Mounting evidence has shown that periodontitis is associated with diabetes. However, a causal relationship remains to be determined. Recent studies reported that periodontitis may be associated with gut microbiota, which plays an important role in the development of diabetes. Therefore, we hypothesized that gut microbiota might mediate the link between periodontitis and diabetes. Periodontitis was induced by ligatures. Glycemic homeostasis was evaluated through fasting blood glucose (FBG), serum glycosylated hemoglobin (HbA1c), and intraperitoneal glucose tolerance test. Micro-computed tomography and hematoxylin and eosin staining were used to evaluate periodontal destruction. The gut microbiota was analyzed using 16S ribosomal RNA gene sequencing and bioinformatics. Serum endotoxin, interleukin (IL) 6, tumor necrosis factor α (TNF-α), and IL-1β were measured to evaluate the systemic inflammation burden. We found that the levels of FBG, HbA1c, and glucose intolerance were higher in the periodontitis (PD) group than in the control (Con) group (P < 0.05). When periodontitis was eliminated, the FBG significantly decreased (P < 0.05). Several butyrate-producing bacteria were decreased in the gut microbiota of the PD group, including Lachnospiraceae_NK4A136_group, Eubacterium_fissicatena_group, Eubacterium_coprostanoligenes_group, and Ruminococcaceae_UCG-014 (P < 0.05), which were negatively correlated with serum HbA1c (P < 0.05). Subsequently, the gut microbiota was depleted using antibiotics or transplanted through cohousing. Compared with the PD group, the levels of HbA1c and glucose intolerance were decreased in the gut microbiota-depleted mice with periodontitis (PD + Abx) (P < 0.05), as well as the serum levels of endotoxin and IL-6 (P < 0.05). The serum levels of IL-6, TNF-α, and IL-1β in the PD + Abx group were higher than those of the Con group (P < 0.05). Antibiotics exerted a limited impact on the periodontal microbiota. When the PD mice were cohoused with healthy ones, the elevated FBG and HbA1c significantly recovered (P < 0.05), as well as the aforementioned butyrate producers (P < 0.05). Thus, within the limitations of this study, our data indicated that the gut microbiota may mediate the influence of periodontitis on prediabetes.

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