Dysregulated cysteine metabolism leads to worsened liver pathology in diabetes-tuberculosis comorbid condition

Abstract

Diabetes mellitus (DM) is a risk factor for developing active tuberculosis (TB) with a 3-fold increase in susceptibility and a 4-fold higher relapse rate. With increasing DM prevalence in TB endemic regions, understanding pathophysiological changes associated with DM-TB comorbidity is imperative. In this study, streptozotocin (STZ)-induced DM C57BL/6 mice were aerosol infected with low dose (100-120 CFU) Mycobacterium tuberculosis H37Rv. At 3 weeks post infection (w.p.i.), multiple tissue mycobacterial load and metabolites were profiled. The liver proteome of DM-TB and controls were analyzed using quantitative proteomics, and multi-omics data were integrated. DM-TB mice showed dysregulated multi-tissue (lungs, liver, brain, kidney and thigh muscle) metabolism. In contrast, the mycobacterial burden in the lung, spleen and liver was similar at 3 w.p.i. in DM-TB and TB groups. Enrichment analysis of deregulated liver metabolites (n=20; log2DM-TB/TB>±1.0) showed significant perturbation in cysteine-methionine, glycine-serine, BCAA and fatty acid metabolism. Sixty out of 1660 identified liver proteins showed deregulation (log2DM-TB/TB>±1.0) and contributed from perturbed cysteine-methionine metabolism corroborating metabolomics data. In addition, amino acid biosynthesis, retinol metabolism and polyol biosynthetic process were also differentially enriched in the livers of DM-TB groups. Global correlation analysis of liver metabolome and proteome data showed a strong association between aspartic acid, pyruvic acid, leucine and isoleucine with CYP450 enzymes involved in retinol metabolism, while iminodiacetic acid, isoleucine and γ-aminobutyric acid (GABA) strong positive correlation involved in cysteine metabolism. Targeting perturbed cysteine metabolism using micro molecules, like DL-Propargylglycine, might help prevent liver damage in DM-TB comorbid conditions.