E. coli K12 as a dysbiosis-driven catalyst in colorectal cancer: In silico identification of cross-species protein-protein interactions

Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. Emerging evidence suggests that gut microbiota plays a crucial role in the development and progression of CRC, with dysbiosis being strongly associated with increased CRC risk. Certain bacteria, such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, and colibactin producing Escherichia coli, are enriched in CRC patients and are known to produce genotoxins that induce DNA damage and promote carcinogenesis. Specific strains of Escherichia coli (E.coli) are strongly linked to CRC development. With this insight, this study investigates the potential role of E.coli K12, a common commensal strain, as a catalyst in colorectal carcinogenesis through a comprehensive in silico workflow combining subtractive proteomics, host-microbe interaction prediction, molecular docking, and molecular dynamics (MD) simulations. We employed a subtractive proteomics approach to identify E.coli K12 proteins that are non-homologous with human proteins, aiming to pinpoint potential targets involved in CRC. The analysis identified unique E.coli K12 outer membrane proteins that interact with human colon proteome. Subsequent molecular docking studies and MD simulations revealed specific host-microbe interactions that may disrupt normal cellular functions, thereby contributing to a tumorigenic microenvironment. Key E.coli K12 proteins interacting with human colon proteins implicated in carcinogenesis were identified. Complexes such as SLC16A1–UgpA, FLNC–GspO, ADH1A–YgbN, and KARS–YajC exhibited stable dynamics (RMSD <2.5 Å, consistent hydrogen bonding), suggesting potential disruption of host metabolism and cytoskeletal integrity. The findings provide new insights into how commensal E.coli may contribute to CRC under dysbiotic or immunocompromised conditions.