Human Colon Cancer-Derived Clostridioides difficile Strains Drive Colonic Tumorigenesis in Mice

Defining the complex role of the microbiome in colorectal cancer and the discovery of novel, protumorigenic microbes are areas of active investigation. In the present study, culturing and reassociation experiments revealed that toxigenic strains of Clostridioides diffi - cile drove the tumorigenic phenotype of a subset of colorectal cancer patient-derived mucosal slurries in germ-free ApcMin/ + mice. Tumorigenesis was dependent on the C. diffi cile toxin TcdB and was associ-ated with induction of Wnt signaling, reactive oxygen species, and protumorigenic mucosal immune responses marked by the infi ltration of activated myeloid cells and IL17-producing lymphoid and innate lymphoid cell subsets. These fi ndings suggest that chronic colonization with toxigenic C. diffi cile is a potential driver of colorectal cancer in patients. SIGNIFICANCE: Colorectal cancer is a leading cause of cancer and cancer-related deaths worldwide, with a multifactorial etiology that likely includes procarcinogenic bacteria. Using human colon cancer specimens, culturing, and murine models, we demonstrate that chronic infection with the enteric patho-gen C. difficile is a previously unrecognized contributor to colonic tumorigenesis.