# Characterizing the tuberculosis and type 2 diabetes mellitus comorbidity in a South African cohort using untargeted GCxGC-TOFMS metabolomics

## TL;DR

The study explores how tuberculosis and type 2 diabetes interact metabolically in a South African group, revealing disrupted amino acid and lipid metabolism linked to immune suppression.

## Contribution

The paper provides a novel metabolic characterization of TB-T2DM comorbidity using untargeted GCxGC-TOFMS metabolomics in a specific cohort.

## Key findings

- TB-T2DM patients show reduced metabolites in tryptophan, nucleotide, and tyrosine pathways, indicating metabolic disruptions.
- Altered lipid metabolism and glycine conjugates suggest NAD⁺ imbalance and microbial dysbiosis in comorbid patients.
- Findings imply synergistic metabolic stress and immune suppression, linking TB and T2DM progression.

## Abstract

Tuberculosis (TB) and type 2 diabetes mellitus (T2DM) are highly prevalent diseases resulting in high mortality rates globally. Furthermore, T2DM increases susceptibility to TB and vice versa, worsening disease outcomes. This comorbidity is, however, not well described nor understood, despite its rising prevalence globally.

This investigation aimed to better characterize the urinary metabolic profiles of patients with the TB and T2DM comorbidity in a South African cohort, to better understand its metabolic basis and associated clinical implications.

Using untargeted GCxGC-TOFMS metabolomics, urine samples from 17 patients with TB and T2DM and 34 healthy controls were analyzed and statistically compared to identify significantly altered urinary metabolites.

TB-T2DM comorbid patients were characterized by altered metabolism of: (1) tryptophan and kynurenine (reduced kynurenic acid, anthranilic acid, picolinic acid) associated with changes to NAD+ synthesis and a redox imbalance, (2) nucleotides (reduced 3-aminoisobutyric acid, orotic acid, thymine, β-alanine, adenine, hypoxanthine), (3) tyrosine (reduced 3,4-dihydroxyphenylglycol, 4-hydroxy-3-methoxyphenylglycol, hydroxyphenylpyruvate), (4) lipids (reduced dec-2-enedioate, adipic acid, methylmalonic acid), (5) reduced concentrations of various glycine conjugates associated with glycine depletion, and (6) reduced urinary concentrations of various gut microbial metabolites indicative of microbial dysbiosis.

These results indicate several metabolic disruptions to amino acids, nucleotides, lipids, NAD⁺ homeostasis and the host microbiome, in TB-T2DM patients, mainly driven by inflammation and oxidative stress. Overall, the findings indicate synergistic amplification of metabolic stress, associated with immune suppression and TB-T2DM disease progression, and subsequently suggests how TB increases T2DM susceptibility and vice versa, as foundation for further investigations.

The online version contains supplementary material available at 10.1007/s11306-025-02389-y.