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  • CORRECTED! Microbial Genotoxicity, Epigenetic Reprogramming, Host Genotype, and Oncogenic Signaling in Cancer: A Mechanistic Review of Host-Microbiome Crosstalk

  • Seyedeh Sana Alenabi,1 Milad Kharazihay Esfahani,2,*
    1. Islamic Azad University of Gilan, Rasht Branch
    2. University of Saarland


  • Introduction: The intestinal microbiome is increasingly recognized as an active mechanistic component of cancer development rather than a passive marker of disease. Microbial exposure can generate genomic damage, reshape host epigenetic programs, modify immune and metabolic states, and activate oncogenic signaling. This review examines four interconnected mechanisms of host–microbiome crosstalk: bacterial genotoxins and genomic instability; microbial regulation of epigenetic machinery; host genetic and somatic driver–microbiome interactions; and microbial activation of oncogenic signaling cascades. Particular attention is given to colibactin-producing pks-positive Escherichia coli, cytolethal distending toxin (CDT), butyrate, secondary bile acids, host TLR-related variation, KRAS-dependent bacterial selection, and Fusobacterium nucleatum signaling.
  • Methods: A structured literature search was designed around four mechanistic concept blocks covering bacterial genotoxins and DNA damage, microbial metabolites and epigenetic regulation, host genetics and microbiome interactions, and F. nucleatum-associated WNT, NF-κB, and MAPK signaling. PubMed, Scopus, and Web of Science were treated as target databases, with the publication window restricted to September 11, 2021 through September 11, 2026. Peer-reviewed original studies providing experimental, genomic, epigenomic, organoid, animal, or patient-level evidence were prioritized. Sixteen qualifying studies constituted the evidence set. Studies were qualitatively evaluated according to microbial factor, host molecular target, molecular or pathway alteration, experimental model, causal perturbation, cancer phenotype, and degree of human validation, with particular emphasis on bacterial loss-of-function, organoid, mutation-signature, longitudinal, and intervention designs.
  • Results: The reviewed evidence supports a multilayered and bidirectional relationship between microbial activity and tumor evolution. Colibactin-producing E. coli causes DNA lesions, replication-associated double-strand breaks, chromosomal abnormalities, and characteristic mutational patterns including SBS88 and ID18; these effects can be intensified in mismatch-repair-deficient contexts. CDT produced by Campylobacter jejuni induces replication stress and chromosomal instability and is linked to JAK2–STAT3–MMP9 activity and metastatic progression. Microbial metabolites act through complementary regulatory mechanisms. Butyrate can inhibit histone deacetylases and alter DNA methylation, chromatin-associated regulators, metabolic state, and microRNA networks, producing growth suppression or context-dependent transcriptional reprogramming. Microbiota-derived carbon can contribute to host histone acetylation, whereas deoxycholic acid suppresses CD8+ T-cell Ca2+–NFAT2 signaling and can promote colorectal tumor growth. Host genotype also shapes microbial ecology and response: germline variants influence microbial abundance, TLR/VDR polymorphisms can modify responses to microbial translocation, and tumor driver states including KRAS mutations can select for particular bacteria such as F. nucleatum or enterotoxigenic Bacteroides fragilis. Finally, F. nucleatum activates distinct oncogenic branches, including E-cadherin/β-catenin signaling associated with cyclin D1 and MYC, ALPK1/NF-κB/ICAM1 signaling that enhances endothelial adhesion and extravasation, and JNK–AP1/MMP7 signaling linked to migration and invasion. These mechanisms are best interpreted as a temporal network: microbial exposure may initiate DNA or replication damage, epigenetic changes may stabilize altered cellular states, tumor mutations may create ecological niches that favor selected microbes, and microbial signaling may subsequently enhance proliferation, invasion, immune escape, or metastatic colonization. This framework also explains why taxonomic abundance alone is an insufficient biomarker and why organoids, engineered microbial mutants, animal models, and human cohorts provide complementary rather than interchangeable evidence. Collectively, these findings indicate that microbial effects depend strongly on strain, functional gene activity, exposure dose, anatomical compartment, host repair capacity, tumor genotype, immune context, and disease stage.
  • Conclusion: Current evidence supports a model in which microbial functions can influence both initiation and progression of cancer by altering the genomic, epigenetic, ecological, immune, and signaling landscapes of susceptible host cells. The strongest translational opportunities arise when a defined microbial effector is paired with a measurable host response, such as bacterial functional genes with mutation signatures, tissue pathway markers, or host genotype. Potential interventions include selective depletion of genotoxin-producing organisms, phage targeting of microbial metabolic pathways, metabolite or dietary modulation, and pathway-specific host targeting. However, clinical translation remains limited by temporal causality, spatial heterogeneity, strain-specific activity, exposure thresholds, treatment-related microbiome remodeling, and inter-individual variability. Future studies should integrate tumor genomics, strain-level microbial profiling, spatial and longitudinal sampling, metabolomics, and functional assays to develop mechanism-based biomarkers and precise microbiome-directed therapies.
  • Keywords: cancer genomics;bacterial genotoxins;microbial epigenetics;host-microbiome crosstalk;oncogenic signa

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