Abstract
The mechanisms whereby Mycobacterium tuberculosis (Mtb) rewires the host metabolism in vivo are surprisingly unexplored. Here, we used three high-resolution mass spectrometry platforms to track altered lung metabolic changes associated with Mtb infection of mice. The multiplatform data sets were merged using consensus orthogonal partial least squares-discriminant analysis (cOPLS-DA), an algorithm that allows for the joint interpretation of the results from a single multivariate analysis. We show that Mtb infection triggers a temporal and progressive catabolic state to satisfy the continuously changing energy demand to control infection. This causes dysregulation of metabolic and oxido-reductive pathways culminating in Mtb-associated wasting. Notably, high abundances of trimethylamine-N-oxide (TMAO), produced by the host from the bacterial metabolite trimethylamine upon infection, suggest that Mtb could exploit TMAO as an electron acceptor under anaerobic conditions. Overall, these new pathway alterations advance our understanding of the link between Mtb pathogenesis and metabolic dysregulation and could serve as a foundation for new therapeutic intervention strategies. Mass spectrometry data has been deposited in the Metabolomics Workbench repository (data-set identifier: ST001328).
Highlights
Tuberculosis (TB) is caused by the obligate pathogen Mycobacterium tuberculosis (Mtb)
Metabolomics has been employed for the identification of TB diagnostic biomarkers, the evaluation of potential therapeutics, and the study of the biological mechanisms underlying TB disease onset and progression in both in vitro and in vivo animal models, as well as in human patients.[4−6] Characterizing how the host metabolome is altered during Mtb infection is critically important as it may lead to the discovery of new pathways essential for protection against the bacillus and the identification of host-directed therapies
Lesions were clearly visible in the lungs of infected mice, albeit more severe pathology was noted in Mtb+9w compared to Mtb+4w (Figure 2)
Summary
Tuberculosis (TB) is caused by the obligate pathogen Mycobacterium tuberculosis (Mtb). To productively mine large data sets from multiplatform HRMSbased metabolomic approaches, a robust and reproducible statistical data pipeline is necessary (Figure 1A).[26] To obtain a global view of results arising from different analytical platforms (Supporting Table S1), results were combined using the consensus orthogonal partial least squares-discriminant analysis (cOPLS-DA) data fusion algorithm.[27] OPLS-DA-related algorithms calculate mathematical projections, which explain the maximum variability between previously assigned sample groups for a specific metabolite data matrix. After merging of modules with correlation values higher than 0.9, the discrete modularity algorithm was used for careful data interpretation
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