Beyond Genetics: The Microbial Contribution
Colorectal cancer (CRC) is the third most common cancer worldwide, and while germline mutations (APC, Lynch syndrome genes) account for a significant minority, the majority of cases are sporadic — arising from the interaction of diet, lifestyle, chronic inflammation, and increasingly, the gut microbiome. Large-scale metagenomic studies have identified reproducible microbial signatures associated with CRC across geographically and ethnically diverse populations.
Key Bacterial Players
Fusobacterium nucleatum is the most consistently enriched bacterium in colorectal tumours. Originally an oral commensal, it reaches the colon via haematogenous spread and selectively adheres to tumour cells through its FadA adhesin binding to E-cadherin on epithelial cells. Once attached, it promotes tumour proliferation via β-catenin signalling, suppresses anti-tumour immunity by inhibiting NK cell and T cell function, and creates a pro-inflammatory microenvironment through NF-κB activation.
Enterotoxigenic Bacteroides fragilis (ETBF) produces B. fragilis toxin (fragilysin), a metalloprotease that cleaves E-cadherin, disrupts the epithelial barrier, and activates STAT3-dependent inflammatory cascades. Certain strains of Escherichia coli carrying the polyketide synthase (pks) genomic island produce colibactin — a genotoxin that directly alkylates DNA, creating a distinctive mutational signature (SBS88) detectable in CRC genomes.
The Driver-Passenger Model
The current conceptual framework distinguishes between "driver" bacteria — those that initiate pro-carcinogenic changes in normal mucosa — and "passenger" bacteria — those that thrive in the altered tumour microenvironment but did not initiate transformation. Fusobacterium and colibactin-producing E. coli are considered putative drivers, while many of the other CRC-enriched taxa may be opportunistic passengers that exploit the altered metabolic landscape of tumour tissue.
Metabolite-Mediated Mechanisms
Beyond direct bacterial effects, microbial metabolites modulate CRC risk. Secondary bile acids (deoxycholic acid) at high concentrations promote DNA damage and epithelial proliferation. Hydrogen sulphide, produced from dietary protein by sulphate-reducing bacteria, is genotoxic at high concentrations. Conversely, butyrate — the SCFA produced from dietary fibre — is protective: it promotes colonocyte differentiation, induces apoptosis in transformed cells, and inhibits histone deacetylases involved in tumour gene expression.
Screening and Therapeutic Implications
Microbial biomarkers (particularly Fusobacterium abundance in stool) are being investigated as adjuncts to conventional CRC screening (faecal immunochemical test, colonoscopy). Machine learning classifiers combining multiple bacterial signatures show promising sensitivity and specificity in pilot studies. Therapeutically, antibiotic targeting of Fusobacterium in CRC patients has shown tumour growth reduction in preclinical models, and microbiome modulation is being explored as a strategy to enhance immunotherapy response — an area of intense current investigation.