Periodontitis has been demonstrated to increase the risk of metabolic syndrome (MetS), but the underlying mechanism remains unclear. Recent studies have indicated periodontopathic bacteria such as Porphyromonas gingivalis could induce gut microbiota (GM) dysbiosis and aggravate metabolic disorders. However, the effects of microbial metabolites have barely been evaluated. Here, we investigated the alteration of serum metabolome with P. gingivalis-induced metabolic disorders, and explored the correlations of GM and serum metabolites. In this study, we orally administered P. gingivalis ATCC33277 to C57BL/6 mice and performed metagenomic sequencing and untargeted metabolomics with fecal samples and serum collection. In vivo experiments showed a higher proportion of fat mass and worse glucose tolerance in P. gingivalis-administered mice, accompanied with an increase of adipose inflammation and gut permeability, which was similar to HFD-induced obese mice. Metagenomic sequencing indicated a compositional and functional alteration of GM. Untargeted metabolomics revealed an alteration of metabolites in P. gingivalis-administered mice, and most of them were engaged in metabolic pathways, such as tryptophan metabolism and choline metabolism. Correlation analysis between GM and serum metabolome indicated strong relativity with P. gingivalis administration. These results demonstrated some specific microbiota-derived metabolites in the pathogenesis of P. gingivalis-induced metabolic disorders, providing promising targets for the development of novel treatment strategies for MetS.

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.