Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths worldwide. While overall incidence is declining, cases of early-onset CRC (EO CRC) in patients younger than 50 years are rising. It has been suggested that the gut microbiome might play an important role in EO-CRC initiation and progression. However, whether the microbiome composition indeed differs between late-onset CRC (LO CRC) and EO CRC and which specific pathogenic species are involved in development of the latter, currently remain a matter of debate.
To address this, we collected paired tumor and adjacent normal tissue from EO CRC (n=7) and LO CRC (n=10) patients and comprehensively characterized both the microbiome and host transcriptome. 16S-rRNA sequencing revealed no significant differences in diversity or community composition between EO-CRC and LO CRC, nor between tumor and normal tissue, although CRC-associated species were detected in all samples. In contrast, bulk RNA sequencing identified clear transcriptomic differences between tumor and normal tissues, while age had little impact, supporting a tumor- rather than age-specific response. To test functional impact, we established a cell culture model of human colon epithelial cells (HCoEpiCs) that allows co-cultivation with the anaerobic, CRC-associated bacteria. Cell integrity and polarization were validated by microscopy and permeability assays. Transcriptomic and proteomic profiling of HCoEpiCs with different CRC-associated bacteria identified Bacteroides fragilis, Fusobacterium nucleatum, Prevotella intermedia, and Gemella morbillorum as inducers of alterations linked to inflammation and cancer hallmarks. In contrast, Parvimonas micra, Peptostreptococcus stomatis, Solobacterium moorei, and the probiotic Lactocaseibacillus casei had only minor effects on the cells and clustered with the untreated control.
Taken together, these findings demonstrate that specific CRC-associated bacteria drive an oncogenic phenotype in colon epithelial cells. It remains unclear why only certain species trigger such effects, and future studies should dissect whether these are mediated by direct or indirect host–bacteria contact.