Periodontitis-associated gut microbiota disrupts glucose homeostasis through SCFAs depletion and inflammation in germ-free mice

Periodontitis is increasingly linked to systemic conditions such as diabetes, yet the underlying mechanisms remain unclear. This study aimed to determine whether gut microbiota mediates the impact of periodontitis on glucose homeostasis. Germ-free (GF) mice were obtained and maintained in sterile isolators (GemPharmatech, China) and colonized with microbiota derived from donor mice with ligature-induced periodontitis (GF-LIG) or healthy controls (GF-CON). Donor faecal samples were collected from donor mice with ligature-induced periodontitis or healthy controls. Fasting blood glucose (FBG), serum insulin, homeostatic model assessment for insulin resistance (HOMA-IR) and β-cell function (HOMA-β), as well as glucose tolerance, were evaluated. Correlation analyses were performed to explore associations between microbial composition, short-chain fatty acids (SCFAs), and inflammatory markers. SCFA-producing bacteria were supplemented to assess their potential protective effects. Compared with GF-CON mice, GF-LIG mice exhibited significantly higher FBG, serum insulin, HOMA-IR, HOMA-β, and impaired glucose tolerance. The SCFA-producing genus Lachnospirace-ae_NK4A136_group was negatively associated with FBG, HOMA-β, and serum levels of interleukin (IL)-1β, IL-17 A, and tumor necrosis factor (TNF)-α. Moreover, serum levels of IL-1β, IL-17 A, and TNF-α were positively correlated with HbA1c and HOMA-β. Notably, supplementation with SCFA-producing bacteria significantly reduced FBG and HbA1c levels in periodontitis-affected mice. These findings suggest that gut microbiota mediates the impact of periodontitis on glucose homeostasis, potentially through SCFAs depletion and inflammation. Restoration of SCFA-producing bacteria may represent a promising microbiota-targeted strategy for mitigating metabolic disturbances associated with periodontitis.