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  • Gut Microbiome and Colorectal Cancer: Molecular Mechanisms, Biomarkers, and Therapeutic Opportunities

  • Saba Moghadam nia ,1,* Mobina Hassanzadeh Aliabadi,2
    1. Department of Biology, SR.C., Islamic Azad University,Tehran, Iran
    2. Department of Biology, SR.C., Islamic Azad University,Tehran, Iran


  • Introduction: Colorectal cancer (CRC) is among the most frequently diagnosed cancers worldwide and remains a major cause of cancer-related mortality. For many years, genetic mutations were viewed as the primary driver of tumor development. More recent evidence suggests that the gut microbiome also contributes significantly to both the initiation and progression of CRC (Karam et al., 2025; Permain et al., 2024). Rather than being a passive collection of microorganisms, the gut microbiome functions as an active part of host physiology. It helps maintain intestinal balance by regulating immune responses, supporting epithelial barrier integrity, and participating in metabolic and signaling pathways. When this balance is disrupted (dysbiosis), multiple pathological changes may occur, including chronic inflammation, DNA damage, epigenetic alterations, and activation of oncogenic signaling pathways. Bacterial species have also been identified within tumor tissues, suggesting a more direct involvement in cancer biology than previously assumed (Fan et al., 2025).
  • Methods: His descriptive review is based on studies published between 2024 and 2025. The selected literature focused on gut microbiome–CRC interactions, including molecular mechanisms, genomic and epigenetic alterations, microbial metabolites, immune responses, changes in the tumor microenvironment, and microbiome-based therapeutic approaches. The aim was to integrate these findings into a coherent overview of current knowledge in the field (Song et al., 2025; Bai et al., 2025; Zalila-Kolsi et al., 2025).
  • Results: Accumulating evidence indicates that the gut microbiome actively contributes to colorectal carcinogenesis rather than acting as a bystander. Certain bacterial species can induce direct DNA damage through toxic metabolites. For instance, PKs⁺ Escherichia coli produces colibactin, a genotoxin that induces DNA double-strand breaks and genomic instability (Permain et al., 2024). Similarly, enterotoxigenic Bacteroides fragilis releases toxins that impair epithelial integrity. Fusobacterium nucleatum has also been shown to activate oncogenic pathways, including Wnt/β-catenin, NF-KB, and STAT3, which collectively promote tumor growth, inflammation, and immune evasion (Bai et al., 2025). Apart from direct genotoxic effects, the microbiome influences gene regulation through epigenetic mechanisms. One key example is butyrate, a short-chain fatty acid produced by commensal bacteria. Under physiological conditions, butyrate acts as a histone deacetylase inhibitor and helps regulate cell proliferation and apoptosis. A reduction in butyrate-producing bacteria can therefore weaken these regulatory effects and create a permissive environment for tumor development (Zhang et al., 2025). Another important observation is the presence of intratumoral microbiota within colorectal cancer tissues. These microbial communities interact with both immune and cancer cells and may influence inflammation, angiogenesis, metastasis, and therapeutic response (Fan et al., 2025). This finding adds another layer of complexity to tumor biology and the tumor microenvironment. Overall, CRC development appears to result from the combined interaction of inflammation, immune dysregulation, and metabolic reprogramming. Dysbiosis can simultaneously disrupt all of these processes, gradually shifting the tissue environment toward a tumor-supportive state (Song et al., 2025). In recent years, the gut microbiome has also emerged as an encouraging source of biomarkers. Multi-omics approaches, including genomics, transcriptomics, metabolomics, and microbiome profiling, are being used to identify microbial signatures associated with CRC. In parallel, microbiome-based interventions such as probiotics, prebiotics, fecal microbiota transplantation (FMT), phage therapy, and engineered bacteria are under investigation, although most remain in early experimental stages (Zalila-Kolsi et al., 2025; Fan et al., 2025). Together, these findings suggest potential future applications for diagnosis and treatment, but not yet routine clinical use.
  • Conclusion: The gut microbiome plays a complex role in colorectal cancer through mechanisms involving DNA damage, epigenetic regulation, metabolic reprogramming, immune modulation, and remodeling of the tumor microenvironment. While many details are still being clarified, it is increasingly evident that CRC cannot be fully understood without considering host–microbiome interactions. Future studies integrating multi-omics data with computational models may improve early detection and support more personalized therapeutic strategies in CRC (Song et al., 2025).
  • Keywords: Colorectal cancer; Gut microbiome; Dysbiosis; Epigenetics; Multi-omics

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