Aim or purpose: To explore the role of C-reactive protein (CRP) in the periodontal homeostasis of diabetic periodontitis, and whether it regulates periodontal homeostasis by affecting the oral-gut axis microecology. Materials and methods: Crp knockout (KO) rats were randomly divided into control, periodontitis, and diabetic periodontitis groups, respectively. The diabetes model was established using a high-fat diet combined with streptozotocin injection. The periodontitis model was established by ligature combined with lipopolysaccharide (LPS) injection. Alveolar bones were analysed using micro-computed tomography, histology, and immunohistochemistry. 16S rRNA gene sequencing, metagenomic sequencing and microbial metabolomics were used to analyze the composition, distribution, diversity and pathogenicity of microbial communities, and to identify the functional genes and their interactions. The fecal microbiota transplantation method was used to gavage the gut microbiota from CRP gene knockout rats into rats with diabetic periodontitis. The absorption of alveolar bone and inflammation in the rats, as well as the changes in gut and oral microecology, were detected. Results: In diabetic periodontitis, CRP KO decreased the alveolar bone loss and the expression levels of osteoclastogenic markers, while increasing the expression levels of osteogenic markers. CRP gene knockout improves oral and intestinal microbial disturbance in diabetic periodontitis rats. The transplantation of gut microbiota from CRP KO rats alleviated the alveolar bone resorption and improved the composition of gut and oral microecology in diabetic periodontitis group. Conclusions: CRP plays a significant regulatory role in the periodontal homeostasis of diabetic periodontitis, and its specific mechanism is related to the regulation of the oral-gut axis microecology.