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Cerebrospinal fluid fatty acid metabolism and tuberculous meningitis mortality

L TH Nhat(1) K van Abeelen(2) E Ardiansyah(3) J Avila-Pacheco(4) S Dian(3) G Carstens(2) H T Hai(1) L Schramke(2) A Deik(4) J Krejci(4) J Pruyne(4) L Dailey(4) B Alisjahbana(3) M G Netea(2) R Estiasari(5) T TB Tram(1) J Donovan(1) D Heemskerk(1) T TH Chau(1) N D Bang(1) A R Ganiem(3) R L Hamers(5) R Ruslami(3) D Imran(5) K Maharani(5) V Kumar(2) R van Crevel(2) G Thwaites(1) C B Clish(4) N TT Thuong(1) A van Laarhoven(2)

1:Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam; 2:Radboudumc Community for Infectious Diseases, Nijmegen, the Netherlands; 3:Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia; 4:Broad Institute of MIT and Harvard; 5:Faculty of Medicine Universitas Indonesia, Jakarta, Indonesia.

Dysregulation of tryptophan metabolism contributes to the high mortality of tuberculous meningitis (TBM). We aimed to identify novel metabolic pathways associated with TBM mortality through metabolome-wide analysis, to improve understanding TBM pathophysiology and to identify new therapeutic targets.

We measured 619 metabolites using untargeted liquid chromatography-mass spectrometry in pre-treatment cerebrospinal fluid (CSF) from adults with TBM from Indonesia (n=388; 34 HIV-positive) and Vietnam (n=679; 250 HIV-positive). The primary outcome, 60-day mortality, was modelled using a Cox regression, adjusting for age, and HIV-status in a screening–validation approach. Secondary analysis included hierarchical clustering to classify associated metabolites into subgroups; comparison with non-infectious controls, and correlation of metabolites with TBM patient characteristics, CSF cytokines, blood-CSF barrier leakage, and serum metabolite levels.

Sixty-day mortality, the primary endpoint in the analysis, was 21.6%.We confirmed tryptophan as a predictor and identified nine additional CSF metabolites positively associated with hazard ratios for 60-day TBM mortality of 1.3 and above, grouped into two clusters. The strongest predictive metabolites for TBM mortality (independent of disease severity and CSF tryptophan) was 3-hydroxyoctanoate (FA 8:0; 3OH), part of a cluster of fatty acids, also including hydroxy-isocaproate (FA 6:0; OH), hydroxyisobutyrate (FA 4:0; OH), and C4-OH-carnitine. All four fatty acids correlated weakly with and blood-CSF barrier disruption, but serum fatty acids did not show a concomitant increase. 

Concluding, we identified and validated nine new metabolites associated to TBM mortality, independent of HIV-status, disease severity, and tryptophan, pointing to an important role for altered fatty acid beta-oxidation in TBM mortality. 

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