Le Thanh Hoang Nhat, van Abeelen Kirsten C J, Ardiansyah Edwin, Avila-Pacheco Julian, Dian Sofiati, Carstens Gesa, Schramke Lara, Hai Hoang Thanh, Nguyen Tran Binh Minh, Triet Thai Minh, Deik Amy, Krejci Jesse, Pruyne Jeff, Dailey Lucas, Alisjahbana Bachti, Netea Mihai G, Estiasari Riwanti, Bich Tram Trinh Thi, Donovan Joseph, Heemskerk Dorothee, Tran Thi Hong Chau, Bang Nguyen Duc, Ganiem Ahmad Rizal, Hamers Raph L, Ruslami Rovina, Imran Darma, Maharani Kartika, Kumar Vinod, van Crevel Reinout, Thwaites Guy, Clish Clary B, Thuong Nguyen Thuy Thuong, van Laarhoven Arjan
Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.
Department of Internal Medicine and Radboud Community for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
Med. 2025 May 23:100703. doi: 10.1016/j.medj.2025.100703.
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.
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 modeled 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.
Sixty-day mortality was 21.6% and was associated with the concentration of 10 CSF metabolites, including tryptophan. The strongest association was with 3-hydroxyoctanoate (FA 8:0;3OH), part of a cluster of hydroxylated fatty acids also including hydroxy-isocaproate (FA 6:0;OH), hydroxyisobutyrate (FA 4:0;OH), and C4-OH-carnitine. These fatty acids correlated weakly with CSF tumor necrosis factor alpha, interleukin-6 (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.
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 β-oxidation is linked to TBM-associated mortality. Interventions targeting cerebral fatty acid metabolism may improve survival of TBM.
National Institute of Health; Wellcome Trust, UK.
脑脊液（CSF）色氨酸代谢失调导致结核性脑膜炎（TBM）的高死亡率。我们旨在通过非靶向全代谢组分析确定与TBM死亡率相关的新代谢途径。
我们使用非靶向液相色谱 - 质谱法测量了来自印度尼西亚（n = 388，34例HIV阳性）和越南（n = 679，250例HIV阳性）的成年TBM患者治疗前脑脊液中的619种代谢物。使用Cox回归对60天死亡率进行建模，并对年龄和HIV状态进行调整。代谢物在一个筛查亚组（n = 194，印度尼西亚）中进行排名，并在同一队列（n = 194）和外部队列（n = 679，越南）中进行验证。二次分析包括变量选择、聚类以将相关代谢物分类为亚组、与非感染性对照进行比较以及与患者特征、脑脊液细胞因子、脑脊液蛋白和血清代谢物浓度进行相关性分析。
60天死亡率为21.6%，与10种脑脊液代谢物浓度相关，包括色氨酸。最强关联是与3 - 羟基辛酸（FA 8:0;3OH）相关，它是一组羟基化脂肪酸的一部分，还包括羟基异己酸（FA 6:0;OH）、羟基异丁酸（FA 4:0;OH）和C4 - OH -肉碱。这些脂肪酸与脑脊液肿瘤坏死因子α、白细胞介素 - 6（IL - 6）、白细胞计数、细菌载量和脑脊液蛋白的相关性较弱。中介分析表明，脂肪酸的变化直接与死亡率相关，而非通过疾病严重程度。
我们鉴定并验证了9种与TBM死亡率相关的新代谢物，独立于HIV状态、疾病严重程度和色氨酸。这些代谢物表明脂肪酸β -氧化改变与TBM相关死亡率有关。针对脑脂肪酸代谢的干预措施可能会提高TBM患者的生存率。
美国国立卫生研究院；英国惠康信托基金会。
