Urine metabolomic biomarkers linked to C-reactive protein-interleukin-6 axis in persons living with HIV and tuberculosis

Diagnosing pulmonary tuberculosis (PTB) remains challenging, particularly in people living with HIV (PLWH) who have a high rate of false-negative tests using expectorated sputum. Urine, a non-invasive sample, offers a valuable source of metabolites reflecting systemic changes in disease. This study utilized liquid chromatography-mass spectrometry to investigate urinary biomarkers previously identified in other cohorts, using a well-characterized population of people newly-diagnosed with HIV who screened positive for TB symptoms in Port-au-Prince, Haiti. In this study, we identified a urinary metabolomic signature associated with PTB in PLWH, confirming significant elevations of ureidopropionic acid, 3-hydroxykynurenine, and m/z 115.0498. Untargeted metabolomic analysis revealed a putative isoform of hydroxytryptophan and kynurenic acid as additional PTB-associated metabolites. Four of these five metabolites were also significantly elevated in serum when clinically and microbiologically combined PTB groups were analyzed. Serum metabolite levels correlated positively with elevated blood C-reactive protein (CRP) and IL-6, key inflammatory markers associated with PTB pathology. Moreover, the diagnostic performance of urinary metabolites in participants with CD4+T count below 200 cells/mm3 was not different from that of CRP. Urine metabolomic profiling may complement a patient-centered approach, providing a non-invasive means for TB biomarker discovery and investigating the immunometabolic processes underlying TB in PLWH.