Porphyromonas gingivalis secreted factors drive epithelial-mesenchymal transition (EMT) through gingipains and an H2S-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 (P. gingivalis), an oral bacterium, is implicated in the development of colorectal cancer (CRC), and although the exact mechanisms by which P. gingivalis 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 P. gingivalis secreted factors promote CRC neoplasia progression by modulating both the Wnt/β-catenin and the Hippo-YAP signaling pathways. Using specific inhibitors and P. gingivalis mutant strains, our findings demonstrate that cysteine proteases, specifically Lysin-gingipain (Kgp) and Argin-gingipain A (RgpA), 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.