Microbial dysbiosis drives colorectal carcinogenesis via integrated inflammatory, metabolic, and biofilm pathways

Colorectal cancer (CRC) arises from a multifaceted interplay among the intestinal microbiota, chronic inflammation, and host genomic instability, with microbial dysbiosis serving as an active driver rather than a by-product of malignant transformation. Genotoxic Escherichia coli (colibactin-positive), enterotoxigenic Bacteroides fragilis , and Fusobacterium nucleatum contribute to distinct stages of CRC progression by engaging the DNA-damage response and activating β-catenin–dependent Wnt signaling and NF-κB/STAT3 transcriptional programs controlling pro-inflammatory ( IL-6, IL-8 ), pro-survival ( BCL-2, BCL-XL ), and proliferative ( MYC, CCND1 ) gene expression.. Here, we propose a tri-axial pathogenic framework in which (i) cyclic dinucleotide–mediated activation of the cGAS–STING pathway engages TBK1–IRF3 and NF-κB signaling, driving type I interferons ( IFN- β) and pro-inflammatory cytokines ( IL-6, TNF- α) that couple microbial genotoxic stress to innate inflammation; (ii) altered microbial metabolites, including indoles and bile acids, reprogram AhR and FXR/TGR5 signaling; and (iii) crypt-anchored biofilms spatially amplify IL-6 leading to activation of STAT3, epigenetic silencing of tumor suppressors, and immune evasion. This review critically synthesizes current evidence supporting these axes and maps them onto CRC molecular subsets and tumor location. Recognition of these integrated microbial-host circuits identifies mechanistically grounded candidates for biomarker development, microbiome-based diagnostics, and targeted interventions to restore microbial and immune equilibrium, thereby providing a refined framework for the molecular classification and precision management of CRC.