Metabolic Signatures of Resistance to Mycobacterium Tuberculosis Infection: Insights from a Multi-Country Plasma Metabolomics Study
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: Background Tuberculosis (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. Methods We 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. Results There 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 µM, whereas hydroxyproline was lower by 0.90 µM, butyrobetaine was lower by 0.06 µM, and homogentisate was lower by 0.0036 µM at false discovery rate of 0.2. Conclusions Plasma 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.
Source: medRxiv
Authors: Chang Liu, Jeffrey M. Collins, Matheus Fernandes Gyorfy, Mariana Araújo Pereira, Vidya Mave, Senbagavalli Prakash, Kamakshi Prudhula Devalraju, Neil A. Martinson, Fay Willis, Marina C. Figueiredo, Marcelo Cordeiro-Santos, Artur Trancoso Lopo de Queiroz, Venkata Sanjeev Kumar Neela, Rajesh Karyakarte, Timothy R. Sterling, Jerrold J. Ellner, James C.M. Brust, Amita Gupta, Bruno B. Andrade, Yan V. Sun, Neel R. Gandhi
Institutions: Emory University, Johns Hopkins University, Jawaharlal Institute of Post Graduate Medical Education and Research, Mahavir Medical Research Centre, University of the Witwatersrand, Vanderbilt University Medical Center, Fundação de Medicina Tropical, Universidade Nilton Lins, Universidade do Estado do Amazonas, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, B. J. Medical College & Sassoon Hospital, Rutgers Health, Rutgers New Jersey Medical School, Albert Einstein College of Medicine, Johns Hopkins Medicine, Atlanta VA Health Care System
Language: English
Subfield: Infectious Diseases
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: CRDF Global, City University of New York, Emory University, Department of Biotechnology, Ministry of Science and Technology, India, Indian Council of Medical Research, National Institutes of Health, Center for AIDS Research, University of Washington, Medical Research Council, National Institute of Allergy and Infectious Diseases
Awards: G2198174088, G4517903627, Mentorship in Patient-Oriented Research in Tuberculosis, HIV and Global Health, Clinical and Translational Science Award, Characterization of Genomics and Metabolomics among Individuals Highly-Exposed, but resistant to Mtb Infection, Emory/Georgia TB Research Advancement Center (TRAC), ERC Einstein-Rockefeller-CUNY Center for AIDS research, Mentoring Multidisciplinary Patient-Oriented Research in TB, HIV, and Global Health, Mentoring of multidisciplinary global health research in tuberculosis and HIV
OpenAlex ID: W7220460890