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Sex and progression towards active TB in an experimental mouse model. Impact of stress-induced glucocorticoids and intermittent fasting

P Soldevilla(1,2,4) M Vidal(1,2,3) E Fuentes(1,3) M Cortacans(1,2,3) Y Rosales(3) J Díaz(3) P J Cardona(1,2,3,4,5)

1:Unitat de Tuberculosi Experimental, Microbiology Dept. Germans Trias i Pujol Research Institute and Hospital (IGTP-HUGTIP), Badalona, 08916, Spain; 2:Genetics and Microbiology Department, Autonomous University of Barcelona, Barcelona, 08193, Spain; 3:Centre de Medicina Comparativa i Bioimatge de Catalunya (CMCiB), Badalona, 08916, Spain; 4:Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (CIBERES), Madrid, 28029, Spain.; 5:Servei de Microbiologia, LCMN, Hospital Universitari Germanst Trias i Pujol (HUGTiP), Badalona, 08916, Spain

Tuberculosis (TB) affects mostly males (in a 65:35 proportion). We wanted to assess the impact of chronic stress, linked to glucocorticoid stimulation, and sex in its progression. To do so, we interrogated the active TB experimental mouse model. Adult, 6 months old, C3HeB/FeJ mice were infected with 2x10^4 CFUs of Mycobacterium tuberculosis e.v. Animals were divided in three groups: ‘Control’ (without stress), ‘Restriction’ (with daily 5 hours movement restriction), and ‘Intermittent-fasting’ (with daily 5 hours fasting). Animals were euthanized after 28 days post-infection. We measured pulmonary and spleen bacterial load, lung damaged area, and corticosterone concentration in hair. Both bacillary loads and lung damage were worse in females compared to males of the ‘Control’ group, with no differences in corticosterone-in-hair levels. However, in the ‘Restriction’ group females showed lower bacillary loads in lungs and spleen, and less pulmonary damaged area compared with the ‘Control’ group, linked to higher levels of cortisone-in-hair. Interestingly, there was a significant positive correlation between corticosterone-in-hair and pulmonary damaged area. ‘Restriction’ had only a minimal impact in males raising slightly corticosterone-in-hair levels. ‘Intermittent-fasting’ had a positive impact in females in terms of bacillary load and lung damage, non-linked to the modification of corticosterone levels. Our preliminary results highlights the role of chronic stress and the adequate corticosterone production, together with intermittent-fasting to moderate the pro-inflammatory Th17 immune response in females as a possible explanation to understand its protection against progression towards active TB.

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