Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection from Tuberculosis

There is a strong relationship between metabolic state and susceptibility to Mycobacterium tuberculosis (MTB) infection, with energy metabolism setting the basis for an exaggerated immuno-inflammatory response, which concurs with MTB pathogenesis. Herein, we show that controlled caloric restriction (CR), not leading to malnutrition, protects susceptible DBA/2 mice against pulmonary MTB infection by reducing bacterial load, lung immunopathology, and generation of foam cells, an MTB reservoir in lung granulomas. Mechanistically, CR induced a metabolic shift toward glycolysis, and decreased both fatty acid oxidation and mTOR activity associated with induction of autophagy in immune cells. An integrated multi-omics approach revealed a specific CR-induced metabolomic, transcriptomic, and proteomic signature leading to reduced lung damage and protective remodeling of lung interstitial tightness able to limit MTB spreading. Our data propose CR as a feasible immunometabolic manipulation to control MTB infection, and this approach offers an unexpected strategy to boost immunity against MTB. [Display omitted] •Controlled caloric restriction (CR) protects from pulmonary MTB infection•CR enhances immune cell intracellular MTB killing, thus reducing lung bacterial load•CR induces an immunometabolic reprogramming leading to reduction of collateral damage•CR enhances tightness of intercellular junctions and extracellular matrix in the lungs Through an in vivo model of high susceptibility to MTB infection in DBA/2 mice, we utilized a multi-omic approach to show that caloric restriction (CR) is able to control pulmonary MTB infection and associated inflammatory damage through an immunometabolic reprogramming and enhanced anti-MTB capacity of immune cells. These data candidate CR as a novel strategy in the management of MTB infection in countries where TB is rapidly increasing in association with over-nutrition and obesity.