Colorectal cancer (CRC) remains a leading cause of cancer-related mortality worldwide, with rising incidence attributed to environmental, dietary, and lifestyle factors. Beyond genetic and epigenetic drivers, increasing evidence implicates the gut microbiome as a crucial modulator of CRC initiation, progression, and therapeutic response. Dysbiosis—an imbalance in microbial composition—can disrupt intestinal homeostasis, promote chronic inflammation, and facilitate carcinogenesis. This review explores the mechanistic role of the gut microbiota in CRC, evaluates microbial signatures as diagnostic and prognostic biomarkers, and examines therapeutic interventions that target the microbiome.
Gut Microbiome in Colorectal Carcinogenesis
Microbiota influence colorectal carcinogenesis through multiple interrelated pathways:
Inflammation: Microbes such as Fusobacterium nucleatum and Enterotoxigenic Bacteroides fragilis induce pro-inflammatory cytokines, activating NF-κB and STAT3 signaling, which drive tumor-promoting inflammation.
Metabolites: Short-chain fatty acids (SCFAs) like butyrate exert protective effects by promoting apoptosis and regulating immune responses, while secondary bile acids and hydrogen sulfide promote DNA damage and tumor progression.
Genotoxicity: Certain bacteria produce genotoxins (e.g., colibactin from E. coli) that directly damage host DNA, leading to mutations and genomic instability.
Immune modulation: Dysbiosis alters local and systemic immunity, shaping the tumor microenvironment to favor immune evasion and tumor growth.
Microbiome-Based Biomarkers
The gut microbiome provides potential non-invasive biomarkers for CRC screening and prognosis. Fecal microbiota profiles have revealed enrichment of Fusobacterium, Parvimonas, and Peptostreptococcus in CRC patients. Integrating microbial signatures with traditional screening tools (FIT, colonoscopy) may enhance early detection. Moreover, microbial diversity and specific taxa abundance correlate with disease stage, recurrence risk, and treatment outcomes, suggesting prognostic utility.
Therapeutic Modulation of the Microbiome
Given its central role, the microbiome represents a promising therapeutic target in CRC:
Probiotics and prebiotics restore microbial balance and enhance epithelial barrier integrity, reducing inflammation and carcinogen exposure.
Dietary interventions rich in fiber promote SCFA production, counteracting pro-carcinogenic metabolites.
Antibiotics and bacteriophage therapy selectively target pathogenic microbes, though concerns remain regarding off-target effects and resistance.
Fecal microbiota transplantation (FMT) has shown potential in restoring microbial diversity and improving responsiveness to immunotherapy.
Microbiome-informed immunotherapy: The composition of the microbiota influences response to immune checkpoint inhibitors, with specific taxa enhancing therapeutic efficacy. Manipulating the gut microbiome may thus optimize cancer immunotherapy outcomes.
Limitations and Future Perspectives
Despite strong associations, causality between specific microbes and CRC remains difficult to establish due to inter-individual variability and confounding environmental factors. Most studies rely on cross-sectional data, while longitudinal analyses are needed to track microbial dynamics across CRC development. Standardization of sequencing methods and bioinformatic pipelines is also essential for reproducibility. Future directions include personalized microbiome-based diagnostics, microbiota-engineered therapeutics, and integrative multi-omics approaches to unravel host-microbe interactions in CRC.
Conclusion
The gut microbiome has emerged as a key player in colorectal carcinogenesis, offering insights into disease mechanisms, early detection, and novel therapeutic strategies. Harnessing microbial signatures as biomarkers and developing microbiome-targeted therapies hold promise for improving CRC prevention and treatment. However, translation into clinical practice requires rigorous validation, standardized methodologies, and longitudinal studies to establish causality and therapeutic efficacy.
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The study was recently published in the Journal of Translational Gastroenterology .
Journal of Translational Gastroenterology (JTG) dedicates to improving clinical diagnosis and treatment, advancing understanding of the molecular mechanisms, and promoting translation from bench to bedside of gastrointestinal, hepatobiliary, and pancreatic diseases. The aim of JTG is to provide a forum for the exchange of ideas and concepts on basic, translational, and clinical aspects of gastroenterology, and promote cross-disciplinary research and collaboration.
