Integrated serum lipidomics and selected immune profiling identify immunometabolic alterations associated with T2DM-TB comorbidity

Abstract Type 2 diabetes mellitus (T2DM) increases the risk of active tuberculosis (TB) and is associated with unfavorable clinical outcomes. Previous studies have shown that TB-DM comorbidity is accompanied by dyslipidemia and inflammatory alterations, but how selected cellular immune indicators relate to serum lipid species-level remodeling in newly diagnosed T2DM-TB remains incompletely characterized. This study aimed to explore selected immune-marker alterations and serum lipidomic remodeling in patients with T2DM-TB comorbidity. In this cross-sectional study, serum samples and peripheral blood immune data were collected from healthy controls (HC), patients with TB alone, patients with T2DM alone, and patients with T2DM-TB comorbidity. Peripheral T-cell subset percentages and selected cytokines were measured, and serum lipidomics was performed using liquid chromatography–tandem mass spectrometry. Immune indicators measured across all four groups were compared using analysis of covariance with adjustment for body mass index. IFN-γ and IL-2 were measured only in participants with active tuberculosis and were compared between the TB and T2DM-TB groups. IL-6 and TNF-α were not included in the original cytokine panel; therefore, the immune analysis should be interpreted as selected immune-marker profiling rather than comprehensive inflammatory profiling. Differential lipids were identified using predefined statistical and effect-size thresholds, and exploratory lipid–immune association analyses were performed. Patients with T2DM-TB showed alterations in selected immune indicators, characterized mainly by lower CD4 + T-cell percentages, a lower CD4 + /CD8 + ratio, and higher IL-10 levels compared with the other groups. In the TB-related subgroup, IFN-γ and IL-2 levels were lower in T2DM-TB than in TB alone. Serum lipidomics identified broad lipid remodeling in T2DM-TB, involving glycerophospholipids, glycerolipids, and sphingolipids. Compared with T2DM alone, the comorbid group showed prominent membrane phospholipid- and sphingolipid-related changes, whereas comparison with TB alone highlighted glycerolipid, glycerophospholipid, and lipid storage-related alterations. Exploratory correlation analyses identified several nominal lipid–immune associations, mainly along a CD4-negative axis and an IL-10-positive axis; however, none remained significant after Benjamini–Hochberg false discovery rate correction. T2DM-TB comorbidity was associated with alterations in selected immune indicators and broad serum lipid species-level remodeling relative to TB alone, T2DM alone, and healthy controls. These findings suggest a hypothesis-generating immunometabolic profile, rather than a validated diagnostic or mechanistic signature, involving T-cell subset changes, a regulatory cytokine shift, and remodeling of glycerophospholipid, glycerolipid, and sphingolipid pathways. However, the immune panel was limited, IL-6 and TNF-α were not measured, and lipid–immune associations did not survive false discovery rate correction. Larger independent cohorts with broader inflammatory profiling and mechanistic validation are needed.