Adrenal and metabolic hormonal axes shape anti-Tuberculosis immune responses in HIV-TB coinfection

Background: Tuberculosis (TB) remains a leading cause of mortality worldwide among infectious agents, and HIV increases the risk of developing into active disease. HIV-TB coinfection impairs immune responses, while chronic inflammation and infection-associated stress activate neuroendocrine pathways that deeply impact immune homeostasis. Adrenal steroids such as cortisol, dehydroepiandrosterone (DHEA) and its metabolites, along with metabolic hormones like leptin and adiponectin, have emerged as critical regulators of immune function, although their role in TB pathogenesis, particularly in coinfected individuals, remains underexplored. Summary: This review navigates over current evidence on the neuroendocrine-immune crosstalk in HIV-TB coinfection, focusing on adrenal and metabolic hormonal axes. We first summarize how HIV-driven CD4⁺ T cell depletion, chronic immune activation, and altered granuloma dynamics predispose individuals to TB reactivation. We then examine findings indicating that TB and HIV disrupt hypothalamic–pituitary–adrenal (HPA) axis homeostasis, leading to elevated cortisol levels, reduced DHEA and its metabolites, and an unfavorable cortisol/DHEA ratio, which correlated with poor immune control and disease severity. Preclinical studies highlight immunomodulatory properties of DHEA derivatives, such as 7-oxo-DHEA (7-OD), which restore Th1 responses, limit Treg expansion, and enhance macrophage antimicrobial activity. Metabolic hormones, particularly leptin and adiponectin, further shape host immunity and energy allocation; their dysregulation in coinfection contributes to wasting, impaired granuloma formation, and increased immune reconstitution inflammatory syndrome (IRIS) risk. Despite compelling preclinical findings, clinical studies on hormonal modulation remain scarce, emphasizing the need for translational research that links endocrinology and infectious disease immunology. Key Messages: HIV-TB coinfection creates a neuroendocrine-immune imbalance, with dysregulation of the hypothalamic–pituitary–adrenal axis and metabolic hormones contributing to impaired immune control and accelerated disease progression. Adrenal hormones such as DHEA and its metabolite 7-oxo-DHEA show potential as immunomodulatory agents, capable of restoring Th1 responses, limiting Treg expansion, and supporting host-directed therapies. Additionally, leptin and adiponectin emerge as crucial metabolic players that integrate nutritional status and immune activity and may serve as potential biomarkers for TB management. Altogether, integrating endocrine profiling into TB research and advancing the clinical evaluation of hormonal immunomodulators may unlock novel avenues for precision medicine, improving treatment strategies for populations affected by the HIV and TB epidemics.