Novel Metabolomic Biomarkers for Latent Tuberculosis Infection: A Plasma-based Untargeted Metabolomics Approach Using Mass Spectrometry

Abstract

Objective: Latent tuberculosis infection (LTBI) is difficult to diagnose due to the lack of a definitive gold standard. This study aimed to explore plasma metabolic alterations associated with LTBIs using an untargeted metabolomics approach.

Design: In this discovery-phase study, LTBI individuals (QuantiFERON-TB Gold-positive) were recruited from close contacts of tuberculosis patients, while non-LTBI individuals (QuantiFERON-TB Gold-negative) were recruited from prison detainees. Plasma samples were analyzed using ultra-high-performance liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. Multivariate statistical analysis combined with univariate screening was used to identify differential metabolites, followed by receiver operating characteristic analysis.

Results: A total of 43 metabolites showed significant differences between the LTBI (n = 100) and non-LTBI groups (n = 99). Among the 43 metabolites, leucylleucine, tryptophyl-phenylalanine, lysoPE(18:1(11Z)/0:0), and biliverdin displayed relatively high discriminatory ability in this discovery cohort with area under the curve values ranging from 0.975–0.981. Models combining selected metabolites achieved higher apparent classification performance under internal validation, with some area under the curve values approaching 1.00. However, because feature selection and model evaluation were performed within the same cohort and no external validation was performed, these results may overestimate true diagnostic performance.

Conclusions: This study provides exploratory evidence of plasma metabolic differences between LTBI and non-LTBI individuals and identifies four metabolites of potential interest. However, the two groups were drawn from different source populations, which may introduce selection bias and unmeasured confounding. In addition, all metabolites were identified at Metabolomics Standards Initiative level 2 without confirmation using authentic standards and no targeted validation was performed. Therefore, these findings should be interpreted as preliminary and hypothesis-generating. Independent validation in well-matched cohorts with targeted metabolomic approaches is required before any clinical interpretation.

Keywords

Biomarkers / latent tuberculosis infection / metabolomics / plasma

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