Researchers have uncovered the potential role of gut microbes in the early detection and monitoring of colorectal cancer (CRC) in a groundbreaking international study. By analyzing stool samples from over 3,700 individuals across 18 international cohorts, the study mapped microbial changes associated with cancer stages, tumor location, and progression, refining our understanding of the microbiome as a diagnostic and prognostic tool for one of the deadliest cancers worldwide. The study, published in Nature Medicine, holds promise for improving non-invasive stool tests, which could revolutionize the way CRC is detected and treated.
CRC stage-specific microbiome landscape
CRC is the third most common cancer globally and the second leading cause of cancer-related deaths. Although it develops gradually over the years through the adenoma–carcinoma sequence—a process involving benign lesions evolving into malignant tumors—the disease often evades early detection. Currently, only 40% of CRC cases are caught before metastasis, and survival rates plummet in advanced stages, with stage IV colon cancer offering just an 11% five-year survival rate.
The advent of stool-based tests, including DNA assays that detect traces of cancer cells, has revolutionized CRC screening. However, the gut microbiome—home to trillions of microorganisms—has emerged as a new frontier in cancer research. Previous studies have linked specific microbes, such as Fusobacterium nucleatum and pks+ Escherichia coli, to the development of CRC. These microbes appear not only to influence tumor biology but also to reflect distinct stages of cancer, raising hopes for their use as biomarkers.
Led by researchers from the University of Trento in Italy, Masaryk University in the Czech Republic, and the Harvard T.H. Chan School of Public Health, the study utilized advanced metagenomic and machine-learning techniques to identify nuanced microbial signatures associated with CRC. The researchers identified 3,866 bacterial species-level genome bins (SGBs), along with 15 eukaryotic and 23 archaeal organisms.
Key findings included the elevated presence of F. nucleatum, Parvimonas micra, and Bacteroides fragilis in CRC samples compared to controls. Notably, the study also revealed 19 previously uncharacterized SGBs, underscoring the complexity of the CRC microbiome and pointing to new microbial players that may influence cancer biology.
One striking observation was the enrichment of oral-derived bacteria, such as P. micra and Haemophilus hathewayi, in stool samples from late-stage CRC patients. These microbes, known to form biofilms in the oral cavity, may similarly aggregate in the gut, promoting tumor invasion and progression.
The study also explored the relationship between tumor location and microbial composition. Right-sided and transverse colon tumors were enriched with oral bacteria, while left-sided tumors showed higher abundances of unclassified Clostridia species. These variations suggest that the tumor microenvironment and local carcinogenic triggers might shape the gut microbiome in distinct ways.
Interestingly, the research identified strain-level differences within microbial species, hinting at genetic adaptations that may enhance survival in tumor microenvironments. For example, certain strains exhibited accessory genes associated with inflammation and tumor promotion, providing a deeper understanding of how microbes might contribute to cancer progression.
Leveraging CRC patient microbiomes for medicine
The integration of these findings into stool-based screening tests could enhance the detection of CRC at early and intermediate stages. For example, identifying microbial shifts during the transition from benign adenomas to malignant tumors could improve early diagnosis, where intervention is most effective. Moreover, the study’s insights into microbial changes during advanced CRC stages—such as the enrichment of methane-producing Methanobrevibacter smithii—highlight new avenues for monitoring disease progression and tailoring treatment strategies.
The findings align with a broader recognition of the microbiome’s role in health and disease. The study strengthens the notion that gut microbiome composition changes continuously along the CRC progression spectrum, acting more as a continuum than as discrete shifts. Furthermore, the connection between CRC microbiomes and microbes linked to cardiometabolic diseases raises intriguing questions about shared inflammatory pathways and risk factors.
Despite its strengths, the study has limitations. As an association-based analysis, it cannot definitively establish causal relationships between specific microbiome configurations and cancer progression. However, the robust identification of microbial biomarkers opens up future mechanistic studies and clinical applications. Future research will need to explore larger cohorts and incorporate longitudinal analyses to unravel the microbiome’s role in CRC development and metastasis. As the availability of metagenomic data grows, researchers are well-positioned to refine microbiome-based diagnostics and develop targeted interventions that exploit microbial vulnerabilities.
