The metabolic milieu of tuberculosis-type 2 diabetes mellitus comorbidity using 1H-NMR metabolomics

Background The prevalence of tuberculosis (TB) and type 2 diabetes mellitus (T2DM) comorbidity (TB-T2DM) is on the rise globally and negatively impacts disease progression and treatment outcomes for both diseases. T2DM additionally increases the risk of developing active TB and can double the risk of death from TB, and vice versa. A major contributing factor to the growing global prevalence of TB-T2DM is the dearth of knowledge regarding the metabolic interaction of these two diseases and the combined impact on host metabolism. Methods This study aimed to broadly characterise the urinary metabolic profiles of TB-T2DM comorbid patients in a South African cohort using untargeted proton nuclear magnetic resonance spectroscopy ( ¹ H-NMR) metabolomics, by comparing 30 healthy controls and 14 patients with both TB and T2DM. Results Principal component analysis showed the control and comorbid groups as distinct clusters, and 23 urinary metabolites were identified as significantly increased in TB-T2DM versus healthy controls using univariate statistical analyses. The metabolite markers identified indicate inhibited glycolysis (glucose, mannose, sucrose) and tricarboxylic acid (TCA) cycle functionality (citrate, α-ketoglutarate, succinate and fumarate), accompanied by an elevated gluconeogenesis (glucose, pyruvate, lactate, alanine), muscle wasting/amino acid catabolism (leucine, valine, isoleucine, and tyrosine), kidney damage (creatinine, methylguanidine), alterations in gut microbial/one-carbon metabolism (choline, trimethylamine, trimethylamine-N-oxide, dimethylamine and methylamine), ketogenesis (β-hydroxybutyrate), and potentially altered carnitine reabsorption (carnitine). This study further suggests the previously proposed imbalance in the NAD ⁺ /NADH ratio, which is an important outcome that warrants further investigation. Conclusion Overall, this study indicates that the TB-T2DM metabolic changes result from a compounded metabolic effect of both diseases, although some metabolite alterations are more closely associated with those previously seen in T2DM. This study subsequently expands the current understanding of the TB-T2DM comorbid metabolic milieu and identifies new avenues for future research, for a better understanding of the individual effects of each disease and their combined impact in patients with TB-T2DM comorbidity.