<i>Porphyromonas gingivalis</i> secreted factors drive epithelial–mesenchymal transition (EMT) through gingipains and an H _<b>2</b> S-mediated bacterial defense system

Dysbiosis of the gut microbiota is strongly associated with a wide range of pathologies, including various types of cancer. Porphyromonas gingivalis <i>(P. gingivalis</i>), an oral bacterium, is implicated in the development of colorectal cancer (CRC), and although the exact mechanisms by which <i>P. gingivalis</i> contributes to CRC remain unclear, and emerging evidence suggests that various bacterial elements are involved in the bacterium's pathogenic effects. Here, we show that <i>P. gingivalis</i> secreted factors promote CRC neoplasia progression by modulating both the Wnt/β-catenin and the Hippo-YAP signaling pathways. Using specific inhibitors and <i>P. gingivalis</i> mutant strains, our findings demonstrate that cysteine proteases, specifically Lysin-gingipain (<i>Kgp</i>) and Argin-gingipain A (<i>RgpA</i>), as well as hydrogen sulfide (H₂S), strongly induce the expression of epithelial-mesenchymal transition (EMT) markers, leading to cell detachment and increased motility. These findings reveal a novel connection between microbial virulence and defense mechanisms, such as H₂S, and host cell transformation, suggesting a potential role for bacterial secreted factors in driving CRC neoplasia.