Metabolomics and lipidomics Palma et al.

A strong relationship between metabolic state and susceptibility to <i>Mycobacterium Tuberculosis</i> (MTB) infection exists. Indeed, intracellular energy metabolism sets the basis for an exaggerated immuno-inflammatory response which concur to pathogenesis of MTB. Herein, we show that controlled caloric restriction (CR), not leading to malnutrition, induces control of MTB infection by dramatically reducing both bacterial load and lung immunopathology in highly susceptible DBA/2 mice. CR reduced significantly the production of pro-inflammatory cytokines in lung granulomas as well as formation of foam cells, known to represent a major reservoir for MTB replication. Mechanistically, CR induced a shift of the glucose metabolism towards glycolysis in splenocytes and in T cells that associated with reduction of the mechanistic target of rapamycin (mTOR) pathway in the lungs. Further, an integrated multi-OMICS approach revealed a specific CR-induced metabolomic, trascriptomic and proteomic signature leading to both reduced lung damage and slow disease progression. Taken together our data suggest that CR represents a feasible immunometabolic manipulation able to reverse a state of susceptibility towards resistance to MTB infection, and that our approach offers a novel and unexpected strategy to boost therapeutic interventions against MTB infection.<b></b>