Integrating Untargeted Metabolomics and Transcriptomics in Mice with Pulmonary Tuberculosis to Reveal Changes in Linoleic Acid and Its Metabolism in Lung Monocyte-Derived Macrophages

Pulmonary tuberculosis (TB) remains a major global health challenge. The molecular and metabolic responses of monocyte-derived macrophages (MDMs), which are critical for host defense against <i>Mycobacterium tuberculosis</i> (Mtb), are not fully characterized. A murine pulmonary TB model was established by intravenous injection of BALB/c mice with the attenuated Mtb strain H37Ra; controls received saline. After 8 weeks, lung MDMs were isolated for integrated transcriptomic and untargeted metabolomic profiling. Transcriptomic analysis identified 3970 differentially expressed genes (DEGs) in infected MDMs, including upregulated <i>Ptpn1</i>, <i>Dgat2</i>, and <i>Alox5ap</i> and downregulated <i>Cyld</i>, <i>Zfp61</i>, and <i>Mapk11</i>. Metabolomic profiling revealed 113 differentially accumulated metabolites (DAMs). Taurocholic acid and linoleic acid were identified as potential diagnostic biomarkers, both achieving an area under the curve (AUC) of 1.0 in ROC analysis. Integrated omics analysis showed a positive correlation between linoleic acid levels and the expression of <i>Tbxas1</i>, <i>Acaa1b</i>, and <i>Acox1</i>, implicating lipid metabolic pathways in the host response to TB. This multi-omics study delineates key molecular and metabolic alterations in lung MDMs during TB infection. The identified metabolites, taurocholic acid and linoleic acid, show promise as biomarkers, while dysregulated linoleic acid metabolism represents a potential target for novel diagnostic and therapeutic strategies against TB.