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

Diabetes mellitus (DM) is a well-known risk factor for tuberculosis (TB). Interestingly, DM is growing to pandemic proportions in TB endemic South-East Asian countries. DM-TB comorbidity induced pathophysiological changes warrants a better understanding to develop effective therapeutics. Tissue metabolomic profiling of streptozotocin (STZ) induced diabetic animals, infected with Mycobacterium tuberculosis H37Rv, showed metabolic dysregulation in the lungs, liver, brain, kidney and thigh muscle. At 3 w.p.i., the tissue (lungs, spleen, liver) bacterial loads were similar between DM-TB and TB with worsened lung pathology. Enrichment analysis of the deregulated liver metabolites (n=20; log2DM-TB/TB>±1.0) showed major perturbation in the cysteine-methionine, glycine-serine, branched chain amino acid (BCAA) and fatty acid metabolism. Parallel relative quantification of liver proteome of DM-TB and control mice groups (TB, DM and healthy) identified 1833 proteins which showed group specific variations. Enrichment analysis of significantly altered proteins (n=60; log2DM-TB/TB>±1.0) showed major perturbations in cysteine-methionine metabolism corroborating the metabolomics data. In addition, amino acid biosynthesis, retinol metabolism and polyol biosynthetic process were also differentially enriched in DM-TB groups compared to controls. Furthermore, a global correlation analysis of liver metabolome and proteome data showed strong association between aspartic acid, pyruvic acid, leucine and isoleucine with Cyp450 enzymes (Cyp2a5, Cyp3a11, Cyp4a10, Cyp4a14) involved in retinol metabolism. Whereas iminodiacetic acid, isoleucine and γ-aminobutyric acid strongly correlated to enzymes (Cth, Ahcy, Kyat3, Mat1a) involved in the cysteine metabolism. So, targeting the perturbed liver cysteine and retinol metabolism in DM-TB comorbid condition might improve therapeutic outcomes and prevent organ damage.