Functional Gut Microbiota Remodeling Contributes to the Caloric Restriction-Induced Metabolic Improvements

摘要: Summary Caloric restriction (CR) stimulates development of functional beige fat and extends healthy lifespan. Here we show that compositional changes in the gut microbiota contribute to a number CR-induced metabolic improvements promote browning. Mechanistically, these effects are linked lower expression key bacterial enzymes necessary for lipid A biosynthesis, critical lipopolysaccharide (LPS) building component. The decreased LPS dictates tone of innate immune response during CR, leading increased eosinophil infiltration anti-inflammatory macrophage polarization CR animals. Genetic pharmacological suppression LPS-TLR4 pathway or transplantation with Tlr4 −/− bone-marrow-derived hematopoietic cells increases ameliorates diet-induced fatty liver, while microbiota-depleted mice resistant further CR-stimulated alterations. These data reveal signals our understanding of the microbiota-fat signaling axis during CR and provide potential new anti-obesity therapeutics.