Fabbiano, Salvatore; Suárez-Zamorano, Nicolas; Chevalier, Claire; Lazarević, Vladimir; Kieser, Silas; Rigo, Dorothée; Leo, Stefano; Veyrat-Durebex, Christelle; Gaïa, Nadia; Maresca, Marcello; Merkler, Doron; Gomez de Agüero Tamargo, Maria de la Mercedes; Macpherson, Andrew; Schrenzel, Jacques; Trajkovski, Mirko (2018). Functional Gut Microbiota Remodeling Contributes to the Caloric Restriction-Induced Metabolic Improvements. Cell metabolism, 28(6), 907-921.e7. Cell Press 10.1016/j.cmet.2018.08.005
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Caloric restriction (CR) stimulates development of functional beige fat and extends healthy lifespan. Here we show that compositional and functional changes in the gut microbiota contribute to a number of CR-induced metabolic improvements and promote fat browning. Mechanistically, these effects are linked to a lower expression of the key bacterial enzymes necessary for the lipid A biosynthesis, a critical lipopolysaccharide (LPS) building component. The decreased LPS dictates the tone of the innate immune response during CR, leading to increased eosinophil infiltration and anti-inflammatory macrophage polarization in fat of the CR animals. Genetic and pharmacological suppression of the LPS-TLR4 pathway or transplantation with Tlr4 bone-marrow-derived hematopoietic cells increases beige fat development and ameliorates diet-induced fatty liver, while Tlr4 or microbiota-depleted mice are resistant to further CR-stimulated metabolic alterations. These data reveal signals critical for our understanding of the microbiota-fat signaling axis during CR and provide potential new anti-obesity therapeutics.
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