Researchers Investigate a Microbiome Paradox
Scientists have long faced a puzzling contradiction involving the gut bacterium Bacteroides fragilis. On one hand, researchers frequently associate this bacterium with Colorectal Cancer. On the other hand, it also lives harmlessly in the intestines of many healthy individuals.
A research team from Denmark may now have uncovered an important clue. Instead of focusing only on the bacterium itself, the scientists examined its genome and discovered a previously unknown virus embedded within it. Interestingly, this virus appeared significantly more often in cancer patients than in individuals without the disease.
Colorectal Cancer and the Role of the Gut Microbiome
Colorectal cancer is the third most common cancer worldwide and the second leading cause of cancer-related deaths. Researchers estimate that up to 80% of cases are linked to environmental factors, with the gut microbiome playing a major role.
The gut microbiome consists of trillions of microorganisms—including bacteria, fungi, and viruses—that live in the digestive tract. Because of its strong influence on health, scientists believe colorectal cancer may, at least partly, be preventable. However, the precise biological mechanisms connecting the microbiome to cancer remain unclear.
Looking Beyond Bacterial Species
Most microbiome studies focus on identifying which bacterial species are present and how abundant they are. However, this approach has limitations because species often contain enormous genetic diversity.
For example, all domestic dogs belong to the same species—Canis familiaris—yet a Chihuahua and a Great Dane differ dramatically. Similarly, bacteria within the same species can vary greatly at the genetic level.
Therefore, simply identifying which bacterial species exist in the gut may not provide enough detail. Instead, the key may lie in genetic differences between bacterial strains.
A Common Bacterium With a Suspicious Link
Researchers generally consider Bacteroides fragilis a harmless resident of the gut microbiome, and it appears in most healthy individuals. Nevertheless, studies repeatedly show that it is more abundant in people with colorectal cancer.
This observation prompted scientists to ask an important question: Could certain genetic traits within specific strains of B. fragilis explain the connection to cancer?
Viruses That Infect Bacteria
To explore this possibility, researchers examined whether viruses might influence bacterial behavior. All living cells—including bacteria—can become infected by viruses.
Viruses that specifically infect bacteria are known as Bacteriophages. Importantly, these viruses attack bacteria but do not infect human cells.
Not all bacteriophages destroy their bacterial hosts. Some integrate their own genetic material into the bacterial genome, forming structures known as prophages. In this state, the viral DNA becomes a permanent passenger within the bacterium.
Prophages can dramatically alter bacterial behavior. In fact, diseases such as Cholera, Botulism, and Diphtheria occur because prophages introduce toxin-producing genes into otherwise harmless bacteria.
Danish Study Identifies New Viral Signatures
To determine whether viral elements might link B. fragilis to colorectal cancer, the Danish research team sequenced the genomes of bacterial samples from individuals with and without cancer.
First, the scientists examined whether cancer-associated bacteria belonged to a distinct evolutionary lineage. However, they found no such pattern.
Next, they investigated another possibility: horizontal gene transfer, a process through which bacteria acquire genetic material from external sources rather than inheriting it from parent cells. Infection by prophages is one such mechanism.
When the researchers compared the genomes more closely, they discovered two previously unknown prophages that frequently appeared in bacteria from cancer patients but were largely absent in bacteria from healthy individuals.
Unknown Genes Raise New Questions
Although the newly discovered prophages did not contain obvious cancer-causing genes, scientists noted that many prophage genes remain poorly understood. As a result, their biological functions remain unclear.
Nevertheless, the discovery suggests that viral elements within bacteria might influence how microbes interact with the human body.
Large-Scale Analysis Confirms the Pattern
Initially, the study analysed 48 bacterial samples, which raised questions about whether the findings would hold true in a larger population.
To test this, researchers examined microbiome data from 877 individuals across Europe, the United States, and Asia. The dataset included 434 colorectal cancer patients and 443 individuals without the disease.
As reported by medicalxpress, the results showed that people with colorectal cancer were more than twice as likely to carry bacteria containing these prophages.
However, researchers emphasised that this finding represents an association rather than proof of causation. Scientists have not yet identified a clear biological mechanism explaining how the viruses might contribute to cancer development.
Possible Explanations for the Association
Several explanations could account for the observed link.
First, the gut environment in cancer patients might simply favor the growth of certain bacterial strains, allowing prophage-containing bacteria to thrive. In this scenario, cancer would influence the microbiome rather than the other way around.
Alternatively, specific gut environments could simultaneously encourage the growth of these bacterial strains and increase cancer risk.
Study Limitations
The researchers also acknowledged several limitations. The original bacterial samples came from patients with bloodstream infections, not directly from colorectal tumors. In addition, the larger validation study relied on stool samples, which represent a different biological source.
Furthermore, some individuals in the comparison group had not been formally confirmed to be cancer-free, which may affect the interpretation of the results.
Potential Applications for Cancer Screening
Despite these limitations, the findings open the possibility of new screening strategies for colorectal cancer.
Currently, the most common non-invasive test is the Fecal Immunochemical Test (FIT), which detects traces of blood in stool samples.
In theory, researchers could analyse the same stool samples for viral DNA signatures linked to the newly discovered prophages.
In a preliminary analysis, a test based on fragments of the prophage genomes detected around 40% of colorectal cancer cases. Although this result requires much further research, it suggests that viral markers could eventually complement existing screening methods.
Rethinking the Gut Microbiome’s Role in Disease
Ultimately, this research highlights a broader shift in how scientists study the microbiome.
Rather than simply asking which bacteria live in the gut, researchers may need to investigate what lies inside those bacteria—including hidden viruses that influence microbial behavior.
By examining these “hidden passengers,” scientists may gain deeper insights into how the microbiome contributes to human disease and discover new strategies for prevention and early detection.