Home›Gastroenterology› Gut microbiota influence innate immune signaling and promote colibactin-associated mutational signatures in colorectal cancer
Gut microbiota influence innate immune signaling and promote colibactin-associated mutational signatures in colorectal cancerGut Microbiota Influences Immune Response in Colorectal Cancer
Frontiers in MedicinePublished September 10, 2026DOI ↗Editorial oversight: Dr. Amelia Tan, PhD · Internal Medicine & Chronic Disease
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Key Takeaway
Note that gut microbiota influence innate immune signaling, though human longitudinal causal evidence remains limited.
This systematic review explores the complex interactions between the gut microbiota and the innate immune system in the context of colorectal cancer. The authors synthesize evidence regarding how gut microbiota influence innate immune signaling, specifically involving Toll-like receptor and NOD-like receptor signaling, NF-kappaB activation, and the NLRP3 inflammasome. Additionally, the review notes that the innate immune system can reshape microbial composition and metabolic characteristics through antimicrobial effector molecules and mucosal barrier maintenance.
A key finding highlighted is the presence of colibactin-associated mutational signatures directly demonstrated in the genomes of human colorectal cancer tumors. These findings suggest that the microbiota-immune axis plays a role in tumor microenvironment remodeling and immune evasion.
However, the authors note significant limitations, including a lack of longitudinal causal evidence in humans. Many specific microbiota-immune interactions are currently based on animal models, in vitro experiments, or integrative inference. These findings provide a cautious theoretical basis for future mechanistic research and the development of precision intervention strategies in colorectal cancer.
How this fits prior evidence
This systematic review addresses a gap in the understanding of the biological mechanisms of colorectal cancer. While previous evidence noted that distinct immune microenvironment features in thyroid and colorectal cancers drive unique mechanisms of resistance, this review specifically details how the gut microbiota influences innate immune signaling and the presence of colibactin-associated mutational signatures in human tumors.
Researchers reviewed how the gut microbiota and the innate immune system interact in the context of colorectal cancer. The study looked at how these two systems influence each other. Specifically, the gut microbiota can influence immune signaling pathways and inflammation. At the same time, the immune system can reshape the types and locations of microbes in the gut.
One specific finding showed that certain mutations linked to a substance called colibactin were found in human colorectal cancer tumors. This provides a rare piece of direct evidence regarding how specific factors might influence cancer growth. However, it is important to note that much of the current knowledge comes from animal models or laboratory tests rather than long-term studies in humans.
Because much of the evidence comes from non-human models, the results are not yet ready to change standard medical treatments. The goal of this research is to help scientists better understand the relationship between gut health and the immune system. This knowledge may eventually help doctors develop more precise ways to treat patients with colorectal cancer.
What this means for you:
Gut microbes and the immune system interact in ways that may influence the environment around colorectal cancer.
Common questions
How does the gut microbiome affect the immune system?
The gut microbiota can influence several immune signaling pathways, including Toll-like receptors and NOD-like receptors. It also impacts NF-kappaB activation and the NLRP3 inflammasome. These interactions are part of the way the body manages immune signals and metabolic pathways in the gut environment.
How does the immune system affect gut bacteria?
The innate immune system can reshape the composition and distribution of microbes in the gut. It does this through the release of inflammatory mediators, the maintenance of the mucosal barrier, and the use of antimicrobial molecules to clear out certain microbes.
Is this research enough to change current cancer treatments?
No, this research is not yet enough to change standard treatments. Much of the evidence comes from animal models or lab experiments. Because long-term evidence in humans is limited, these findings are currently used to help scientists understand the mechanisms of disease.
Colorectal cancer (CRC) is a common malignancy of the digestive system, and its initiation and progression are associated with multiple factors, including genetic alterations, environmental exposures, changes in the gut microbiota, and disruption of immune homeostasis. In recent years, evidence from human observational studies, animal models, and in vitro experiments has shown that the gut microbiota can influence Toll-like receptor and NOD-like receptor signaling, NF-κB activation, the NLRP3 inflammasome, and immunometabolic pathways through multiple mechanisms, including microbial structural components, metabolic signals, virulence factors, and outer membrane vesicles. These effects are associated with functional remodeling of innate immune components such as macrophages, dendritic cells, neutrophils, and natural killer (NK) cells. Conversely, the innate immune system can reshape microbial composition, spatial distribution, and metabolic characteristics through antimicrobial effector molecules, maintenance of the mucosal barrier, release of inflammatory mediators, and phagocytic clearance, indicating a bidirectional regulatory relationship between the gut microbiota and innate immunity. Current evidence suggests that microbiota–innate immune interactions are associated, to varying degrees, with CRC-related pathological processes, including alterations in immune surveillance and the myeloid microenvironment, barrier dysfunction, low-grade inflammation, remodeling of the tumor microenvironment, epithelial–mesenchymal transition-related phenotypes, and immune evasion. Notably, colibactin-associated mutational signatures have been directly demonstrated in the genomes of human CRC tumors, representing one of the relatively rare forms of high-strength mechanistic evidence in microbiota–CRC research. Beyond such a limited number of well-supported mechanisms, however, many specific microbiota–immune interactions and their roles at different pathological stages remain based primarily on animal models, in vitro experiments, or integrative inference, while longitudinal causal evidence in humans remains generally limited. This review focuses on the bidirectional interactions between the gut microbiota and innate immunity in CRC, systematically summarizing their molecular mechanisms, associated pathological processes, and advances in microbiota-targeted interventions, with particular emphasis on distinguishing among different types of evidence, experimental contexts, and levels of causal certainty. In doing so, we aim to provide a more cautious theoretical basis for mechanistic research on the microbiota–immune axis and for the development of precision intervention strategies in CRC.
