Summary of project PR002365
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR002365. The data can be accessed directly via it's Project DOI: 10.21228/M8XN97 This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR002365 |
| Project DOI: | doi: 10.21228/M8XN97 |
| Project Title: | Pre-treatment untargeted cerebrospinal fluid metabolomic profiling in tuberculous meningitis reveals multiple pathways associated with mortality |
| Project Type: | Metabolomic profiling of cerebrospinal fluid metabolomic in tuberculous meningitis. |
| Project Summary: | 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 modelled 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 ten CSF metabolites, including tryptophan. The strongest association was with 3-hydroxyoctanoate (FA 8:0;3OH), part of a cluster of hydroxylated fatty acids, further including hydroxy-isocaproate (FA 6:0;OH), hydroxyisobutyrate (FA 4:0;OH), and C4-OH-carnitine. These fatty acids correlated weakly with CSF TNF-α, 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 beta-oxidation is linked to TBM associated mortality. Interventions targeting cerebral fatty acid metabolism may improve survival from TBM. |
| Institute: | Broad Institute of MIT and Harvard |
| Last Name: | Avila-Pacheco |
| First Name: | Julian |
| Address: | 415 Main Street |
| Email: | jravilap@broadinstitute.org |
| Phone: | +1 (617) 714-1729 |
| Contributors: | Le Thanh Hoang Nhat, Kirsten CJ van Abeelen, Edwin Ardiansyah,, Julian Avila-Pacheco, Sofiati Dian, Gesa Carstens, Lara Schramke, Hoang Thanh Hai, Nguyen Tran Binh Minh, 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, Tran Thi Hong Chau, 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 |
Summary of all studies in project PR002365
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST003788 | Pre-treatment untargeted cerebrospinal fluid metabolomic profiling in tuberculous meningitis reveals multiple pathways associated with mortality | Homo sapiens | Broad Institute of MIT and Harvard | MS* | 2025-05-23 | 1 | 1233 | Uploaded data (62.7M) |
