Summary of Study ST003788

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

This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.

Study ID	ST003788
Study Title	Pre-treatment untargeted cerebrospinal fluid metabolomic profiling in tuberculous meningitis reveals multiple pathways associated with mortality
Study 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	(617) 714-1729
Submit Date	2025-03-03
Raw Data Available	Yes
Raw Data File Type(s)	raw(Thermo)
Analysis Type Detail	LC-MS
Release Date	2025-03-13
Release Version	1

Select appropriate tab below to view additional metadata details:

Project:

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

Subject:

Subject ID:	SU003922
Subject Type:	Human
Subject Species:	Homo sapiens
Taxonomy ID:	9606
Age Or Age Range:	14-87

Factors:

Subject type: Human; Subject species: Homo sapiens (Factor headings shown in green)

mb_sample_id	local_sample_id	Sample source	HIV	TBM_grade	diagnosis_ultimate
SA411832	05TB21027	CSF	HIV-negative	Grade I	Cryptococcal meningitis
SA411833	23TB03-131	CSF	HIV-negative	Grade I	Definite TBM
SA411834	23TB03-141	CSF	HIV-negative	Grade I	Definite TBM
SA411835	2300195	CSF	HIV-negative	Grade I	Definite TBM
SA411836	900490	CSF	HIV-negative	Grade I	Definite TBM
SA411837	23TB03-117	CSF	HIV-negative	Grade I	Definite TBM
SA411838	23TB03-118	CSF	HIV-negative	Grade I	Definite TBM
SA411839	23TB03-112	CSF	HIV-negative	Grade I	Definite TBM
SA411840	23TB03-120	CSF	HIV-negative	Grade I	Definite TBM
SA411841	23TB03-121	CSF	HIV-negative	Grade I	Definite TBM
SA411842	23TB03-146	CSF	HIV-negative	Grade I	Definite TBM
SA411843	23TB03-145	CSF	HIV-negative	Grade I	Definite TBM
SA411844	23TB03-143	CSF	HIV-negative	Grade I	Definite TBM
SA411845	23TB03-142	CSF	HIV-negative	Grade I	Definite TBM
SA411846	23TB03-140	CSF	HIV-negative	Grade I	Definite TBM
SA411847	23TB03-132	CSF	HIV-negative	Grade I	Definite TBM
SA411848	23TB03-139	CSF	HIV-negative	Grade I	Definite TBM
SA411849	23TB03-122	CSF	HIV-negative	Grade I	Definite TBM
SA411850	23TB03-123	CSF	HIV-negative	Grade I	Definite TBM
SA411851	23TB03-108	CSF	HIV-negative	Grade I	Definite TBM
SA411852	23TB03-138	CSF	HIV-negative	Grade I	Definite TBM
SA411853	23TB03-126	CSF	HIV-negative	Grade I	Definite TBM
SA411854	23TB03-137	CSF	HIV-negative	Grade I	Definite TBM
SA411855	23TB03-128	CSF	HIV-negative	Grade I	Definite TBM
SA411856	23TB03-135	CSF	HIV-negative	Grade I	Definite TBM
SA411857	23TB03-134	CSF	HIV-negative	Grade I	Definite TBM
SA411858	23TB03-115	CSF	HIV-negative	Grade I	Definite TBM
SA411859	23TB03-124	CSF	HIV-negative	Grade I	Definite TBM
SA411860	05TB41010	CSF	HIV-negative	Grade I	Definite TBM
SA411861	05TB41025	CSF	HIV-negative	Grade I	Definite TBM
SA411862	05TB21040	CSF	HIV-negative	Grade I	Definite TBM
SA411863	05TB41001	CSF	HIV-negative	Grade I	Definite TBM
SA411864	05TB41002	CSF	HIV-negative	Grade I	Definite TBM
SA411865	05TB41003	CSF	HIV-negative	Grade I	Definite TBM
SA411866	05TB41004	CSF	HIV-negative	Grade I	Definite TBM
SA411867	05TB41005	CSF	HIV-negative	Grade I	Definite TBM
SA411868	05TB41007	CSF	HIV-negative	Grade I	Definite TBM
SA411869	05TB41008	CSF	HIV-negative	Grade I	Definite TBM
SA411870	05TB41009	CSF	HIV-negative	Grade I	Definite TBM
SA411871	05TB41011	CSF	HIV-negative	Grade I	Definite TBM
SA411872	05TB41027	CSF	HIV-negative	Grade I	Definite TBM
SA411873	05TB41012	CSF	HIV-negative	Grade I	Definite TBM
SA411874	05TB41013	CSF	HIV-negative	Grade I	Definite TBM
SA411875	05TB41014	CSF	HIV-negative	Grade I	Definite TBM
SA411876	05TB41015	CSF	HIV-negative	Grade I	Definite TBM
SA411877	05TB41016	CSF	HIV-negative	Grade I	Definite TBM
SA411878	05TB41020	CSF	HIV-negative	Grade I	Definite TBM
SA411879	05TB41022	CSF	HIV-negative	Grade I	Definite TBM
SA411880	05TB41023	CSF	HIV-negative	Grade I	Definite TBM
SA411881	05TB41026	CSF	HIV-negative	Grade I	Definite TBM
SA411882	05TB41029	CSF	HIV-negative	Grade I	Definite TBM
SA411883	23TB03-105	CSF	HIV-negative	Grade I	Definite TBM
SA411884	05TB41046	CSF	HIV-negative	Grade I	Definite TBM
SA411885	23TB03-101	CSF	HIV-negative	Grade I	Definite TBM
SA411886	900558	CSF	HIV-negative	Grade I	Definite TBM
SA411887	900618	CSF	HIV-negative	Grade I	Definite TBM
SA411888	05TB21141	CSF	HIV-negative	Grade I	Definite TBM
SA411889	900654	CSF	HIV-negative	Grade I	Definite TBM
SA411890	1300074	CSF	HIV-negative	Grade I	Definite TBM
SA411891	1300168	CSF	HIV-negative	Grade I	Definite TBM
SA411892	05TB41047	CSF	HIV-negative	Grade I	Definite TBM
SA411893	05TB41045	CSF	HIV-negative	Grade I	Definite TBM
SA411894	05TB41030	CSF	HIV-negative	Grade I	Definite TBM
SA411895	05TB41044	CSF	HIV-negative	Grade I	Definite TBM
SA411896	05TB41043	CSF	HIV-negative	Grade I	Definite TBM
SA411897	1300196	CSF	HIV-negative	Grade I	Definite TBM
SA411898	05TB41041	CSF	HIV-negative	Grade I	Definite TBM
SA411899	05TB41040	CSF	HIV-negative	Grade I	Definite TBM
SA411900	05TB41039	CSF	HIV-negative	Grade I	Definite TBM
SA411901	05TB41038	CSF	HIV-negative	Grade I	Definite TBM
SA411902	05TB41035	CSF	HIV-negative	Grade I	Definite TBM
SA411903	05TB41033	CSF	HIV-negative	Grade I	Definite TBM
SA411904	05TB21147	CSF	HIV-negative	Grade I	Definite TBM
SA411905	05TB41024	CSF	HIV-negative	Grade I	Definite TBM
SA411906	05TB21138	CSF	HIV-negative	Grade I	Definite TBM
SA411907	05TB21066	CSF	HIV-negative	Grade I	Definite TBM
SA411908	900159	CSF	HIV-negative	Grade I	Definite TBM
SA411909	05TB21081	CSF	HIV-negative	Grade I	Definite TBM
SA411910	900180	CSF	HIV-negative	Grade I	Definite TBM
SA411911	900297	CSF	HIV-negative	Grade I	Definite TBM
SA411912	05TB21077	CSF	HIV-negative	Grade I	Definite TBM
SA411913	05TB21074	CSF	HIV-negative	Grade I	Definite TBM
SA411914	05TB21069	CSF	HIV-negative	Grade I	Definite TBM
SA411915	900323	CSF	HIV-negative	Grade I	Definite TBM
SA411916	05TB21007	CSF	HIV-negative	Grade I	Definite TBM
SA411917	900083	CSF	HIV-negative	Grade I	Definite TBM
SA411918	05TB21062	CSF	HIV-negative	Grade I	Definite TBM
SA411919	05TB21054	CSF	HIV-negative	Grade I	Definite TBM
SA411920	05TB21019	CSF	HIV-negative	Grade I	Definite TBM
SA411921	05TB21051	CSF	HIV-negative	Grade I	Definite TBM
SA411922	05TB21049	CSF	HIV-negative	Grade I	Definite TBM
SA411923	900374	CSF	HIV-negative	Grade I	Definite TBM
SA411924	05TB21047	CSF	HIV-negative	Grade I	Definite TBM
SA411925	05TB21044	CSF	HIV-negative	Grade I	Definite TBM
SA411926	900138	CSF	HIV-negative	Grade I	Definite TBM
SA411927	05TB21075	CSF	HIV-negative	Grade I	Definite TBM
SA411928	05TB21094	CSF	HIV-negative	Grade I	Definite TBM
SA411929	05TB21123	CSF	HIV-negative	Grade I	Definite TBM
SA411930	05TB21137	CSF	HIV-negative	Grade I	Definite TBM
SA411931	05TB21135	CSF	HIV-negative	Grade I	Definite TBM

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Collection:

Collection ID:	CO003915
Collection Summary:	According to routine care, all patients with suspected meningitis underwent lumbar puncture (spinal tap) before starting antimicrobial or corticosteroid treatment.
Sample Type:	Cerebrospinal fluid

Treatment:

Treatment ID:	TR003931
Treatment Summary:	CSF samples were processed according to in-house developed protocols and according to the “Standardized approaches for clinical sampling and endpoint ascertainment in tuberculous meningitis studies” (PMID: 32399496), with the exception that centrifugation speed has changed over time, ranging from 865-3000 x g, for 15 minutes. The resulting supernatants were stored at -80°C.

Sample Preparation:

Sampleprep ID:	SP003928
Sampleprep Summary:	LC–MS samples were prepared from CSF samples for each profiling method as follows: - HILIC-pos: CSF (10 μL) samples were extracted with the addition of nine volumes of 74.9:24.9:0.2 v/v/v acetonitrile/methanol/formic acid containing stable isotope-labeled internal standards (valine-d8, Isotec; and phenylalanine-d8, Cambridge Isotope Laboratories). The samples were centrifuged (10 min, 9,000g, 4°C), and the supernatants (10 μL)injected directly onto column. - C8-pos: CSF samples (10 μL) were extracted using 190 μL isopropanol containing 1-dodecanoyl-2-tridecanoyl-sn-glycero-3-phosphocholine as an internal standard (Avanti Polar Lipids; Alabaster, AL). After centrifugation (10 min, 9,000g, ambient temperature), supernatants (2 μl) were injected directly onto column. - C18-neg: CSF samples (30 μL) were extracted using 90 μl methanol containing 15R-15-methyl ProstaglandinA2,15R-15-methyl ProstaglandinF2α, 15S-15-methyl ProstaglandinD2, 15S-15-methyl Prostaglandin E1, and 15S-15-methyl Prostaglandin E2 as internal standards (Cayman Chemical Co.) and centrifuged (10 min, 9,000g, 4°C). The supernatants (10 μL) were injected onto column. - HILIC-neg: CSF samples (30 μL) were extracted with the addition of four volumes of 80% methanol containing inosine-15N4, thymine-d4 and glycocholate-d4 internal standards (Cambridge Isotope Laboratories). The samples were centrifuged (10 min, 9,000g, 4°C) and the supernatants 10 μL) were injected directly onto column.

Sampleprep ID:

SP003928

Sampleprep Summary:

LC–MS samples were prepared from CSF samples for each profiling method as follows: - HILIC-pos: CSF (10 μL) samples were extracted with the addition of nine volumes of 74.9:24.9:0.2 v/v/v acetonitrile/methanol/formic acid containing stable isotope-labeled internal standards (valine-d8, Isotec; and phenylalanine-d8, Cambridge Isotope Laboratories). The samples were centrifuged (10 min, 9,000g, 4°C), and the supernatants (10 μL)injected directly onto column. - C8-pos: CSF samples (10 μL) were extracted using 190 μL isopropanol containing 1-dodecanoyl-2-tridecanoyl-sn-glycero-3-phosphocholine as an internal standard (Avanti Polar Lipids; Alabaster, AL). After centrifugation (10 min, 9,000g, ambient temperature), supernatants (2 μl) were injected directly onto column. - C18-neg: CSF samples (30 μL) were extracted using 90 μl methanol containing 15R-15-methyl ProstaglandinA2,15R-15-methyl ProstaglandinF2α, 15S-15-methyl ProstaglandinD2, 15S-15-methyl Prostaglandin E1, and 15S-15-methyl Prostaglandin E2 as internal standards (Cayman Chemical Co.) and centrifuged (10 min, 9,000g, 4°C). The supernatants (10 μL) were injected onto column. - HILIC-neg: CSF samples (30 μL) were extracted with the addition of four volumes of 80% methanol containing inosine-15N4, thymine-d4 and glycocholate-d4 internal standards (Cambridge Isotope Laboratories). The samples were centrifuged (10 min, 9,000g, 4°C) and the supernatants 10 μL) were injected directly onto column.

Combined analysis:

Analysis ID	AN006224	AN006225	AN006226	AN006227
Analysis type	MS	MS	MS	MS
Chromatography type	HILIC	Reversed phase	HILIC	Reversed phase
Chromatography system	Shimadzu Nexera X2	Shimadzu Nexera X2	Shimadzu Nexera X2	Shimadzu Nexera X2
Column	Waters Atlantis HILIC (150 x 2 mm, 3 µm)	Waters Acquity BEH C8 (100 x 2.1mm, 1.7um)	Phenomenex Luna NH2 (150 x 2.1mm, 3um)	Waters ACQUITY UPLC BEH C18 (150 x 1.7mm,2.1um)
MS Type	ESI	ESI	ESI	ESI
MS instrument type	Orbitrap	Orbitrap	Orbitrap	Orbitrap
MS instrument name	Thermo Orbitrap ID-X Tribrid	Thermo Orbitrap ID-X Tribrid	Thermo Q Exactive Plus Orbitrap	Thermo Orbitrap ID-X Tribrid
Ion Mode	POSITIVE	POSITIVE	NEGATIVE	NEGATIVE
Units	Abudances	Abudances	Abudances	Abudances

Chromatography:

Chromatography ID:	CH004719
Instrument Name:	Shimadzu Nexera X2
Column Name:	Waters Atlantis HILIC (150 x 2 mm, 3 µm)
Column Temperature:	30℃
Flow Gradient:	Isocratically with 5% mobile phase A for 1 minute followed by a linear gradient to 40% mobile phase B over 10 minutes
Flow Rate:	250 µL/min
Solvent A:	100% water; 10 mM Ammonium formate; 0.1% Formic acid
Solvent B:	100% acetonitrile; 0.1% Formic acid
Chromatography Type:	HILIC

Chromatography ID:	CH004720
Instrument Name:	Shimadzu Nexera X2
Column Name:	Waters Acquity BEH C8 (100 x 2.1mm, 1.7um)
Column Temperature:	40℃
Flow Gradient:	The column was eluted at a flow rate of 450 µL/min isocratically for 1 minute at 80% mobile phase A, followed by a linear gradient to 80% mobile-phase B over 2 minutes, a linear gradient to 100% mobile phase B over 7 minutes, and then 3 minutes at 100% mobile-phase B.
Flow Rate:	450 µL/min
Solvent A:	95% water/5% methanol; 10 mM Ammonium acetate; 0.1% Acetic acid
Solvent B:	100% methanol; 0.1% Acetic acid
Chromatography Type:	Reversed phase

Chromatography ID:	CH004721
Instrument Name:	Shimadzu Nexera X2
Column Name:	Phenomenex Luna NH2 (150 x 2.1mm, 3um)
Column Temperature:	30℃
Flow Gradient:	The column was eluted with initial conditions of 10% mobile phase A and 90% mobile phase B followed by a 10 min linear gradient to 100% mobile phase A.
Flow Rate:	400 µL/min
Solvent A:	100% water; 20 mM ammonium acetate; 20 mM ammonium hydroxide
Solvent B:	75% acetonitrile/25% methanol; 10 mM ammonium hydroxide
Chromatography Type:	HILIC

Chromatography ID:	CH004722
Instrument Name:	Shimadzu Nexera X2
Column Name:	Waters ACQUITY UPLC BEH C18 (150 x 1.7mm,2.1um)
Column Temperature:	45℃
Flow Gradient:	The column was eluted isocratically at a flow rate of 450 µL/min with 20% mobile phase A for 3 minutes followed by a linear gradient to 100% mobile phase B over 12 minutes.
Flow Rate:	450 µL/min
Solvent A:	100% water; 0.01% formic acid
Solvent B:	100% acetonitrile; 0.01% acetic acid
Chromatography Type:	Reversed phase

MS:

MS ID:	MS005928
Analysis ID:	AN006224
Instrument Name:	Thermo Orbitrap ID-X Tribrid
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	Raw data were processed using TraceFinder 3.3 software (Thermo Fisher Scientific; Waltham, MA) and Progenesis QI (Nonlinear Dynamics; Newcastle upon Tyne, UK). Metabolite identities were confirmed using authentic reference standards or reference samples.
Ion Mode:	POSITIVE

MS ID:	MS005929
Analysis ID:	AN006225
Instrument Name:	Thermo Orbitrap ID-X Tribrid
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	Raw data were processed using TraceFinder 3.3 software (Thermo Fisher Scientific; Waltham, MA) and Progenesis QI (Nonlinear Dynamics; Newcastle upon Tyne, UK). Metabolite identities were confirmed using authentic reference standards or reference samples.
Ion Mode:	POSITIVE

MS ID:	MS005930
Analysis ID:	AN006226
Instrument Name:	Thermo Q Exactive Plus Orbitrap
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	Raw data were processed using TraceFinder 3.3 software (Thermo Fisher Scientific; Waltham, MA) and Progenesis QI (Nonlinear Dynamics; Newcastle upon Tyne, UK). Metabolite identities were confirmed using authentic reference standards or reference samples.
Ion Mode:	NEGATIVE

MS ID:	MS005931
Analysis ID:	AN006227
Instrument Name:	Thermo Orbitrap ID-X Tribrid
Instrument Type:	Orbitrap
MS Type:	ESI
MS Comments:	Raw data were processed using TraceFinder 3.3 software (Thermo Fisher Scientific; Waltham, MA) and Progenesis QI (Nonlinear Dynamics; Newcastle upon Tyne, UK). Metabolite identities were confirmed using authentic reference standards or reference samples.
Ion Mode:	NEGATIVE