-resolution metabolomics (HRM) is an innovative method to discover low-abundance metabolites as putative blood biomarkers to detect TB disease, including those known to be produced by the causative organism, Mycobacterium tuberculosis (Mtb). METHODS: We used HRM profiling to measure the plasma metabolome for 17 adults with active pulmonary TB disease and 16 of their household contacts without active TB. We used a suspect screening approach to identify metabolites previously described in cell culture studies of Mtb based on retention time and accurate mass matches. RESULTS: The association of relative metabolite abundance in active TB disease subjects compared to their household contacts predicted three Mtb-associated metabolites that were significantly increased in the active TB patients based on accurate mass matches phosphatidylglycerol (PG) (160_181), lysophosphatidylinositol (Lyso-PI) (180) and acylphosphatidylinositol mannoside (Ac1PIM1) (561) (p<0.001 for all). These three metabolites provided excellent classification accuracy for active TB disease (AUC = 0.97). Ion dissociation spectra (tandem MS/MS) supported the identification of PG (160_181) and Lyso-PI (180) in the plasma of patients with active TB disease, though the identity of Ac1PIM1 could not be definitively confirmed. CONCLUSIONS: Presence of the Mtb-associated lipid metabolites PG (160_181) and Lyso-PI (180) in plasma accurately identified patients with active TB disease. Consistency of in vitro and in vivo data suggests suitability for exploring these in future studies for possible development as TB disease biomarkers.