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.

代谢状态与结核分枝杆菌的易感性之​​间存在密切关系(MTB) 感染，能量代谢为过度的免疫炎症反应奠定了基础，这与 MTB 的发病机制一致。在此，我们表明控制热量限制 (CR) 不会导致营养不良，可通过减少细菌负荷、肺免疫病理学和泡沫细胞（肺肉芽肿中的 MTB 储库）的产生来保护易感 DBA/2 小鼠免受肺 MTB 感染。从机制上讲，CR 诱导代谢转变为糖酵解，并降低与诱导免疫细胞自噬相关的脂肪酸氧化和 mTOR 活性。综合的多组学方法揭示了特定的 CR 诱导的代谢组学、转录组学和蛋白质组学特征，导致肺损伤减少和肺间质紧密度的保护性重塑，能够限制 MTB 扩散。