Metabolic Signatures of Resistance to Mycobacterium Tuberculosis Infection: Insights from a Multi-Country Plasma Metabolomics Study
- 1Emory University
Abstract
BackgroundTuberculosis (TB) remains the leading infectious disease cause of mortality worldwide. A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) remain TST/IGRA-negative despite sustained exposure, termed "TB resisters". The biological mechanisms underlying this resistance remain poorly understood. We applied untargeted high-resolution metabolomics to determine whether systemic metabolic profiles differ between TB resisters and matched Mtb-infected close contacts.
MethodsWe compared untargeted high-resolution plasma metabolomics using liquid chromatography mass spectrometry between 269 TB resisters and 269 matched Mtb-infected close contacts, enrolled across Brazil, India, and South Africa. TB resisters were defined as highly exposed close contacts who slept in the same room or spent at least 5 hours indoors per day with an infectious pulmonary TB index patient, but remained TST/IGRA-negative. Mtb-infected close contacts were those who were TST/IGRA positive. Metabolome-wide association studies (MWAS) were conducted using paired t-tests.
ResultsThere were 1,787 features with nominal differences between TB resisters and matched Mtb-infected contacts (p < 0.05). Pathway enrichment identified fructose and mannose metabolism and bile acid biosynthesis in the overall cohort, while lipid-related pathways were enriched in Brazil. Among metabolites with confirmed chemical identities, glyceric acid concentrations were higher in TB resisters by 0.53 {micro}M, whereas hydroxyproline was lower by 0.90 {micro}M, butyrobetaine was lower by 0.06 {micro}M, and homogentisate was lower by 0.0036 {micro}M at false discovery rate of 0.2.
ConclusionsPlasma metabolomic profiles differed between TB resisters and matched Mtb-infected close contacts. These findings indicate that systemic metabolic differences are associated with resistance to Mtb infection.
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BibTeX
@misc{liu2026metabolic,
title = {{Metabolic Signatures of Resistance to Mycobacterium Tuberculosis Infection: Insights from a Multi-Country Plasma Metabolomics Study}},
author = {C. Liu and J. M. Collins and M. F. Gyorfy and M. Araujo Pereira and V. Mave and S. Prakash and K. P. Devalraju and N. A. Martinson and F. Willis and M. C. Figueiredo and M. Cordeiro-Santos and A. Trancoso Lopo de Queiroz and V. S. K. Neela and R. Karyakarte and T. R. Sterling and J. J. Ellner and J. C. M. Brust and A. Gupta and B. B. Andrade and Y. V. Sun and N. R. Gandhi and TB GWAS collaboration},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.29.26364337},
url = {https://www.medrxiv.org/content/10.64898/2026.09.29.26364337v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Metabolic Signatures of Resistance to Mycobacterium Tuberculosis Infection: Insights from a Multi-Country Plasma Metabolomics Study
AU - C. Liu
AU - J. M. Collins
AU - M. F. Gyorfy
AU - M. Araujo Pereira
AU - V. Mave
AU - S. Prakash
AU - K. P. Devalraju
AU - N. A. Martinson
AU - F. Willis
AU - M. C. Figueiredo
AU - M. Cordeiro-Santos
AU - A. Trancoso Lopo de Queiroz
AU - V. S. K. Neela
AU - R. Karyakarte
AU - T. R. Sterling
AU - J. J. Ellner
AU - J. C. M. Brust
AU - A. Gupta
AU - B. B. Andrade
AU - Y. V. Sun
AU - N. R. Gandhi
AU - TB GWAS collaboration
PY - 2026
DA - 2026/09/29
PB - medRxiv
DO - 10.64898/2026.09.29.26364337
UR - https://www.medrxiv.org/content/10.64898/2026.09.29.26364337v1
AB - BackgroundTuberculosis (TB) remains the leading infectious disease cause of mortality worldwide. A subset of individuals exposed to Mycobacterium tuberculosis (Mtb) remain TST/IGRA-negative despite sustained exposure, termed "TB resisters". The biological mechanisms underlying this resistance remain poorly understood. We applied untargeted high-resolution metabolomics to determine whether systemic metabolic profiles differ between TB resisters and matched Mtb-infected close contacts. MethodsWe compared untargeted high-resolution plasma metabolomics using liquid chromatography mass spectrometry between 269 TB resisters and 269 matched Mtb-infected close contacts, enrolled across Brazil, India, and South Africa. TB resisters were defined as highly exposed close contacts who slept in the same room or spent at least 5 hours indoors per day with an infectious pulmonary TB index patient, but remained TST/IGRA-negative. Mtb-infected close contacts were those who were TST/IGRA positive. Metabolome-wide association studies (MWAS) were conducted using paired t-tests. ResultsThere were 1,787 features with nominal differences between TB resisters and matched Mtb-infected contacts (p < 0.05). Pathway enrichment identified fructose and mannose metabolism and bile acid biosynthesis in the overall cohort, while lipid-related pathways were enriched in Brazil. Among metabolites with confirmed chemical identities, glyceric acid concentrations were higher in TB resisters by 0.53 {micro}M, whereas hydroxyproline was lower by 0.90 {micro}M, butyrobetaine was lower by 0.06 {micro}M, and homogentisate was lower by 0.0036 {micro}M at false discovery rate of 0.2. ConclusionsPlasma metabolomic profiles differed between TB resisters and matched Mtb-infected close contacts. These findings indicate that systemic metabolic differences are associated with resistance to Mtb infection.
ER -