Alcohol accelerates the development of esophageal squamous cell carcinoma through elevated Gram-negative bacteria in peripheral circulation.

Alcohol consumption is intricately linked to the incidence of esophageal squamous cell carcinoma (ESCC). This study comprehensively investigates the role of alcohol-induced microbial alterations in ESCC progression. A retrospective analysis of 328 patients demonstrated that alcohol consumption markedly increases the risk of ESCC and boosts the expression of the proliferation marker Ki67. Patients with alcohol-related ESCC exhibited substantially higher blood microbiome diversity, characterized by the dominance of Gram-negative bacteria, and elevated serum lipopolysaccharides (LPS) levels. In a mouse model, alcohol consumption not only augmented tumor burden but also compromised gut barrier integrity, facilitating bacterial translocation. Significant elevations in Gram-negative bacteria, such as Bacteroidales in the blood and Escherichia coli in esophageal tissues, were observed. Mechanistically, alcohol and LPS synergistically activated pro-inflammatory pathways, including TNF, TLR, NF-κB, and MAPK, which fueled ESCC cell proliferation. Meanwhile, LPS triggered necroptosis in normal esophageal epithelial cells. These findings reveal that alcohol-induced microbial dysbiosis in peripheral circulation and LPS-mediated inflammatory responses form a novel pathogenic mechanism in ESCC. Targeting Gram-negative bacteria and LPS could provide a promising therapeutic strategy for managing alcohol-related ESCC. Further research is urgently warranted to explore the interaction between microbial changes and the tumor microenvironment.