ARAF and colorectal carcinoma: Other important questions involve how pks genes are regulated, what environmental cues promote colibactin production, what is the importance of temporal and biogeographical factors (e.g., exposure to pks+E. coli in the colonic crypt near the stem cell compartment, as depicted in Figure 1), what level of pks+E. coli bacterial load is problematic, and whether there are critical interactions with other microbial virulence factors within the tumoral or luminal microbiota that influence colibactin’s effects on CRC development.