Periodontitis aggravates diet-induced obesity and metabolic disorders through intestinal translocation of P. gingivalis and inactivation of the aryl hydrocarbon receptor signaling

Abstract Background: Metabolic disorders are prevalent health concerns worldwide, and periodontitis, an oral inflammatory disease, has been emphasized as a risk factor. Increasing evidence has indicated the role of gut microbiota and its derived metabolites during the pathogenesis of metabolic disorders. Given that the oral and gut mucosae are physically connected, it is possible that the periodontopathic bacterium may invade and alter the gut microbiota to aggravate metabolic disorders. In this study, a periodontitis mouse model was established to evaluate metabolic disorders induced by high fat diet (HFD). Metabolic labeling and in vivo imaging were introduced to determine the intestinal translocation of periodontopathic bacterium, Porphyromonas gingivalis (P. gingivalis). Moreover, metagenome sequencing and nontargeted metabolomics analysis were applied to investigate the mechanism underlying periodontitis and metabolic disorders. Results: Our study demonstrated that periodontitis aggravated metabolic disorders induced by HFD in C57BL6/N mice. P. gingivalis, a main periodontopathic bacterium, was enriched in the feces of mice with periodontitis. Moreover, the orally administered P. gingivalis could translocate to the gastrointestinal tract alive, and elicit metabolic disorders, while administration of the pasteurized P. gingivalis had no effect. Metagenome sequencing indicated that administration altered the composition, abundance, and function of gut microbiota, in which “tryptophan metabolism pathway” demonstrated a significant difference. Nontargeted metabolomics analysis revealed indole and its derivatives were decreased with P. gingivalis administration, leading to inactivation of aryl hydrocarbon receptor (AhR) signaling. Moreover, supplementation with Ficz, an AhR agonist, alleviated periodontitis-associated metabolic disorders, in which the restoration of gut barrier function might play an important role. Conclusions: Our study illustrated that periodontitis aggravated diet-induced metabolic disorders through intestinal translocation of pathogenic bacterium P. gingivalis, which elicited gut microbiota dysfunction and decreased indole and its derivatives, leading to inactivation of AhR signaling. Supplementation of AhR agonist improved metabolic disorders by restoring AhR activity and the gut barrier function, providing a novel mechanism and treatment strategy linking periodontal disease and metabolic disorders.