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. © 2020 Elsevier Inc. 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.