Colorectal Tumour Mucosa Microbiome Is Enriched in Oral Pathogens and Defines Three Subtypes That Correlate with Markers of Tumour Progression

Simple Summary: Dysbiosis of the gut microbiome may contribute to the heterogeneity of colorectal cancer from phenotypic, prognostic and response to treatment perspectives. We analysed CRC microbiome by 16S rRNA gene sequencing of paired tumourmucosa, adjacent visually normalmucosa and stool swabs of 178 patients with stage 0-IV CRC. We observed that tumour mucosa is dominated by pathogenic bacteria of oral origin and proposed a CRC tumour microbiome subtyping system. The subtypes and tumour mucosa genera were associated with prognostic clinical covariates (tumour grade, localisation, TNM, BRAF mutation and MSI). In contrast, changes in the stool microbiome were associated with lymph node involvement and the presence of synchronous metastases. We discovered new associations between microorganisms and CRC and clinical parameters. Our study represents a step forward in understanding the role of the microbiome and its interactions with factors involved in tumour progression, and it opens novel avenues for exploring new treatments and biomarkers. Long-term dysbiosis of the gut microbiome has a significant impact on colorectal cancer (CRC) progression and explains part of the observed heterogeneity of the disease. Even though the shifts in gut microbiome in the normal-adenoma-carcinoma sequence were described, the landscape of the microbiome within CRC and its associations with clinical variables remain under-explored. We performed 16S rRNA gene sequencing of paired tumour tissue, adjacent visually normal mucosa and stool swabs of 178 patients with stage 0-IV CRC to describe the tumour microbiome and its association with clinical variables. We identified new genera associated either with CRC tumour mucosa or CRC in general. The tumour mucosa was dominated by genera belonging to oral pathogens. Based on the tumour microbiome, we stratified CRC patients into three subtypes, significantly associated with prognostic factors such as tumour grade, sidedness and TNM staging, BRAF mutation and MSI status. We found that the CRC microbiome is strongly correlated with the grade, location and stage, but these associations are dependent on the microbial environment. Our study opens new research avenues in the microbiome CRC biomarker detection of disease progression while identifying its limitations, suggesting the need for combining several sampling sites (e.g., stool and tumour swabs).