Virulome over taxonomy: refining the driver-passenger model in colorectal carcinogenesis

Colorectal carcinogenesis is increasingly viewed as a predominantly microbiome-driven process, yet it extends well beyond simple taxonomic associations. The taxon-based classical driver-passenger model, while conceptually useful, may benefit from incorporating the underlying mechanisms of microbial participation and the functional complexity of taxa contributions across CRC stages. In particular, the same taxa may exert distinct effects across carcinogenesis, and individual metabolic pathways frequently mediate multiple and divergent host responses. To address these limitations, we re-examine the roles of CRC-associated microbiota through the lens of individual virulence factor effects on the host, demonstrating their functional pleiotropy, and propose an expanded driver-passenger model. This approach highlights the central role of the virulome in CRC initiation, promotion and progression. By shifting the analytical focus from taxonomy to function, the proposed framework enables improved causality assessment and supports the development of stage-specific diagnostic and prognostic markers, as well as more targeted microbiome-directed therapeutic strategies.