Immune dysregulation in tuberculosis-diabetes comorbidity: mechanistic and translational insights

Abstract

Background: Tuberculosis (TB) remains a leading cause of infectious disease mortality worldwide, and the rising prevalence of diabetes mellitus (DM) represents a major obstacle to TB control. DM increases susceptibility to TB, worsens disease severity, delays treatment response, and is associated with poorer outcomes, largely through disruption of host immunity. Methods: We conducted a systematic review of studies published between 1974 and May 31, 2023 that examined immunological mechanisms through which DM alters TB pathogenesis. In total, 81 eligible studies involving animal models, human participants, or combined approaches were identified and synthesised across different stages of TB. Results: Across studies, DM was associated with broad dysregulation of innate and adaptive immune responses, altered cytokine signalling, impaired granuloma structure and function, and reduced control of Mycobacterium tuberculosis (Mtb). Distinct immune profiles emerged between TB disease with DM and latent TB infection with DM, with heterogeneity partly explained by differences in study design, metabolic status, and disease stage. Importantly, emerging evidence indicates that pre-diabetes and intermediate hyperglycaemia may also compromise TB immunity and contribute to disease progression. Conclusion: Our findings highlight DM as a key immunometabolic modifier of TB pathogenesis. They also suggest that earlier metabolic optimisation and hostdirected therapeutic strategies could be explored as potential approaches to improve outcomes in this growing high-risk TB-DM population. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023431040.