PR002365 (Project)

Description:Background Dysregulation of cerebrospinal fluid (CSF) tryptophan metabolism contributes to the high mortality of tuberculous meningitis (TBM). We aimed to identify novel metabolic pathways associated with TBM mortality through untargeted metabolome-wide analysis. Methods We measured 619 metabolites using untargeted liquid chromatography-mass spectrometry in pre-treatment CSF from adults with TBM from Indonesia (n=388; 34 HIV-positive) and Vietnam (n=679; 250 HIV-positive). Sixty-day mortality was modelled using Cox regression, adjusting for age and HIV-status. Metabolites were ranked in a screening subset (n=194, Indonesia), and validated in the same cohort (n=194) and externally (n=679, Vietnam). Secondary analysis included variable selection, clustering to classify associated metabolites into subgroups, comparison with non-infectious controls, and correlation with patient characteristics, CSF cytokines, CSF protein, and serum metabolite concentrations. Findings Sixty-day mortality was 21.6% and was associated with the concentration of ten CSF metabolites, including tryptophan. The strongest association was with 3-hydroxyoctanoate (FA 8:0;3OH), part of a cluster of hydroxylated fatty acids, further including hydroxy-isocaproate (FA 6:0;OH), hydroxyisobutyrate (FA 4:0;OH), and C4-OH-carnitine. These fatty acids correlated weakly with CSF TNF-α, IL-6, leukocyte counts, bacterial load and CSF protein. Mediation analysis showed that the variation in fatty acids was linked directly to mortality rather than through disease severity. Conclusion We identified and validated nine new metabolites associated with TBM mortality, independent of HIV-status, disease severity, and tryptophan. These metabolites suggest that altered fatty acid beta-oxidation is linked to TBM associated mortality. Interventions targeting cerebral fatty acid metabolism may improve survival from TBM.