Colorectal cancer (CRC) is a leading global health burden, ranking as the third most common malignancy and the second most deadly cancer worldwide. While bacterial dysbiosis in the gut has long been implicated in colorectal carcinogenesis, the contribution of viruses—the virome—remains relatively understudied.
Addressing this gap, this study has provided the first integrated mucosal virome-transcriptome landscape of colorectal polyps, the precursors of CRC, offering new insights into viral-host interactions at this early disease stage.
The study enrolled 41 patients undergoing colonoscopy for colorectal polyps. For each participant, matched mucosal biopsies were obtained from the polyp and an adjacent normal site located 3–4 cm away.
Using comprehensive multi-omics profiling, the investigators conducted whole-transcriptome and microRNA sequencing on one sample pair, and viral metagenomic sequencing on another, following enrichment of virus-like particles, aming to delineate the interplay between the host transcriptome and mucosal virome in the adenoma–carcinoma sequence (ACS), the dominant pathway through which most sporadic CRCs arise.
Transcriptomic reprogramming in polyp tissues
Transcriptomic profiling revealed extensive alterations in host gene expression between polyp and adjacent normal tissues. A total of 4628 differentially expressed RNAs (DERs) and 256 differentially expressed microRNAs (DEMs) were identified. Among these, the most upregulated genes included MMP7, KLK6, FEZF1-AS1, and SLCO1B3, whereas AQP8, CA1, and SLC26A3 were markedly downregulated—many of which have been previously linked to CRC development and epithelial dysfunction.
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Pathway enrichment analysis revealed that these transcriptomic shifts were predominantly associated with metabolism and absorption, neurotransmission, and cell signaling, highlighting the metabolic and neuroepithelial remodeling characteristic of early tumorigenesis. Notably, the WNT and MAPK signaling pathways, both established oncogenic drivers, were among the most enriched.
A dysbiotic mucosal virome emerges
Beyond host transcriptional alterations, the mucosal virome displayed significant compositional changes. The mucosal viral community of colorectal polyps was dominated by Caudoviricetes (54.5%), followed by Retroviridae (14.2%) and Poxviridae (7.9%), though overall viral richness and evenness were markedly reduced compared with adjacent normal mucosa.
Principal coordinate analyses revealed distinct clustering between polyp and normal mucosal viromes, confirming significant beta diversity differences (PERMANOVA p=0.009). Importantly, the study identified specific viral taxa associated with the polyp state: Poxviridae, Retroviridae, and BeAn 58058 virus were significantly enriched, while Caudoviricetes sp., a bacteriophage class, was depleted.
Viral–host interaction networks
Network analyses unveiled 117 significant correlations between viral taxa and host gene or microRNA expression. Two distinct clusters emerged:
(1) Potentially protective viruses — Caudoviricetes sp. abundance was negatively correlated with genes upregulated in polyps, particularly those involved in Wnt signaling, epithelium morphogenesis, and angiogenesis. This suggests a possible protective role of Caudoviricetes in maintaining mucosal homeostasis and suppressing oncogenic signaling.
(2) Potentially oncogenic viruses — In contrast, Poxviridae, Retroviridae, and BeAn 58058 virus were negatively correlated with genes downregulated in polyps, including MAPK8IP2 (pro-apoptotic JNK signaling) and CD177P1 (innate immune activation). The authors propose that these viruses may suppress tumor-suppressive and immune pathways, facilitating early neoplastic changes.
These findings align with prior evidence that certain eukaryotic viruses, including John Cunningham virus, may promote colorectal tumorigenesis by inactivating key tumor suppressors such as p53 and Rb.
Implications for cancer biology and clinical research
This integrative study is the first to demonstrate coordinated alterations in both DNA and RNA mucosal viromes and human transcriptomes within colorectal polyps. The discovery that specific viruses are associated with oncogenic or tumor-suppressive transcriptomic profiles suggests that viral activity might not be a mere bystander phenomenon but an active contributor to early neoplastic transformation.
From a clinical perspective, the mucosal virome could emerge as a biomarker source for identifying high-risk polyps or early CRC lesions. Moreover, if causal mechanisms are established, modulation of the mucosal virome—through antivirals, probiotics, or bacteriophage therapies—could represent a novel preventive or therapeutic avenue.
Strengths and limitations
Compared to prior mucosal virome studies in CRC, the current work introduces several methodological strengths. It employed a rigorous four-tool viral classification pipeline (CAT, VirSorter2, geNomad, and Kraken2) with cross-validation, improving specificity and reducing false positives. Statistical modeling via MaAsLin2 allowed adjustment for confounders such as age and sex, enhancing robustness.
However, the study’s descriptive design precludes causal inference. The absence of healthy and carcinoma samples limits the ability to map the full adenoma–carcinoma trajectory. Additionally, the predominance of large adenomas in the cohort may restrict generalizability to smaller lesions. Despite these constraints, the integration of multi-omics data sets a new standard for mucosal virome research.
In conclusion, this pioneering multiomics study reveals that the mucosal DNA and RNA virome of colorectal polyps is markedly altered and intricately linked to host gene and microRNA expression. Enrichment of Poxviridae, Retroviridae, and BeAn 58058 virus alongside depletion of Caudoviricetes sp. suggests that viral dysbiosis may modulate oncogenic and tumour-suppressive pathways in early colorectal tumorigenesis. These findings expand the understanding of CRC initiation and highlight the mucosal virome as a promising target for future diagnostic and therapeutic strategies.
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