Periodontitis has been implicated as a risk factor for metabolic disorders such as type 2 diabetes, atherosclerotic vascular diseases, and non-alcoholic fatty liver disease. Although bacteremias from dental plaque and/or elevated circulating inflammatory cytokines emanating from the inflamed gingiva are suspected mechanisms linking periodontitis and these diseases, direct evidence is lacking. We hypothesize that disturbances of the gut microbiota by swallowed bacteria induce a metabolic endotoxemia leading metabolic disorders. To investigate this hypothesis, changes in the gut microbiota, insulin and glucose intolerance, and levels of tissue inflammation were analysed in mice after oral administration of Porphyromonas gingivalis, a representative periodontopathogens. Pyrosequencing revealed that the population belonging to Bacteroidales was significantly elevated in P. gingivalis-administered mice which coincided with increases in insulin resistance and systemic inflammation. In P. gingivalis-administered mice blood endotoxin levels tended to be higher, whereas gene expression of tight junction proteins in the ileum was significantly decreased. These results provide a new paradigm for the interrelationship between periodontitis and systemic diseases.

Most Foxp3⁺ regulatory T (T_reg) cells develop in the thymus as a functionally mature T cell subpopulation specialized for immune suppression. Their cell fate appears to be determined before Foxp3 expression; yet molecular events that prime Foxp3^- T_reg precursor cells are largely obscure. We found that T_reg cell-specific super-enhancers (T_reg-SEs), which were associated with Foxp3 and other T_reg cell signature genes, began to be activated in T_reg precursor cells. T cell-specific deficiency of the genome organizer Satb1 impaired T_reg-SE activation and the subsequent expression of T_reg signature genes, causing severe autoimmunity due to T_reg cell deficiency. These results suggest that Satb1-dependent T_reg-SE activation is crucial for T_reg cell lineage specification in the thymus and that its perturbation is causative of autoimmune and other immunological diseases.