Porphyromonas gingivalis induces intestinal inflammation through gingipain-dependent gut microbiome dysbiosis

BACKGROUND: Porphyromonas gingivalis (Pg), a key pathogen in periodontitis, is implicated in various systemic diseases such as pancreatic cancer and Alzheimer's disease. However, as a periodontal pathogen that can directly enter the lower gastrointestinal tract via saliva, its potential impact on the gut microbiome, intestinal inflammation, and its underlying mechanisms remains largely elusive. RESULTS: Here, we observed that oral administration of Pg exacerbates intestinal inflammation in mice by inducing gut microbiome dysbiosis, increasing Th17 cells and the release of pro-inflammatory cytokines. Inhibition of Th17 activity with GSK805 or an anti-IL-17A blocking antibody mitigated this inflammatory response, highlighting the mediating role of Th17 cells. Gingipains, the virulence factors of Pg, played a crucial role in this process. Sequential knockout of gingipain genes revealed a gradual reduction in inflammatory phenotypes, with statistically significant alleviation observed when all three gingipain genes were deleted. Co-housing experiments showed that gut microbiota remodeling effectively protected against Th17-driven inflammatory response. Furthermore, immunization with inactivated Pg effectively prevented gut microbiome dysbiosis and Th17 cell-mediated inflammation. CONCLUSION: Our findings suggest that Pg may exacerbate intestinal inflammation, potentially via its gingipain virulence proteases, which are linked to gut microbiota dysbiosis and enhanced Th17-mediated immune responses. These results suggest that gingipains could be promising targets for further investigation in Pg-associated intestinal disorders. Video Abstract.