Cigarette smoke induces colon cancer by regulating the gut microbiota and related metabolites

Abstract The causal relationship between smoking and colorectal cancer (CRC) remains unclear. In this study, a cigarette smoke–exposed mouse model demonstrated that smoking significantly increased CRC incidence by inducing gut microbiota dysbiosis and altering related metabolites. Smoke exposure reduced beneficial bacteria (e.g., Lactobacillus), increased harmful bacteria (e.g., Firmicutes and Clostridium), elevated metabolites such as histamine, and suppressed the tumor suppressor genes PARG, CPT2, and ALDH1A1, thereby promoting tumor development. Functional assays in CRC cell lines further confirmed that CPT2 knockdown enhanced malignant phenotypes, including proliferation, migration, and invasion. Clinical analysis showed that these genes were markedly downregulated in smoking-related CRC patients, with strong diagnostic value (AUC > 0.8). Conclusion Smoking promotes CRC by inducing gut microbiota dysbiosis, metabolic reprogramming, and suppression of tumor suppressor genes, particularly CPT2. These findings highlight the importance of smoking cessation in CRC prevention and provide potential biomarkers for early diagnosis and therapeutic intervention.