Colorectal cancer (CRC) is the third most common cancer worldwide, but it is increasingly recognized as two distinct diseases. Right-sided tumors differ from left-sided ones in patient demographics, molecular features, and clinical outcomes. Right-sided cancers are more common in older women and often carry BRAF mutations and microsatellite instability, while left-sided tumors typically involve APC and TP53 mutations. Despite these well-established differences, whether the gut microbiome varies by tumor location has remained unclear, with previous studies yielding inconsistent results. Due to these unresolved questions, there is a pressing need for comprehensive, spatially resolved investigations into the microbial ecology of CRC at different anatomic sites.
Researchers from the Centre for Microbiome Medicine at Nanyang Technological University (NTU) in Singapore and The Chinese University of Hong Kong in China conducted a prospective study published (DOI: 10.20892/j.issn.2095-3941.2025.0846) in Cancer Biology & Medicine—a peer-reviewed open-access journal of the China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The team collected 690 samples—including stool, colonic aspirates, and mucosal biopsies—from 93 patients with normal colonoscopies, adenomas, or CRC, and performed 16S rRNA gene sequencing to profile the microbial communities across multiple sites along the colorectum.
The study uncovered striking spatial heterogeneity in the mucosal microbiome. Using unsupervised clustering, the researchers identified five distinct mucosal microbial communities, or "metacommunities" (MC), that varied significantly between left- and right-sided cancers. More than 95% of biopsy samples from left-sided CRC patients belonged to a single metacommunity (MC-D), whereas right-sided cancers were split almost equally between two different metacommunity types (MC-D and MC-E). Patients with left-sided tumors showed an enrichment of Fusobacterium species, while right-sided cancers harbored a more diverse polymicrobial network involving Bacteroidaceae, Lachnospiraceae, and Peptostreptococcaceae. Notably, the rectum harbored a tumor microbiome distinctly different from that at other anatomic sites. The researchers also observed that cancerous tumors extensively altered the mucosal microbiome well beyond the tumor site itself, affecting nearly the entire colorectum—a phenomenon the authors describe as a "metagenomic field effect."
"The microbiome is not uniform across the colorectum—it changes with geography, and so does its relationship with cancer," the authors said. "We were surprised to find that left-sided tumors are dominated by a single microbial community type, while right-sided tumors show a much more divided microbial landscape. This tells us that the microbial environment of a tumor is intimately linked to its location, and that location-specific microbial signatures could potentially be used to guide treatment decisions."
The findings have significant clinical implications. If the mucosal microbiome differs consistently between left- and right-sided cancers, it may be possible to develop site-specific microbial biomarkers for early detection or risk stratification. The observed "metagenomic field effect" also suggests that microbiome changes extend beyond the tumor, potentially enabling detection through non-invasive sampling of nearby normal mucosa. Furthermore, because left- and right-sided CRCs respond differently to therapies such as anti-EGFR treatments, understanding how the tumor microbiome varies by location could inform personalized treatment strategies. The authors note that these microbiome differences may contribute to the distinct tumor microenvironments that underlie differential therapeutic responses, though this hypothesis requires validation in future studies.
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References
DOI
10.20892/j.issn.2095-3941.2025.0846
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0846
Funding Information
This work was supported by Agriculture Biobreeding Major Project (2023ZD0405503) and Fundamental Research Funds for the Central Universities (SWU-XDJH202311 and SWU-KQ22061).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 12.4), with all full texts freely visible to clinicians and researchers all over the world (http://www.ncbi.nlm.nih.gov/pmc/journals/2000/).