Gut Microbiome-Mediated Genetic and Epigenetic Alterations in Colorectal Cancer: Population-Specific Insights

Colorectal cancer (CRC) remains a major global challenge, with growing attention to its pathogenesis as mediated by the gut microbiome and epigenetic regulation. Despite therapeutic progress, clinical management remains difficult. CRC accounts for ~10% of cancers and is the second leading cause of cancer death worldwide. Romania bears a substantial burden, with many diagnoses at advanced stages. Etiology-Integrated Genetic, Environmental, and Microbial Determinants. Hereditary syndromes explain 10-15% of cases; most are sporadic, with hypermutated MSI/POLE (~15%), non-hypermutated chromosomal instability (~85%), and a CpG island methylator phenotype (~20%). GWAS implicate loci near SMAD7, TCF7L2, and CDH1; in Romania, SMAD7 rs4939827 associates with risk. Lifestyle exposures-high red/processed meat, low fiber, adiposity, alcohol, and smoking-shape susceptibility. Microbiome-Epigenome Interactions. Dysbiosis promotes carcinogenesis via genotoxins (e.g., colibactin), hydrogen sulfide, activation of NF-κB/STAT3, barrier disruption, and epigenetic remodeling of DNA methylation and microRNAs. Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and pks⁺ Escherichia coli exemplifies these links. Population-Specific Risk-Romania within Lifestyle-Microbiome Evidence. Incidence is rising, including early-onset disease. Romania lacks CRC-specific microbiome datasets. However, metabolic cohorts show loss of butyrate producers, enrichment of pathobionts, and SCFA imbalance-patterns that mirror European CRC cohorts-and exhibit regional heterogeneity. Beyond Fusobacterium nucleatum. Additional oncobacteria shape tumor biology. Peptostreptococcus stomatis activates integrin α6/β4→ERBB2-MAPK and can bypass targeted inhibitors, while Parvimonas micra enhances WNT/β-catenin programs and Th17-skewed immunity. Together, these data support a systems view in which microbial cues and host epigenetic control jointly drive CRC initiation, progression, metastasis, and treatment response.