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Human colon cancer-derived Clostridioides difficile strains drive colonic tumorigenesis in mice


Drewes JLJulia L , Chen JJie , Markham NONicholas O , Knippel RJReece J , Domingue JCJada C , Tam AJAda J , Chan JLJune L , Kim LLana , McMann MMadison , Stevens CCourtney , Dejea CMChristine M , Tomkovich SSarah , Michel JJohn , White JRJames R , Mohammad FFuad , Campodonico VLVictoria L , Heiser CNCody N , Wu XXinqun , Wu SShaoguang , Ding HHua , Simner PPatricia , Carroll KKaren , Shrubsole MJMartha J , Anders RARobert A , Walk STSeth T , Jobin CChristian , Wan FFengyi , Coffey RJRobert J , Housseau FFranck , Lau KSKen S , Sears CLCynthia L . Cancer discovery. 2022 6 9; ().


Defining the complex role of the microbiome in colorectal cancer (CRC) and the discovery of novel, pro-tumorigenic microbes are areas of active investigation. In the present study, culturing and reassociation experiments revealed that toxigenic strains of Clostridioides difficile drove the tumorigenic phenotype of a subset of CRC patient-derived mucosal slurries in germ-free ApcMin/+ mice. Tumorigenesis was dependent on the C. difficile toxin TcdB and was associated with induction of Wnt signaling, reactive oxygen species, and pro-tumorigenic mucosal immune responses marked by infiltration of activated myeloid cells and interleukin-17 (IL-17)-producing lymphoid and innate lymphoid cell subsets. These findings suggest that chronic colonization with toxigenic C. difficile is a potential driver of CRC in patients.