Diabetes mellitus and tuberculosis comorbidity induce unique microbial gut dysbiosis and associated metabolome

Abstract Background Patients with diabetes and tuberculosis (DMTB) often exhibit atypical disease progression and poor treatment outcomes. Alterations in gut microbiota may contribute to the impaired immune response in diabetes. Understanding the microbiota composition and associated metabolite profiles in DMTB could provide insights for developing targeted adjunctive therapies to improve patient prognosis. Method Nicotinamide (NA) and streptozotocin (STZ) induced diabetic C57BL/6 mice were aerosol infected with 100-120 CFU of Mycobacterium tuberculosis H37Rv. At different time points (2 days pre-infection and 3- and 8 weeks post-infection; wpi), faecal samples were collected for microbiome and metabolome profiling using 16S rRNA sequencing and gas chromatography-time of flight-mass spectrometry (GC-TOF-MS), respectively. Results Diabetic mice showed gut dysbiosis, with 16 bacterial genera significantly altered between DMTB and TB groups at 3 wpi, which reduced to 11 at 8 wpi. Among the 93 identified faecal metabolites, 11 and 10 metabolites were significantly deregulated (log 2 FC>±1.0, p<0.05) in the DMTB group compared to TB group at 3 and 8 wpi, respectively. A negative correlation between faecal valeric acid levels in DMTB with the abundances of Coriobacteriaceae, Granulicatella, Veillonella, Achromobacter, Erysipelatrichaceae, Atopobiaceae, Citrobacter , and Lactiplantibacillus were observed. Stronger correlations between microbiota and metabolite were observed in DMTB comorbidity compared to TB. Additionally, correlation analysis also revealed a phylogenetic distance-dependent synchrony in amino acid metabolism across five clades, each containing three or more bacterial genera. Conclusion This study reveals significant differences in the gut microbiome and metabolome between DMTB and TB groups. The identified microbes and metabolic products may serve as potential prebiotic or probiotic candidates for improving recovery in DMTB comorbid conditions.