Pre-treatment untargeted cerebrospinal fluid metabolomic profiling in tuberculous meningitis uncovers pathways associated with mortality.

IF 11.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL

Med Pub Date : 2025-05-23 DOI:10.1016/j.medj.2025.100703

Thanh Hoang Nhat Le, Kirsten C J van Abeelen, Edwin Ardiansyah, Julian Avila-Pacheco, Sofiati Dian, Gesa Carstens, Lara Schramke, Hoang Thanh Hai, Tran Binh Minh Nguyen, Thai Minh Triet, Amy Deik, Jesse Krejci, Jeff Pruyne, Lucas Dailey, Bachti Alisjahbana, Mihai G Netea, Riwanti Estiasari, Trinh Thi Bich Tram, Joseph Donovan, Dorothee Heemskerk, Thi Hong Chau Tran, Nguyen Duc Bang, Ahmad Rizal Ganiem, Raph L Hamers, Rovina Ruslami, Darma Imran, Kartika Maharani, Vinod Kumar, Reinout van Crevel, Guy Thwaites, Clary B Clish, Nguyen Thuy Thuong Thuong, Arjan van Laarhoven

{"title":"Pre-treatment untargeted cerebrospinal fluid metabolomic profiling in tuberculous meningitis uncovers pathways associated with mortality.","authors":"Thanh Hoang Nhat Le, Kirsten C J van Abeelen, Edwin Ardiansyah, Julian Avila-Pacheco, Sofiati Dian, Gesa Carstens, Lara Schramke, Hoang Thanh Hai, Tran Binh Minh Nguyen, Thai Minh Triet, Amy Deik, Jesse Krejci, Jeff Pruyne, Lucas Dailey, Bachti Alisjahbana, Mihai G Netea, Riwanti Estiasari, Trinh Thi Bich Tram, Joseph Donovan, Dorothee Heemskerk, Thi Hong Chau Tran, Nguyen Duc Bang, Ahmad Rizal Ganiem, Raph L Hamers, Rovina Ruslami, Darma Imran, Kartika Maharani, Vinod Kumar, Reinout van Crevel, Guy Thwaites, Clary B Clish, Nguyen Thuy Thuong Thuong, Arjan van Laarhoven","doi":"10.1016/j.medj.2025.100703","DOIUrl":null,"url":null,"abstract":"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 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.Findings: 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.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 β-oxidation is linked to TBM-associated mortality. Interventions targeting cerebral fatty acid metabolism may improve survival of TBM.Funding: National Institute of Health; Wellcome Trust, UK.","PeriodicalId":29964,"journal":{"name":"Med","volume":" ","pages":"100703"},"PeriodicalIF":11.8000,"publicationDate":"2025-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Med","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.medj.2025.100703","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}

引用次数: 0

Abstract

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 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.

Findings: 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.

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 β-oxidation is linked to TBM-associated mortality. Interventions targeting cerebral fatty acid metabolism may improve survival of TBM.

Funding: National Institute of Health; Wellcome Trust, UK.

查看原文本刊更多论文

结核性脑膜炎治疗前非靶向脑脊液代谢组学分析揭示了与死亡率相关的途径。

背景：脑脊液（CSF）色氨酸代谢失调是结核性脑膜炎（TBM）高死亡率的原因之一。我们旨在通过非靶向代谢组分析确定与TBM死亡率相关的新代谢途径。方法：采用非靶向液相色谱-质谱法对来自印度尼西亚（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619种代谢物进行了检测。60天死亡率采用Cox回归建模，调整了年龄和艾滋病毒状况。代谢物被列入筛选子集（n = 194，印度尼西亚），并在同一队列（n = 194）和外部（n = 679，越南）中进行验证。二级分析包括变量选择、聚类将相关代谢物分类为亚组、与非感染性对照组的比较、与患者特征、CSF细胞因子、CSF蛋白和血清代谢物浓度的相关性。结果：60天死亡率为21.6%，与包括色氨酸在内的10种脑脊液代谢物的浓度有关。关联最强的是3-羟基辛酸酯（FA 8:0;3OH），它是羟基化脂肪酸簇的一部分，还包括羟基异己酸酯（FA 6:0；OH）、羟基异丁酸酯（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、细菌负荷和脑脊液蛋白的相关性较弱。中介分析表明，脂肪酸的变化与死亡率直接相关，而不是与疾病的严重程度有关。结论：我们鉴定并验证了9种与TBM死亡率相关的新代谢物，与HIV状态、疾病严重程度和色氨酸无关。这些代谢物表明，脂肪酸β氧化的改变与tbm相关的死亡率有关。针对脑脂肪酸代谢的干预措施可能提高TBM的生存率。资助：国家卫生研究所；惠康信托，英国

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.