introduction
Gut microbiome: a dynamic ecosystem
Microbial dysbiosis and colorectal cancer
Stomach cancer Helicobacter pylori
Microbial metabolites and host signaling
Host immune response and tumor microenvironment
Clinical significance and future direction
References
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This article describes how host-microbiome interactions contribute to gastrointestinal cancer risk through microbial genotoxins, metabolic signaling pathways, immune dysregulation, and tumor microenvironment remodeling in colorectal and gastric cancers. Together, current evidence shows how dysbiosis, microbial metabolites, and pathogen signaling alter epithelial integrity. inflammationand treatment response.

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introduction

Increased incidence of colorectal, pancreatic, esophageal, and other less common gastrointestinal (GI) cancers has been reported among patients younger than 50 years, especially among racial and ethnic minorities. Emerging evidence indicates that host-microbiota metabolic crosstalk, immunomodulation, and microbial genotoxins play central mechanistic roles in tumor initiation, progression, and therapeutic response across gastrointestinal malignancies. Importantly, many of the microbiome-cancer associations come from observational and preclinical studies, and causality in humans remains an active area of ​​research.^1-3

interaction between intestinal flora and colon cancer¹

Gut microbiome: a dynamic ecosystem

In gut microbiota dysbiosis, characterized by reduced microbial diversity within the gastrointestinal tract, an increase in pathogenic taxa causes chronic low-grade inflammation. Gut dysbiosis is usually accompanied by depletion of beneficial butyrate-producing taxa (e.g. rosebria, Lachnospiraceae) and enrichment of pro-inflammatory pathogens such as Fusobacterium nucleatumenterotoxigenic Bacteroides fragilis (ETBF), PKS positive Escherichia coli.^1-3 However, the microbial composition varies between individuals, tumor subtypes, and anatomical regions of the gastrointestinal tract, contributing to heterogeneous findings across studies.^1,2 This inflammatory environment induces continued activation of proinflammatory pathways such as nuclear factor kappa B (NF-κB) and signal transducer and activator of transcription 3 (STAT3), which disrupts epithelial integrity and increases cell proliferation.^1,3

Disruption of the intestinal barrier also occurs as a result of changes in the microbial community that impair tight junctions and mucosal immunity. This leaky gut condition allows bacteria and their products, including lipopolysaccharides, to migrate into host tissues, further amplifying immune activation and maintaining a tumor-promoting microenvironment.^1,3 specific strain Escherichia coli and Bacteroides fragilis It also produces toxins and metabolites that cause DNA damage through oxidative stress, generation of reactive oxygen and nitrogen species, and double-strand breaks.^1,3 For example, pks+ Escherichia coli While producing colibactin, a genotoxin that alkylates DNA and induces double-strand breaks, ETBF secretes frazilysin, a metalloprotease that cleaves E-cadherin and activates β-catenin signaling.^{1, 2}

Differences between bacteria in a favorable state of intestinal flora and an abnormal state of intestinal flora.¹

Microbial dysbiosis and colorectal cancer

Microbial dysbiosis increases the risk of colorectal cancer by promoting long-term immune activation that contributes to continued epithelial damage, thereby supporting tumor development and progression.^1,3 Dysbiosis also compromises the integrity of the intestinal barrier, allowing bacteria and toxins to enter the body, causing inflammation and tissue damage, further increasing the risk of cancer.^1,3

Microorganisms associated with abnormalities in the intestinal flora (e.g., specific bacterial strains) Escherichia coli and Bacteroides fragilis, It releases toxins and metabolites such as colibactin, secondary bile acids, and reactive oxygen species (ROS), which directly induce DNA damage, genomic instability, and epigenetic changes. Fusobacterium nucleatum Furthermore, it promotes tumorigenesis through the FadA adhesin, which binds to E-cadherin and activates Wnt/β-catenin signaling, increasing the expression of oncogenes such as c-Myc and cyclin D1.¹ High intratumoral abundance F. nucleatum It is also associated with certain molecular subtypes of CRC, such as CpG island methylation phenotype (CIMP) positivity and microsatellite instability (MSI).¹ The combination of these genotoxic effects and chronic inflammation and intestinal barrier disruption promote the development of colorectal cancer.^1,3

Stomach cancer Helicobacter pylori

Helicobacter pylori (H. pylori) is the most established example of a bacterium that directly contributes to the risk of gastric cancer and is consequently classified as a Group I carcinogen. Long-term colonization of gastric mucosa Helicobacter pylori It causes chronic active gastritis, during which immune cells continue to infiltrate and release pro-inflammatory cytokines, ROS, and reactive nitrogen species (RNS). This chronic inflammatory state causes oxidative DNA damage and impaired epithelial repair mechanisms, both of which are ideal conditions for neoplastic transformation.^{2, 3}

induced by chronic inflammation Helicobacter pylori It ultimately leads to progressive mucosal damage, causing atrophic gastritis and loss of acid-secreting parietal cells, followed by the formation of intestinal metaplasia. These precancerous changes, often described in the Corea cascade, increase susceptibility to gastric adenocarcinoma. Reducing gastric acidity further alters the gastric microbiota, allowing colonization by non-gastrointestinal bacteria.Helicobacter pylori Bacteria that can produce carcinogenic metabolites such as N-nitroso compounds, further increasing the risk of cancer.^{2, 3} This progression has been described as a “Helicobacter pylori initiation-non-Helicobacter pylori acceleration” cascade, in which secondarily colonized organisms contribute to tumor promotion.²

in parallel, Helicobacter pylori Actively manipulates host immune responses. Specifically, virulence factors such as cytotoxin-associated gene A (CagA) and vacuolating cytotoxin A (VacA) dysregulate key signaling pathways such as the NF-κB pathway and the mitogen-activated protein kinase (MAPK) pathway, promoting immune evasion, epithelial proliferation, and tumorigenesis.^{2, 3} CagA-positive strains further activate Wnt/β-catenin, PI3K/Akt, JAK/STAT3, ERK/MAPK, and Hedgehog signaling pathways, while promoting PD-L1 expression to promote immune evasion. Epstein-Barr virus (EBV)-associated gastric cancer represents a separate microbiologically influenced subtype characterized by distinct immune and epigenetic features. Emerging evidence also suggests that fungal dysbiosis, including an increase in Ascomycota species, may be associated with gastric carcinogenesis.²

Short-chain fatty acids (SCFAs), such as acetic acid, propionic acid, and butyric acid, are produced by bacterial fermentation of fibers. During homeostasis, SCFAs promote epithelial energy metabolism, barrier reinforcement, and regulatory T cell (Treg) function, while suppressing proinflammatory signals. In particular, butyrate exerts antitumor effects by promoting apoptosis and cell cycle arrest of transformed epithelial cells while limiting excessive proliferation.^1,3 SCFAs also act as histone deacetylase inhibitors that transduce signals through G protein-coupled receptors (e.g., GPR41, GPR43) and regulate the expression of immune and tumor suppressor genes.³ Furthermore, the metabolism of tryptophan by microorganisms produces indole derivatives that activate the aryl hydrocarbon receptor (AhR), influencing immune cell differentiation and mucosal homeostasis.³

Comparatively, dysbiosis interferes with bile acid metabolism, thereby increasing the production of secondary bile acids such as deoxycholic acid. This damages DNA and the intestinal epithelium and activates oncogenic pathways involving NF-κB and Wingless-associated integration site (Wnt)/β-catenin signaling. Secondary bile acids can also impair apoptosis, promote chronic inflammation, and promote a tumor-permissive microenvironment.^1,3

Host immune response and tumor microenvironment

The gut microbiome is an important architect of the host immune response and tumor microenvironment in gastrointestinal cancers. Microorganisms and their products, including pathogen-associated molecular patterns and metabolites, engage host pattern recognition receptors, such as Toll-like receptors, leading to activation of proinflammatory signaling pathways such as NF-κB. NF-κB induces the expression of pro-inflammatory cytokines such as interleukin-6 (IL-6), IL-1β, and tumor necrosis factor alpha (TNF-α), perpetuating the cancer environment.^{2, 3}

Microbial signals influence adaptive immunity by altering T cell differentiation, effector function, and exhaustion, and by modulating immune checkpoints such as programmed death ligand 1 (PDL-1) expression on epithelial and immune cells.^{2, 3} Enterobacteriaceae also shape macrophage polarization into pro-tumorigenic M2-like tumor-associated macrophages and promote the expansion of myeloid-derived suppressor cells, thereby suppressing cytotoxic CD8+ T cell activity.² Dysbiosis can also impair dendritic cell maturation, alter natural killer (NK) cell function, influence the formation of tertiary lymphoid structures within tumors, and collectively reshape antitumor immunity.²

Clinical significance and future direction

recent advances metagenomics And metabolomics makes it possible to precisely identify changes in cancer-associated bacteria and metabolic pathways. These non-invasive tools enable the detection of genotoxin-producing bacteria and unique metabolic signatures, helping researchers understand tumor development and offering new possibilities for early diagnosis and personalized treatment.^1,3 Microbiome composition has also been associated with chemotherapy efficacy, immunotherapy responsiveness, and treatment-related toxicity in gastrointestinal cancers.^1,2

Regarding treatment, multiple approaches targeting the microbiome are under investigation. For example, researchers are increasingly investigating the role of probiotics, prebiotics, dietary fiber fortification, and fecal microbiota transplantation (FMT) in restoring microbial equilibrium and improving treatment outcomes.^1,2

Although promising, the complex host-microbe interactions and high inter-individual variability limit general application. Translating this research into real-world treatments will require large-scale, long-term human cohort studies, integration of multi-omics platforms, and standardized analytical methods.^1,3

References

1. 1. Cintoni, M., Palombaro, M., Zoli, E., others. (2025). Interactions between gut microbiota and colorectal cancer: a review of the literature. microorganisms 13(6). Toi:10.3390/Microorganisms13061410. https://www.mdpi.com/2076-2607/13/6/1410
   2. Elganum, MT, MH, Hassanien, YA, Ameen; others. (2025). Gut microbiome and gastric cancer: microbial interactions and therapeutic potential. Enteric pathogens 17. Toi: 10.1186/s13099-025-00729-w. https://link.springer.com/article/10.1186/s13099-025-00729-w
   3. Yu, Jay, Lee, L, Tao, X, others. (2024). Host-gut microbiota metabolic interactions: new possibilities for accurate diagnosis and therapeutic discovery of future gastrointestinal cancers – a review. Critical Reviews in Oncology/Hematology 203. Toi: 10.1016/j.critrevonc.2024.104480. https://www.sciencedirect.com/science/article/pii/S1040842824002233

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Last updated: February 19, 2026