How Gut Bacteria Drive Colorectal Cancer and What We Can Do About It
A comprehensive 2025 review maps how bacterial, fungal, and viral dysbiosis fuels colorectal cancer — and points to new diagnostic and therapeutic targets.
Summary
This 2025 review from Shanghai Jiao Tong University synthesizes the latest evidence on how gut microbial imbalance drives colorectal cancer. Key bacterial culprits include Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, pks+ E. coli, and Peptostreptococcus anaerobius, each promoting tumor growth through distinct mechanisms including DNA damage, immune suppression, and oncogenic signaling. Fungi like Candida and viruses including Epstein-Barr virus also contribute. Microbial metabolites — particularly butyrate and secondary bile acids — act as both risk factors and potential therapeutic agents. The review highlights emerging clinical applications including microbiome-based biomarkers for early CRC detection, next-generation probiotics, and microbiome-targeted interventions to improve immunotherapy response.
Detailed Summary
Colorectal cancer is the third most commonly diagnosed cancer globally and the second leading cause of cancer death, with nearly 1.9 million new cases annually. This comprehensive 2025 review from Shanghai Jiao Tong University's digestive disease institute synthesizes the rapidly expanding body of evidence linking gut microbial dysbiosis to CRC initiation, progression, therapy resistance, and potential treatment. The authors draw on metagenomic sequencing studies, murine models, organoid experiments, and clinical cohort data to construct a detailed mechanistic picture of how specific microorganisms reshape the colorectal tumor microenvironment.
On the bacterial front, pks+ Escherichia coli produces colibactin, a genotoxin that causes DNA double-strand breaks and interstrand cross-links, leaving a distinctive mutational signature in AT-rich genomic regions. Murine colon organoid studies showed colibactin exposure disrupts p53 signaling and drives Wnt-independent growth. Enterotoxigenic Bacteroides fragilis secretes BFT toxin, which cleaves E-cadherin, releases β-catenin for nuclear translocation, upregulates c-Myc, and suppresses miR-149-3p to promote Th17-driven inflammation. Fusobacterium nucleatum — particularly the Fna C2 clade — translocates from the oral cavity to colorectal tumors via saliva, using adhesins RadD, Fap2, and FadA to activate PI3K-AKT-NF-κB, β-catenin, and TIGIT-mediated immune evasion pathways. F. nucleatum also promotes chemoresistance by activating TLR4/MYD88-driven autophagy and impairs PD-1 immunotherapy by suppressing the cGAS-STING pathway through succinic acid.
Peptostreptococcus anaerobius contributes through its surface protein PCWBR2 binding integrin α2β1, triggering PI3K-Akt-NF-κB signaling and expanding myeloid-derived suppressor cells (MDSCs) to create an immunosuppressive environment. Its metabolite trans-3-indoleacrylic acid inhibits ferroptosis via the AHR-ALDH1A3-FSP1 axis, allowing CRC cells to evade this form of cell death. Other implicated bacteria include Clostridium symbiosum, Clostridioides difficile, Porphyromonas gingivalis, Parvimonas micra, and Peptostreptococcus stomatis, each with distinct pro-tumorigenic mechanisms.
Beyond bacteria, the review covers the mycobiome and virome. Candida species promote CRC through β-glucan-mediated Dectin-1 signaling and prostaglandin E2 production, while Malassezia activates complement pathways. Epstein-Barr virus and human cytomegalovirus promote immune evasion and inflammation in CRC tissues. Bacteriophages modulate the bacterial microbiome composition and may indirectly influence CRC risk. Microbial metabolites receive substantial attention: butyrate, a short-chain fatty acid produced by protective species like Faecalibacterium prausnitzii and Akkermansia muciniphila, inhibits histone deacetylases and suppresses tumor growth, while secondary bile acids such as deoxycholic acid promote DNA damage and inflammation when produced in excess by dysbiotic communities.
Clinically, the review highlights several translational opportunities. Microbial signatures — including F. nucleatum abundance, colibactin-DNA adducts, and multi-species panels — show promise as non-invasive CRC biomarkers in stool. Next-generation probiotics using Akkermansia muciniphila and Faecalibacterium prausnitzii are being explored to restore protective microbial function. Fecal microbiota transplantation and dietary interventions targeting bile acid metabolism represent additional strategies. The authors also note that microbiome composition influences immunotherapy response, with F. nucleatum-derived butyric acid improving anti-PD-1 efficacy in microsatellite-stable CRC. The review calls for larger prospective studies to validate biomarker panels and establish causality in human populations.
Key Findings
- pks+ E. coli produces colibactin causing DNA double-strand breaks with a distinct mutational signature in AT-rich regions; cystic fibrosis patients show elevated colibactin-DNA adduct formation despite lower pks+ E. coli prevalence due to altered mucus composition
- ETBF's BFT toxin cleaves E-cadherin, releases β-catenin for nuclear translocation, upregulates c-Myc, and suppresses miR-149-3p, promoting Th17 differentiation and inflammatory cytokine production that drives tumor growth
- F. nucleatum's Fna C2 clade harbors unique genes for nutrient scavenging, immune evasion, and metabolic flexibility; its succinic acid inhibits the cGAS-STING pathway, reducing CD8+ T-cell infiltration and impairing PD-1 immunotherapy efficacy
- P. anaerobius metabolite trans-3-indoleacrylic acid inhibits ferroptosis via the AHR-ALDH1A3-FSP1 axis, and its surface protein PCWBR2 recruits MDSCs through integrin α2β1-NF-κB-CXCL1 to induce anti-PD1 resistance
- Candida species promote CRC via β-glucan-Dectin-1 signaling and prostaglandin E2 production; Malassezia activates complement cascade pathways contributing to tumor-promoting inflammation
- F. nucleatum-derived butyric acid improves anti-PD-1 therapy response in microsatellite-stable CRC by reducing PD-1 expression on CD8+ T cells, demonstrating dual pro- and anti-tumor roles for microbial metabolites
- Germ-free mice develop significantly fewer intestinal tumors than conventionally raised counterparts, providing foundational evidence that the microbiome is mechanistically required for CRC development
Methodology
This is a narrative review article (classified as a 'Year Review') synthesizing findings from metagenomic sequencing studies, murine tumor models, colon organoid experiments, clinical cohort studies, and mechanistic in vitro research. No original data were collected; the authors performed a literature synthesis without formal systematic review or meta-analytic methods. The review covers bacterial, fungal, viral, and metabolite contributions to CRC, drawing on studies published primarily between 2020 and 2024. No specific statistical methods or inclusion/exclusion criteria for study selection are reported.
Study Limitations
As a narrative review, this paper does not employ systematic search methodology or meta-analytic statistics, making it susceptible to selection bias in the literature cited. Most mechanistic evidence derives from murine models and in vitro studies, and causal relationships in human populations remain largely unestablished. The authors do not report conflicts of interest disclosures within the available text, and the review acknowledges that larger prospective human studies are needed to validate microbial biomarkers and therapeutic targets.
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