Advanced glycation end products promote Porphyromonas gingivalis dissemination via an ROS-dependent, inflammation-independent mechanism

Porphyromonas gingivalis (P. gingivalis), an opportunistic periodontal pathogen, is increasingly implicated in multiple systemic diseases, though its dissemination mechanisms remain unclear. Here, we show that advanced glycation end products (AGEs), the hallmark pathogenic molecules of diabetes mellitus, significantly promote P. gingivalis Infection and dissemination. By establishing in vitro, in vivo, and oxygen-gradient gingiva-on-chip models and using clinical samples, we demonstrate that while spontaneous P. gingivalis Infection barely penetrates the endothelial barrier, AGEs of pathophysiological concentration substantially promote P. gingivalis infectivity and dissemination across epithelial/endothelial barriers. Mechanistic investigations reveal that AGEs cause prominent barrier dysfunction, which is driven by surged mitochondrial Reactive Oxygen Species (mtROS) but without inflammatory consequences. Of particular significance, it is validated that pharmacological scavenging of mtROS effectively prohibits AGEs-enhanced P. gingivalis dissemination. Our findings identify AGE-driven mtROS-mediated barrier dysfunction as a key mechanism enabling P. gingivalis dissemination and suggest a host-targeted therapeutic strategy thereof.