The gastrointestinal tract hosts a rich ecosystem of bacteria, fungi, viruses, archaea, and parasites that colonizes the host early in life and co-evolves through adulthood. While these communities perform essential functions in nutrient utilization and homeostasis, they become dysregulated in disease. Because gut microbes are in intimate, continuous contact with the epithelial lining of the digestive tract, they are heavily implicated in the pathogenesis of cancers arising there. Mechanistic studies have revealed microbes as an integral component of the tumor microenvironment, interacting with tumor cells, immune cells, and stromal cells through microbial protein-host receptor binding, metabolite exchange, and modulation of antitumor immunity. The field has now moved beyond simple microbial profiling toward strain-specific functional characterization, spatial mapping of intratumoral bacteria, and translational applications.

Colorectal cancer, the third most common cancer worldwide and the second leading cause of cancer death, was among the earliest malignancies linked to the gut microbiome, and recent work has delivered striking surprises. Whereas most studies previously reported associations at the species level, researchers are now uncovering dramatic strain-to-strain variation in cancer-promoting effects. A comprehensive analysis of Fusobacterium nucleatum strains isolated from colorectal tumors and healthy oral cavities, using PacBio long-read sequencing, revealed that the subspecies F. nucleatum sub-species animalis is predominantly enriched in colorectal cancer. This subspecies splits into two clades, and only one, Fna C2, is enriched in tumors. Fna C2 expresses the adhesin fap2, which aids its adherence to and invasion of the colon, and its superior protumorigenic effect was validated in mouse models.

Similar precision has been applied to pks-positive Escherichia coli, a bacterium carrying the genetic island needed to synthesize the genotoxin colibactin. Comparing the non-pathogenic Nissle 1917 strain with the pathogenic 11G5 strain, researchers found that although both harbor the pks island, only 11G5 drove tumorigenesis in mice. The difference lay in a variant of the FimH adhesin, which allows 11G5 to bind colon epithelial cells and inflict DNA damage. Critically, targeting this bacterium-host cell interaction prevented 11G5-induced tumorigenesis, pointing to a therapeutic strategy. Fungi are also entering the picture: Aspergillus rambellii promotes colorectal cancer growth in vitro and in vivo, and the commensal yeast Candida albicans has been shown to synergize with F. nucleatum, ferrying the bacterium to the colonic mucosa through a Flo9-RadD interaction, evidence of bacteriome-mycobiome interplay in cancer.

Spatial profiling technologies have added a remarkable new dimension. Integrating spatial host multiomics with microbiota profiles has shown that intratumoral bacteria are heterogeneously distributed and concentrated in microniches that are infiltrated by immunosuppressive cells, with elevated neutrophils and exclusion of CD3-positive T cells. Bacteria-colonized niches show lower tumor cell proliferation but increased cell migration, suggesting that promoting growth may not be the dominant mechanism of intratumoral bacteria. A follow-up spatial imaging study found that intratumoral bacteria such as F. nucleatum exist in the extracellular milieu, where they disrupt cell-cell contacts among tumor cells and trigger a quiescent, immune-evasive phenotype that promotes chemoresistance. On the diagnostic front, stool-based single- and multi-bacterial gene biomarkers, alone or combined with the fecal immunochemical test, discriminate colorectal cancer from healthy controls with high accuracy and improve detection of adenomas, while several probiotic strains have suppressed tumorigenesis in animal models.

Perhaps the most clinically consequential findings concern therapy. Wong and Yu’s group systematically analyzed baseline gut microbiome profiles as predictors of chemotherapy response and identified Bacteroides fragilis as the top enriched bacterium in non-responders. B. fragilis drives chemoresistance through its surface protein SusD/RagB, which activates NOTCH1 signaling in colorectal cancer cells. To counter this, the team isolated a novel bacteriophage, VA7, that selectively eliminates B. fragilis in the mouse colon and reverses the chemoresistant phenotype. On the immunotherapy side, immune checkpoint blockade works only in microsatellite instability-high colorectal cancer, leaving the more than 85 percent of patients with microsatellite stable tumors largely unresponsive. The researchers discovered that the tumor-resident probiotic Clostridium butyricum potentiates anti-PD1 efficacy in both settings. Its surface protein secD binds the tumor cell receptor GRP78, suppressing the PI3K-AKT-NF-kappa-B pathway and reducing secretion of the immunosuppressive cytokine IL-6, which reactivates cytotoxic CD8-positive T cells and suppresses tumor-associated macrophages, an effect validated in humanized mice and organoid co-cultures.

In a paradoxical twist, F. nucleatum, normally a cancer-promoting pathogen, was found to enhance anti-PD1 response in microsatellite stable colorectal cancer. Intratumoral F. nucleatum secretes abundant butyrate, which inhibits histone deacetylases in CD8-positive T cells and epigenetically represses PD-1 expression, alleviating T cell exhaustion. Intratumoral F. nucleatum may therefore serve as a biomarker predicting anti-PD1 response in this patient subgroup. These findings position gut microbes as promising adjuvants for improving colorectal cancer immunotherapy.

Gastric cancer research is likewise moving beyond its long-standing obsession with Helicobacter pylori, a class I carcinogen long assumed to be the sole trigger of the Correa cascade from chronic gastritis to adenocarcinoma. Yet most infected people never develop cancer, H. pylori eradication only modestly reduces gastric cancer risk and fails in those with advanced precancerous lesions, and H. pylori abundance actually declines as lesions progress. Metagenomic sequencing across the gastric tumorigenesis sequence revealed enrichment of oral pathogens, including Streptococcus anginosus, Parvimonas micra, Peptostreptococcus stomatis, Prevotella intermedia, and F. nucleatum, whose persistence after H. pylori eradication correlated with inflammation, atrophy, and intestinal metaplasia. Causation was established when fecal microbiota transplantation from gastric cancer patients promoted precancerous lesions in germ-free mice, and when S. anginosus gavage reproduced the full gastritis-atrophy-metaplasia-dysplasia cascade in mice. The bacterium’s surface protein TMPC binds Annexin A2 on gastric cells, activating MAPK and PI3K oncogenic signaling, and additional mechanisms involving ornithine and methionine production and NLRP3 inflammasome induction are emerging. Translational prospects include S. anginosus and oral microbiota signatures as non-invasive diagnostic biomarkers, protective bacteria such as Lactobacillus paracasei, and phage-based strategies against the oral pathogen network.

Liver cancer presents a different geography of microbial mischief. The liver is not directly exposed to gut microbes in health, but the gut-liver axis channels microbial metabolites and products through the portal vein, and a leaky gut barrier in dysbiosis allows lipopolysaccharides, lipoteichoic acid, and secondary bile acids to inflame the liver. Fecal microbiota transplantation from hepatocellular carcinoma patients spontaneously triggered liver inflammation, fibrosis, and dysplasia in mice, and accelerated hepatocarcinogenesis in disease models. Strikingly, part of the translocated community, especially Klebsiella pneumoniae, survived as live bacteria colonizing the mouse liver; its surface protein PBP1B binds TLR4 on liver cancer cells and drives proliferation. A second pathogen, Catenibacterium mitsuokai, attaches to hepatocytes via Gtr1/RagA binding to gamma-catenin and secretes quinolinic acid to activate the TIE2-PI3K/Akt cascade. Metabolites matter too: in a high-fat, high-cholesterol diet model of metabolic dysfunction-associated liver cancer, the microbial metabolite 3-indolepropionic acid was depleted and shown to suppress tumor cell proliferation, while obesity-driven deoxycholic acid and Clostridium-mediated bile acid biotransformation impair antitumor immunosurveillance by natural killer T cells. Probiotics such as Bifidobacterium pseudolongum and Lactobacillus acidophilus, which produce acetate and valeric acid respectively, offer prophylactic promise.

Significant challenges remain before microbiome medicine becomes routine. Most human studies are still correlational, and the chicken-and-egg question, whether dysbiosis causes cancer or cancer reshapes the microbiome, remains unresolved, though recent evidence implicating colibactin-induced driver mutations as an early event in colorectal cancer supports a causal role. Fecal transplantation faces pathogen transmission risks and regulatory uncertainty, next-generation probiotics lack a unified marketing framework, and phage therapy suffers from a shortage of evidence-based clinical research. Microbiome diagnostics must also prove robust across geographically, ethnically, and dietary diverse populations, demanding large international validation cohorts. Still, with strain-level resolution, spatial mapping, and mechanistic dissection converging, the authors argue that well-designed clinical trials could soon translate gut microbes into diagnostics, chemopreventives, and immunotherapy adjuvants capable of meaningfully reducing the global burden of gastrointestinal cancers.

Subject of Research: The role of the gut microbiome in the development, diagnosis, and treatment of gastrointestinal cancers

Article Title: Advances in microbiome in gastrointestinal cancer

Article References: Wong, C. C., & Yu, J. (2026). Advances in microbiome in gastrointestinal cancer. Holistic Integrative Oncology, 5(1), Article 22. https://doi.org/10.1007/s44178-026-00241-4

Image Credits: AI Generated

DOI: 10.1007/s44178-026-00241-4

Keywords: gut microbiome, gastrointestinal cancer, colorectal cancer, gastric cancer, liver cancer, gut dysbiosis, Fusobacterium nucleatum, Streptococcus anginosus, immunotherapy, probiotics, bacteriophage therapy, microbiome diagnostics