Insights from LC-MS-based cerebrospinal fluid metabolomics in tuberculous meningitis

Tuberculous meningitis (TBM) remains the most devastating form of extra-pulmonary tuberculosis (TB) and is associated with high mortality and neurological deficits, often due to delayed diagnosis. Disease outcome in TBM depends critically on early diagnosis and timely initiation of treatment. However, the non-specific clinical presentation of TBM poses a major diagnostic challenge, as no single test can reliably establish a definitive diagnosis. The recommended diagnostic approach, GeneXpert MTB/RIF ultra, combined with mycobacterial culture of cerebrospinal fluid (CSF), remains limited by suboptimal sensitivity and restricted availability in many resource-constrained settings. These limitations underscore the urgent need for novel biomarkers that reflect TBM-specific pathophysiology and enable a single rapid, reliable, and accessible diagnosis. This perspective paper draws on insights from LC-MS-based CSF metabolomic profiling to highlight metabolic alterations in TBM. Key metabolic pathways-fatty acid β-oxidation reflected by altered acylcarnitine profiles, amino acid perturbations, and the tryptophan-kynurenine pathway-are discussed in relation to cellular energy disruption and neuroinflammation. Based on these alterations, free carnitine and quinolinic acid emerge as priority candidates for further investigation. Free carnitine reflects TBM-associated energy dysregulation, while quinolinic acid appears to mirror the severity of neuroinflammation. Future studies should focus on validating these metabolites in independent cohorts and on assessing their translational potential in more readily accessible biofluids, with the ultimate goal of enabling simplified, widely implemented diagnostic assays.