Gut microbiota alterations and their association with tumorigenic pathways in colorectal cancer: insights from a pooled analysis of 109 microbiome datasets

Background: Colorectal cancer (CRC) is a significant global health burden, ranking amongst the top causes of cancer-associated mortality. Emerging evidences implicate gut microbiota as a prominent mediator of cell signalling, immune, and metabolic pathways in the pathophysiology of CRC. Methods: We analysed 16S rRNA amplicon sequencing data (PRJEB7774) from faecal samples of 46 CRC patients and 63 healthy controls to assess shifts in microbial composition, diversity, and biomarker taxa. Differential abundances of microbiota were determined using Linear Discriminant Analysis Effect Size (LEfSe) and Random Forest (RF) models. Host-microbiota interactions were explored using the Human Microbiome Affect the Host Epigenome (MIAOME) and Host Genetic and Immune Factors Shaping Human Microbiota (GIMICA) databases, with key host genes validated using Gene Expression Profiling Interactive Analysis (GEPIA) and The Cancer Genome Atlas (TCGA) datasets. Functional enrichment analyses were performed to uncover associated biological processes and pathways. Results: CRC samples exhibited significantly reduced alpha diversity and distinct beta diversity profiles, compared to controls. Taxonomic profiling revealed an enrichment of potentially pathogenic bacteria, including Prevotella copri, Methanobrevibacter smithii, Bacteroides eggerthii, and Dialister invisus, and depletion of beneficial microbes such as Bifidobacterium animalis and Ruminococcus sp. Predicted host-microbe interactions highlighted associations between key microbial biomarkers and inflammation-related genes (CD44, CXCL8, DUSP16, FOXP3, IFNGR2, IL18), all significantly overexpressed in CRC samples. Enrichment analyses linked these genes to immune pathways, including NF-κB, TLR and cytokine signalling. Conclusions: Our study reveals a distinct gut microbiota signature in CRC and suggests functional interactions between microbial dysbiosis and host inflammatory responses. These findings emphasize the potential of microbiota-based interventions and microbial metabolites as adjunctive strategies for the management of CRC.