A new study by the OUCRU Tuberculosis research group, in collaboration with partners from Indonesia, the Netherlands, and the United States, has identified new metabolites in the cerebrospinal fluid (CSF) linked to survival prediction in tuberculosis meningitis (TBM), potentially paving the way for improved diagnosis and treatments.
Tuberculous meningitis (TBM) is a severe form of tuberculosis, affecting 164,000 adults globally in 2019. The disease is caused by an excessive inflammatory response in the meninges, but there is still no effective treatment to control the inflammation. Even for patients receiving the standard tuberculosis treatment, including dexamethasone, half of those who survive are left with long-term complications.
The researchers hypothesised that metabolic pathways may influence disease outcome and help develop more effective host-directed therapy. They analysed 619 metabolites in CSF from 1,067 TBM Indonesian and Vietnamese patients before treatment.
The study used untargeted liquid chromatography-massspectrometry (LC-MS), a metabolomics platform developed by the Broad Institute of MIT and Harvard. This cutting-edge technique combines ultra-high sensitivity, broad metabolite coverage and untargeted analysis on minimal CSF volumes, enabling far broader and deeper discovery than previous tools used in TBM research.
Metabolic clues to survival in tuberculous meningitis
Published in Med, the study identified ten metabolites consistently higher in patients who did not survive within 60 days of diagnosis. Aside from tryptophan, which was previously reported, the other nine were newly linked to TBM outcomes. They include mainly hydroxylated fatty acids such as 3-hydroxyoctanoate (FA 8:0;3OH), hydroxy-isocaproate (FA 6:0;OH), hydroxyisobutyrate (FA 4:0;OH), and a related molecule, C4-OH carnitine.
These metabolites are correlated with traditional indicators of disease severity, such as Glassgow Coma Score (GSC), total leukocyte counts, bacterial load, or inflammatory cytokines in the CSF. Two metabolites, fatty acid 8:0;3OH and tryptophan, emerged as strongest predictors of mortality, independent of GSC or other pre-treatment severity measures.
“We identified two distinct molecular groups linked to lower survival in TBM patients: fatty acids and tryptophan. Fatty acids surged in patients with higher bacterial load and inflammation, while more tryptophan was found in those with lower levels of both. It suggests that multiple biological pathways may shape the survival outcome of TBM.”
The findings open the door to further investigation of the biological mechanisms driving poor outcomes in TBM, from how genetics shape CSF metabolic profiles to how these metabolites interact with proteins during infection or change as treatment begins. Together with our collaborators, the OUCRU research team led by Prof Guy Thwaites, Asso Prof Nguyễn Thụy Thương Thương and Dr Lê Thanh Hoàng Nhật is now exploring these questions in follow-up studies.
Collaborators:
1. Department of Internal Medicine and Radboud Community for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
2. Research Center for Care and Control of Infectious Diseases, Universitas Padjadjaran, Bandung, Indonesia
3. Broad Institute of MIT and Harvard, Cambridge, MA, USA,
4. Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.
5. Pham Ngoc Thach Hospital, Ho Chi Minh City, Vietnam
