Comprehensive Examination of the Mouse Lung Metabolome Following Mycobacterium tuberculosis Infection Using a Multiplatform Mass Spectrometry Approach

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).