Integrated approaches to target nuclear receptors for managing the co-morbidity of tuberculosis and diabetes.

Introduction: The dual epidemic of tuberculosis (TB) and type 2 diabetes mellitus (T2DM) presents a critical global health challenge, as diabetic immunosuppression increases TB susceptibility while TB infection exacerbates glucose intolerance. Because nuclear receptors (NRs) regulate both metabolic pathways and infectious disease responses, they represent promising therapeutic targets. This study aimed to evaluate the therapeutic potential of targeting overlapping NRs to manage TB-T2DM comorbidity. Methods: A comorbid mouse model was established by inducing T2DM via a high-fat diet and streptozotocin, followed by an aerosol challenge with Mycobacterium tuberculosis (M. tb). Mice were categorized into three groups: uninfected controls, M. tb-infected non-diabetic, and M. tb-infected diabetic mice. NR expression profiling was performed on alveolar macrophages, specifically screening endocrine, adopted orphan, and orphan NRs. Based on this profile, comorbid mice were treated with a combination therapy (CT) consisting of specific ligands for the most promising NR targets Vdr, Lxr and Rev-erbα. Results: Expression screening identified Vdr, Rev-erbα, and Lxr as key dysregulated receptors with dual roles in TB and T2DM pathogenesis. Administration of the triple-ligand CT to comorbid mice significantly alleviated both metabolic and infectious symptoms compared to untreated comorbid controls. Specifically, CT-treated mice demonstrated reduced T2DM severity (stabilized body weight, decreased blood glucose, and lowered glycated hemoglobin) alongside reduced TB disease burden, evidenced by lower bacterial colony-forming unit (CFU) counts and fewer pulmonary granulomatous lesions. Discussion: These findings demonstrate that simultaneous modulation of Vdr, Rev-erbα, and Lxr effectively mitigates the severe manifestations of TB-T2DM comorbidity. Integrating metabolic and antimicrobial treatments via host-directed nuclear receptor therapies offers a potent, novel strategy to combat this complex dual epidemic, particularly in high-prevalence regions.