{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T15:59:59Z","timestamp":1781711999175,"version":"3.54.5"},"reference-count":57,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T00:00:00Z","timestamp":1632787200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>From the World Health Organization\u2019s global TB report for 2020, it is estimated that in 2019 at least 80,000 children (a particularly vulnerable population) developed tuberculous meningitis (TBM)\u2014an invariably fatal disease if untreated\u2014although this is likely an underestimate. As our latest technologies have evolved\u2014with the unprecedented development of the various \u201comics\u201d disciplines\u2014a mountain of new data on infectious diseases have been created. However, our knowledge and understanding of infectious diseases are still trying to keep pace. Metabolites offer much biological information, but the insights they permit can be difficult to derive. This review summarizes current metabolomics studies on cerebrospinal fluid (CSF) from TBM cases and collates the metabolic data reported. Collectively, CSF metabolomics studies have identified five classes of metabolites that characterize TBM: amino acids, organic acids, nucleotides, carbohydrates, and \u201cother\u201d. Taken holistically, the information given in this review serves to promote the mechanistic action of hypothesis generation that will drive and direct future studies on TBM.<\/jats:p>","DOI":"10.3390\/metabo11100661","type":"journal-article","created":{"date-parts":[[2021,9,28]],"date-time":"2021-09-28T21:38:09Z","timestamp":1632865089000},"page":"661","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["CSF Metabolomics of Tuberculous Meningitis: A Review"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2945-5768","authenticated-orcid":false,"given":"Shayne","family":"Mason","sequence":"first","affiliation":[{"name":"Human Metabolomics, Faculty of Natural and Agricultural Sciences, North-West University, Potchefstroom 2531, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regan","family":"Solomons","sequence":"additional","affiliation":[{"name":"Department of Paediatrics and Child Health, Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg 7505, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S122","DOI":"10.1016\/j.tube.2015.02.021","article-title":"Tuberculosis origin: The Neolithic scenario","volume":"95","author":"Hershkovitz","year":"2015","journal-title":"Tuberculosis"},{"key":"ref_2","unstructured":"WHO (2020). Global Tuberculosis Report 2020, World Health Organization. Available online: https:\/\/www.who.int\/publications\/i\/item\/9789240013131."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Seddon, J.A., Tugume, L., Solomons, R., Prasad, K., Bahr, N.C., and Tuberculous Meningitis International Research Consortium (2019). The current global situation for tuberculous meningitis: Epidemiology, diagnostics, treatment and outcomes. Wellcome Open Res., 4.","DOI":"10.12688\/wellcomeopenres.15535.1"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"928","DOI":"10.5588\/ijtld.11.0679","article-title":"The evolving epidemic of drug-resistant tuberculosis among children in Cape Town, South Africa","volume":"16","author":"Seddon","year":"2012","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1133","DOI":"10.1093\/cid\/ciw083","article-title":"GeneXpert MTB\/Rif to diagnose tuberculous meningitis: Perhaps the first test but not the last","volume":"62","author":"Bahr","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","unstructured":"Boyles, T.H., Lynen, L., Seddon, J.A., and Tuberculous Meningitis International Research Consortium (2020). Decision-making in the diagnosis of tuberculous meningitis. Wellcome Open Res., 5.","DOI":"10.12688\/wellcomeopenres.15611.1"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Cresswell, F.V., Davis, A.G., Sharma, K., Roy, R.B., Ganiem, A.R., Kagimu, E., Solomons, R., Wilkinson, R.J., Bahr, N.C., and Thuong, N.T.T. (2019). Recent developments in tuberculous meningitis pathogenesis and diagnostics. Wellcome Open Res., 4.","DOI":"10.12688\/wellcomeopenres.15506.1"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Davis, A.G., Nightingale, S., Springer, P.E., Solomons, R., Arenivas, A., Wilkinson, R.J., Anderson, S.T., Chow, F.C., and Tuberculous Meningitis International Research Consortium (2019). Neurocognitive and functional impairment in adult and pediatric tuberculous meningitis. Wellcome Open Res., 4.","DOI":"10.12688\/wellcomeopenres.15516.1"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Davis, A.G., Donovan, J., Bremer, M., van Toorn, R., Schoeman, J., Dadabhoy, A., Lai, R.P., Cresswell, F.V., Boulware, D.R., and Wilkinson, R.J. (2020). Host directed therapies for tuberculous meningitis. Wellcome Open Res., 5.","DOI":"10.12688\/wellcomeopenres.16474.1"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Donovan, J., Rohlwink, U.K., Tucker, E.W., Hiep, N.T.T., Thwaites, G.E., Figaji, A.A., and Tuberculous Meningitis International Research Consortium (2019). Checklists to guide the supportive and critical care of tuberculous meningitis. Wellcome Open Res., 4.","DOI":"10.12688\/wellcomeopenres.15512.1"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1093\/cid\/ciaa473","article-title":"Xpert MTB\/RIF ultra for the diagnosis of tuberculous meningitis: A small step forward","volume":"71","author":"Donovan","year":"2020","journal-title":"Clin. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Imran, D., Hill, P.C., McKnight, J., van Crevel, R., and Tuberculous Meningitis International Research Consortium (2019). Establishing the cascade of care for patients with tuberculous meningitis. Wellcome Open Res., 4.","DOI":"10.12688\/wellcomeopenres.15515.1"},{"key":"ref_13","first-page":"501","article-title":"Standardized methods for enhanced quality and comparability of tuberculous meningitis studies","volume":"64","author":"Marais","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Marais, S., van Toorn, R., Chow, F.C., Manesh, A., Siddiqi, O.K., Figaji, A., Schoeman, J.F., Meintjes, G., and Tuberculous Meningitis International Research Consortium (2019). Management of intracranial tuberculous mass lesions: How long should we treat for?. Wellcome Open Res., 4.","DOI":"10.12688\/wellcomeopenres.15501.2"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Misra, U.K., Kalita, J., and Tuberculous Meningitis International Research Consortium (2019). Mechanism, spectrum, consequences and management of hyponatremia in tuberculous meningitis. Wellcome Open Res., 4.","DOI":"10.12688\/wellcomeopenres.15502.1"},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Rohlwink, U.K., Chow, F.C., Wasserman, S., Dian, S., Lai, R.P., Chaidir, L., Hamers, R.L., Wilkinson, R.J., Boulware, D.R., and Cresswell, F.V. (2019). Standardized approaches for clinical sampling and endpoint ascertainment in tuberculous meningitis studies. Wellcome Open Res., 4.","DOI":"10.12688\/wellcomeopenres.15497.1"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Seddon, J.A., Thwaites, G.E., and Tuberculous Meningitis International Research Consortium (2019). Tuberculous meningitis: New tools and new approaches required. Wellcome Open Res., 4.","DOI":"10.12688\/wellcomeopenres.15591.1"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Seddon, J.A., Wilkinson, R., van Crevel, R., Figaji, A., Thwaites, G.E., and Tuberculous Meningitis International Research Consortium (2019). Knowledge gaps and research priorities in tuberculous meningitis. Wellcome Open Res., 4.","DOI":"10.12688\/wellcomeopenres.15573.1"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dai, Y.N., Huang, H.J., Song, W.Y., Tong, Y.X., Yang, D.H., Wang, M.S., Huang, Y.C., Chen, M.J., Zhang, J.J., and Ren, Z.Z. (2017). Identification of potential metabolic biomarkers of cerebrospinal fluids that differentiate tuberculous meningitis from other types of meningitis by a metabolomics study. Oncotarget, 8.","DOI":"10.18632\/oncotarget.21942"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Isaiah, S., Loots, D.T., Solomons, R., van Der Kuip, M., Tutu Van Furth, A., and Mason, S. (2020). Overview of brain-to-gut axis exposed to chronic CNS bacterial infection(s) and a predictive urinary metabolic profile of a brain infected by Mycobacterium tuberculosis. Front. Neurosci., 14.","DOI":"10.3389\/fnins.2020.00296"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1016\/j.cca.2017.01.002","article-title":"Cerebrospinal fluid metabolomic profiling in tuberculous and viral meningitis: Screening potential markers for differential diagnosis","volume":"466","author":"Li","year":"2017","journal-title":"Clin. Chim. Acta"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1007\/s11306-014-0741-z","article-title":"A hypothetical astrocyte\u2013microglia lactate shuttle derived from a 1H NMR metabolomics analysis of cerebrospinal fluid from a cohort of South African children with tuberculous meningitis","volume":"11","author":"Mason","year":"2015","journal-title":"Metabolomics"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12879-016-1597-9","article-title":"Cerebrospinal fluid in tuberculous meningitis exhibits only the L-enantiomer of lactic acid","volume":"16","author":"Mason","year":"2016","journal-title":"BMC Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3389\/fnins.2017.00043","article-title":"Lactate shuttles in neuroenergetics\u2014Homeostasis, allostasis and beyond","volume":"11","author":"Mason","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"534","DOI":"10.3389\/fnins.2017.00534","article-title":"Cerebrospinal fluid amino acid profiling of pediatric cases with tuberculous meningitis","volume":"11","author":"Mason","year":"2017","journal-title":"Front. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"460","DOI":"10.3389\/fnins.2020.00460","article-title":"A novel, multi-faceted perception of lactate in neurology","volume":"14","author":"Mason","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1016\/S1473-3099(18)30053-7","article-title":"Cerebral tryptophan metabolism and outcome of tuberculous meningitis: An observational cohort study","volume":"18","author":"Dian","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.jinf.2020.06.078","article-title":"Metabolic characterization of tuberculous meningitis in a South African pediatric population using 1H NMR metabolomics","volume":"81","author":"Loots","year":"2020","journal-title":"J. Infect."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1016\/j.meegid.2019.01.003","article-title":"1H nuclear magnetic resonance-based metabolic profiling of cerebrospinal fluid to identify metabolic features and markers for tuberculosis meningitis","volume":"68","author":"Zhang","year":"2019","journal-title":"Infect. Genet. Evol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1086\/497836","article-title":"Proton nuclear magnetic resonance\u2014Based metabonomics for rapid diagnosis of meningitis and ventriculitis","volume":"41","author":"Coen","year":"2005","journal-title":"Clin. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s11306-016-1073-y","article-title":"Comprehensive 1H NMR metabolic profiling of body fluids for differentiation of meningitis in adults","volume":"12","author":"Chatterji","year":"2016","journal-title":"Metabolomics"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1016\/j.cca.2017.03.015","article-title":"Proton NMR metabolic profiling of CSF reveals distinct differentiation of meningitis from negative controls","volume":"469","author":"Chatterji","year":"2017","journal-title":"Clin. Chim. Acta"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3109\/00365549709019042","article-title":"Adenylate kinase activity in the cerebrospinal fluid of children with tuberculous meningitis and its relationship to neurological outcome","volume":"29","author":"Carlini","year":"1997","journal-title":"Scand. J. Infect. Dis."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e178","DOI":"10.1016\/j.wneu.2017.12.007","article-title":"Correlation of lactate concentration in peripheral plasma and cerebrospinal fluid with Glasgow outcome scale for patients with tuberculous meningitis complicated by acute hydrocephalus treated with fluid diversions","volume":"111","author":"Faried","year":"2018","journal-title":"World Neurosurg."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1111\/j.1651-2227.1993.tb12577.x","article-title":"Concentrations of nucleotides, nucleosides, purine bases and urate in cerebrospinal fluid of children with meningitis","volume":"82","author":"Camina","year":"1993","journal-title":"Acta Paediatr."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1016\/S0387-7604(02)00160-2","article-title":"Neuron-specific enolase, nucleotides, nucleosides, purine bases, oxypurines and uric acid concentrations in cerebrospinal fluid of children with meningitis","volume":"25","author":"Cid","year":"2003","journal-title":"Brain Dev."},{"key":"ref_37","first-page":"19","article-title":"Cerebrospinal fluid lactate and lactate dehydrogenase levels as diagnostic aids in tuberculous meningitis","volume":"67","author":"Donald","year":"1985","journal-title":"S. Afr. Med. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"81","DOI":"10.3109\/00365548809117221","article-title":"Serial lactate determinations in tuberculous meningitis","volume":"20","author":"Tang","year":"1988","journal-title":"Scand. J. Infect. Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1093\/tropej\/35.5.263","article-title":"Cerebrospinal fluid lactate and raised intracranial pressure in tuberculous meningitis","volume":"35","author":"Donald","year":"1989","journal-title":"J. Trop. Pediatr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1007\/s15010-001-1100-3","article-title":"The prognostic factors of adult tuberculous meningitis","volume":"29","author":"Lu","year":"2001","journal-title":"Infection"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1016\/S0140-6736(02)11318-3","article-title":"Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features","volume":"360","author":"Thwaites","year":"2002","journal-title":"Lancet"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1105","DOI":"10.1086\/378642","article-title":"Pathophysiology and prognosis in Vietnamese adults with tuberculous meningitis","volume":"188","author":"Thwaites","year":"2003","journal-title":"J. Infect. Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1007\/s00381-015-2745-z","article-title":"The diagnostic value of cerebrospinal fluid chemistry results in childhood tuberculous meningitis","volume":"31","author":"Solomons","year":"2015","journal-title":"Childs Nerv. Syst."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1016\/S1473-3099(19)30550-X","article-title":"Xpert MTB\/RIF Ultra for the diagnosis of HIV-associated tuberculous meningitis: A prospective validation study","volume":"20","author":"Cresswell","year":"2020","journal-title":"Lancet Infect. Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S0167-7799(98)01214-1","article-title":"Systematic functional analysis of the yeast genome","volume":"16","author":"Oliver","year":"1998","journal-title":"Trends Biotechnol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/cfg.82","article-title":"Combining genomics, metabolome analysis, and biochemical modelling to understand metabolic networks","volume":"2","author":"Fiehn","year":"2001","journal-title":"Comp. Funct. Genomics"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1","DOI":"10.17159\/sajs.2016\/20150086","article-title":"Tuberculous meningitis in infants and children: Insights from nuclear magnetic resonance metabolomics","volume":"112","author":"Mason","year":"2016","journal-title":"S. Afr. J. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.cca.2018.04.022","article-title":"Mass spectrometry-based metabolomics for tuberculosis meningitis","volume":"483","author":"Zhang","year":"2018","journal-title":"Clin. Chim. Acta"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/gm337","article-title":"Multi-platform characterization of the human cerebrospinal fluid metabolome: A comprehensive and quantitative update","volume":"4","author":"Mandal","year":"2012","journal-title":"Genome Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Leen, W.G., Willemsen, M.A., Wevers, R.A., and Verbeek, M.M. (2012). Cerebrospinal fluid glucose and lactate: Age-specific reference values and implications for clinical practice. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0042745"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1016\/S0197-0186(97)00061-2","article-title":"The neurochemical markers in cerebrospinal fluid to differentiate between aseptic and tuberculous meningitis","volume":"32","author":"Qureshi","year":"1998","journal-title":"Neurochem. Int."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/S1473-3099(10)70138-9","article-title":"Tuberculous meningitis: A uniform case definition for use in clinical research","volume":"10","author":"Marais","year":"2010","journal-title":"Lancet Infect. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/j.jinf.2011.02.010","article-title":"Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial meningitis from aseptic meningitis: A meta-analysis","volume":"62","author":"Sakushima","year":"2011","journal-title":"J. Infect."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Huy, N.T., Thao, N.T., Diep, D.T., Kikuchi, M., Zamora, J., and Hirayama, K. (2010). Cerebrospinal fluid lactate concentration to distinguish bacterial from aseptic meningitis: A systemic review and meta-analysis. Crit. Care, 14.","DOI":"10.1186\/cc9395"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1002\/1099-1492(200008)13:5<297::AID-NBM648>3.0.CO;2-I","article-title":"High-resolution proton nuclear magnetic resonance spectroscopy of ovarian cyst fluid","volume":"13","author":"Boss","year":"2000","journal-title":"NMR Biomed."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1016\/j.jmr.2015.07.014","article-title":"Can NMR solve some significant challenges in metabolomics?","volume":"260","author":"Gowda","year":"2015","journal-title":"J. Magn. Reson."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Emwas, A.H., Roy, R., McKay, R.T., Tenori, L., Saccenti, E., Gowda, G.A., Raftery, D., Alahmari, F., Jaremko, L., and Jaremko, M. (2019). NMR spectroscopy for metabolomics research. Metabolites, 9.","DOI":"10.3390\/metabo9070123"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/11\/10\/661\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:06:32Z","timestamp":1760166392000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/11\/10\/661"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,28]]},"references-count":57,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["metabo11100661"],"URL":"https:\/\/doi.org\/10.3390\/metabo11100661","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,28]]}}}