How Childhood Microbiota Lays the Foundation for Colorectal Cancer

Colorectal cancers traditionally affect people over 50. However, for two decades, the incidence of this cancer has exploded in young adults, a phenomenon noted in more than 27 countries. The explanation does not only reside in factors known as obesity or industrial food.

A new study, published in the journal Nature by an international team conducted by the University of California in San Diego, in collaboration with the International Agency for Research on Cancer and Wellcome Sanger Institute, points to an unexpected cause: exhibition in childhood to a bacterial toxin, Colibactin, produced by certain strains of Escherichia coli. This toxin leaves a lasting genetic imprint on colon cells. The link between intestinal microbiota, early environment and cancer is becoming clearer, raising crucial public health and prevention issues from an early age.

A silent mutation, but deep

The researchers used a comparative genomic approach to analyze in detail the mutational profiles of the tumors of 981 patients around the world. They distinguished the microsatellitarian instability cancers from those with stable genome. It was in them that they detected the signatures associated with the Colibactin, named SBS88 and ID18, with a marked frequency. These signatures characterize a specific mutagen agent. In fact, their over -representation in colorectal cancers of young adults suggests a common and persistent origin.

The study highlights a molecular chronology. Mutations appear very early in tumor development, long before the first symptoms appear. This temporality combines with early exposure, probably during the first years of life, during which the intestinal microbiota is in full structuring. These early mutations can then persist silently for decades. This until a trigger event promotes the emergence of the tumor.

© © Díaz-Gay, M., et al., 2025

a) Distribution of 981 patients in 11 countries according to the incidence of colorectal cancer and the share of cases before 50 years. b) Location of tumors in the colon and rectum, with the proportion of early cases per area. © Díaz-Gay, M., et al., 2025

The complexity of the tumor genome has also made it possible to observe that these co-dependent mutations combine with other genetic alterations to accelerate progression to cancer. This type of analysis dates back to the origins of the tumor process. Thus researchers lift the veil on invisible but determining processes beginner long before diagnosis.

Microbial origin of cancers: the enemy is in the microbiota

But what is Colibactin? It is a secondary metabolite synthesized by strains ofEscherichia coli having a particular genetic island called pks (Synthase polyketide). Unlike the classic pathogenic strains, these bacteria belong to the commensal flora of the intestine. In other words, they usually coexist without causing symptoms. However, their ability to produce this toxin gives some of them a single mutagen potential capable of interfere directly with the integrity of the DNA of host cells.

Colibactin acts by forming added on DNA. Adduits are chemical bonds formed between a foreign molecule (like a toxin) and DNA, which can disturb its structure and cause mutations. Here the Colibactin then causes particularly deleterious double-Brin breaks. These lesions can cause repair errors, promoting the accumulation of mutations. Some of these alterations affect key genes involved in the regulation of the cell cycle, including APC (Adenomatous Polyposis coli), a tumor suppressant gene. When APC is inactivated, cell proliferation becomes uncontrolled. Which then lays down the first bases of tumor development.

The conditions conducive to the implementation of these strains pks+ seem to be taking shape from childhood. Food diets poor in fiber, but rich in refined sugars, saturated fats and additives, disturb the microbiota balance. This imbalance, or dysbiosis, creates an environment favorable to the dominance of competitive bacteria such as the E. coli producers of Colibactin. By eliminating their rivals via the secretion of toxins, they ensure their expansion. But they damage the colonic epithelium in passing.

Thus, this mechanism calls into question the supposed neutrality of certain strains of the intestinal microbiota. And it would be a track to understand the worrying increase in cancers …

A global epidemiological turning point for colorectal cancers

Indeed, the silent epidemic of early colorectal cancer is gradually installed as a new reality of public health. Formerly concentrated in the elderly, the disease now strikes a younger audience. And the most surprising is the absence of family history and known risk factors. This inversion of the epidemiological profile raises major concerns. Health systems, still stuck on late screening recommendations, may miss out on many early diagnoses.

The trend is all the more worrying since it is observed on several continents, in a synchronized manner. Significant increases are recorded in countries as diverse as Japan, the United States or Colombia. This globality implies that it is not simply a statistical effect or a better diagnostic identification, but a real phenomenon, with probably multiple causes.

The correlation between the frequency of certain genetic signatures, such as those associated with the Colibactin, and the countries most affected by these early cancers, opens a new track. It suggests the existence of environmental or microbial determinants specific to certain regions. Dr. Marcos Díaz-Gay insists on this geographic dimension: ” We must understand why some countries see an explosion of cases while others remain stable ».

This epidemiological turning point requires a paradigm shift. It is no longer just a question of trying to treat colorectal cancer in young people, but of understanding its deep origins. Prevention and screening policies must be adapted.

Towards early screening and prevention strategies

The identification of mutational signatures specific to Colibactin opens the way to a new generation of diagnostic tools. Researchers are currently working on the development of non -invasive tests, based on tumor DNA analysis present in the stool. These tests would make it possible to detect characteristic genetic alterations early, long before the appearance of symptoms. In parallel, the team explores targeted therapeutic interventions on the microbiota, in particular by the reasoned use of probiotics. The objective is to selectively eradicate the strains pks+ d 'E. coli while preserving the overall balance of the intestinal microbiota.

This change of course to personalized prevention is based on the ability to identify individuals at risk from childhood. Ludmil Alexandrov stresses that these changes appear very early, sometimes from the first ten years of life. This reality makes early intervention crucial, both to reduce exposure and to limit the installation of potentially carcinogenic strains.

For David Scott, of cancer Research UK, the urgency is double, he explains to the Guardian. “” These works do not provide a final response, but they lay solid foundations to understand a global phenomenon still poorly explained ». He calls for a massive investment in research. He believes that ” The next steps will require significant resources to translate these discoveries into concrete solutions ».

In short, this microbial hypothesis does not close the debate, but moves it: from treatment to prevention, from adult to child, from symptoms to origin. A switch that could lastingly change the fight against early cancers.

Source: Díaz-Gay, M., Dos Santos, W., Moody, S. et al., “Geographic and Age Variations in Mutational Processes in Colorectal Cancer”. Nature (2025).