Characterizing tuberculous meningitis in a South African pediatric cohort using GCxGC-TOFMS metabolomics

The objective of this study was to characterize the metabolic profile of tuberculous meningitis (TBM) in the cerebrospinal fluid (CSF) of a South African pediatric cohort using two-dimensional gas chromatography linked to time-of-flight mass spectrometry (GCxGC-TOFMS). A metabolite extraction and derivatization protocol was performed using CSF samples from 21 cases of bacteriologically confirmed TBM and 24 controls without meningitis, and analyzed by GCxGC-TOFMS, followed by univariate and multivariate statistical comparisons to identify differentiating compounds. A total of 48 metabolites (involved in glycolysis and amino acid and fatty acid metabolism) were identified that differentiated the two groups (effect size d-value > 0.5 and partial least squares discriminant analysis VIP value > 1.0, with 16 metabolites highlighted as significant (p-value < 0.05). Eight novel metabolites (linked to imines, alkenes, and volatile organic compounds), never before identified in a TBM study, characterize TBM in this cohort. This study confirms existing metabolomics research aimed at characterizing the metabolic profile of TBM. Some affected metabolic pathways include glycolysis, pentose phosphate pathway, amino acids, and fatty acid metabolism. New information is provided on the effect TBM has on neurometabolism, how TBM can reduce the neuroprotective function of some metabolites in the brain, resulting in the neurological symptoms typically associated with this disease, and contribute to our understanding of the pathogenesis of TBM; ultimately, contributing to the development of a metabolic model of TBM.