The gut microbiome in colorectal cancer: molecular paradigms and translational frontiers

The gut microbiome is now recognized as a causal driver of colorectal cancer (CRC) rather than a mere commensal ecosystem. This review elucidates the molecular mechanisms of keystone pathogens, specifically Fusobacterium nucleatum, pks ⁺ Escherichia coli, and enterotoxigenic Bacteroides fragilis, which induce DNA interstrand crosslinks, hyperactivate Wnt/β-catenin signaling, compromise the epithelial barrier, and reshape the tumor immune microenvironment. We discuss how bioengineered human organoids and microfluidic Organ-on-a-Chip platforms resolve the aerobic-anaerobic co-culture paradox, enabling patient-specific mechanistic dissection of host-microbe crosstalk. From a clinical perspective, we evaluate multi-omics signatures for noninvasive screening, intratumoral bacterial load as a prognostic indicator, and emerging therapeutic strategies including narrow-spectrum antimicrobials, bacteriophage-guided drug delivery, fecal microbiota transplantation for immunotherapy sensitization, and engineered living probiotics. By integrating mechanistic paradigms, organoid-guided validation, and translational applications, we delineate actionable trajectories for precision microbiome targeting in CRC management.