Tuberculosis (TB) is the leading cause of death from a single bacterial infectious agent and is one of the most relevant issues of public health. Another pandemic disease is type II
diabetes mellitus (T2D) that is estimated to affect half a billion people in the world. T2D is directly associated with
obesity and a sedentary lifestyle and is frequently associated with immunosuppression. Immune dysfunction induced by
hyperglycemia increases
infection frequency and severity. Thus, in developing countries the T2D/TB co-morbidity is frequent and represents one of the most significant challenges for the health-care systems. Several immunoendocrine abnormalities are occurring during the chronic phase of both diseases, such as high extra-adrenal production of active
glucocorticoids (GCs) by the activity of 11-β-hydroxysteroid
dehydrogenase type 1 (11-βHSD1). 11-βHSD1 catalyzes the conversion of inactive
cortisone to active
cortisol or
corticosterone in lungs and liver, while 11-β-hydroxysteroid
dehydrogenase type 2 (11-βHSD2) has the opposite effect. Active GCs have been related to
insulin resistance and suppression of Th1 responses, which are deleterious factors in both T2D and TB. The anabolic adrenal
hormone dehydroepiandrosterone (
DHEA) exerts antagonistic effects on GC signaling in immune cells and metabolic tissues; however, its
anabolic effects prohibit its use to treat immunoendocrine diseases. 16α-bromoepiandrosterone (BEA) is a water miscible synthetic
sterol related to
DHEA that lacks an
anabolic effect while amplifying the immune and metabolic properties with important potential
therapeutic uses. In this work, we compared the expression of 11-βHSD1 and the therapeutic efficacy of BEA in diabetic mice infected with
tuberculosis (TB) (T2D/TB) with respect to non-diabetic TB-infected mice (TB). T2D was induced by feeding mice with a high-fat diet and administering a single low-dose of
streptozotocin. After 4 weeks of T2D establishment, mice were infected intratracheally with a high-dose of Mycobacterium tuberculosis strain H37Rv. Then, mice were treated with BEA three times a week by subcutaneous and intratracheal routes.
Infection with TB increased the expression of 11-βHSD1 and
corticosterone in the lungs and liver of both T2D/TB and TB mice; however, T2D/TB mice developed a more severe
lung disease than TB mice. In comparison with untreated animals, BEA decreased GC and 11-βHSD1 expression while increasing 11-βHSD2 expression. These molecular effects of BEA were associated with a reduction in
hyperglycemia and
liver steatosis, lower lung bacillary loads and
pneumonia. These results uphold BEA as a promising effective
therapy for the T2D/TB co-morbidity.