Molecular perturbations in pulmonary tuberculosis patients identified by pathway-level analysis of plasma metabolic features

Abstract

Insight into the metabolic biosignature of tuberculosis (TB) may inform clinical care, reduce adverse effects, and facilitate metabolism-informed therapeutic development. However, studies often yield inconsistent findings regarding the metabolic profiles of TB. Herein, we conducted an untargeted metabolomics study using plasma from 63 Korean TB patients and 50 controls. Metabolic features were integrated with the data of another cohort from China (35 TB patients and 35 controls) for a global functional meta-analysis. Specifically, all features were matched to a known biological network to identify potential endogenous metabolites. Next, a pathway-level gene set enrichment analysis-based analysis was conducted for each study and the resulting p-values from the pathways of two studies were combined. The meta-analysis revealed both known metabolic alterations and novel processes. For instance, retinol metabolism and cholecalciferol metabolism, which are associated with TB risk and outcome, were altered in plasma from TB patients; proinflammatory lipid mediators were significantly enriched. Furthermore, metabolic processes linked to the innate immune responses and possible interactions between the host and the bacillus showed altered signals. In conclusion, our proof-of-concept study indicated that a pathway-level meta-analysis directly from metabolic features enables accurate interpretation of TB molecular profiles.

Circulating Lipids as Biomarkers for Diagnosis of Tuberculosis: A Multi-cohort, Multi-omics Data Integration Analysis

“…Notably, our previous work consistently highlighted the role of lipids in the pathogenesis of TB and their potential to aid in TB management [21,42]. We also found that host metabolic perturbations in TB were associated with innate immune responses to the pathogen [22]. PC has been implicated in the host immune response to pathogens [21,42,43], and PC-derived lipid mediators play a role in immune modulation [44].…”

“…A universal diagnostic test capable of differentiating TB from NTM, other lung diseases, LTBI, and healthy individuals remains necessary [14]. Circulating immune and metabolic biomarkers hold promise for this purpose [19][20][21][22][23]. For example, Hur et al identified several cytokines, such as interleukin-2, as potential adjunctive biomarkers for distinguishing TB from NTM [19].…”

Push forward LC-MS-based therapeutic drug monitoring and pharmacometabolomics for anti-tuberculosis precision dosing and comprehensive clinical management

“…Horizontal (metabolomics and lipidomics) and vertical (genomics, transcriptomics, proteomics, and metabolomics) multi-omics data integration present a powerful approach to capture a holistic view of the molecular landscape, which could provide a comprehensive understanding of an individual's response to anti-TB drugs [ 123 , 124 ]. These approaches are described as prospects to improve the better-personalized medicine of TB and allow the discovery of biosignatures for treatment monitoring and clinical outcomes (efficacy and AEs) [ 123 , [125] , [126] , [127] ]. Long et al.…”