Abstract
Abstract Inflammatory bowel disease (IBD) patients with poorly controlled intestinal inflammation are at an elevated risk for colorectal cancer (CRC). IBD patients exhibit intestinal dysbiosis with expanded proteobacteria such as E. coli. Here, we find that colonization with an E. coli isolated from the intestine of an IBD patient (E. coli 541-15) prevents tumorigenesis in an inflammation-related model of CRC. Colonization increased tumor infiltration of T helper 1 (Th1) cells, cytotoxic T lymphocytes (CTLs), and type 1 innate lymphoid cells (ILC1s) and decreased myeloid derived suppressor cells (MDSCs) and regulatory T cells (Tregs). Prevention of tumorigenesis occurs if colonization takes place before induction of inflammation. Intestinal inflammation in colitis models was ameliorated by E. coli 541-15 and this protection depended on IL-10 production by macrophages and IL-10 signaling to the intestinal epithelium. Colonization with E. coli 541-15 also promotes these IL-10 pathways if colonization occurs after tumorigenesis is established. However, this leads to worse CRC outcome, with increased tumor burden alongside decreased tumor infiltration of Th1 cells, CTLs, and ILC1s and increased MDSCs and Tregs. These results identify activation of an IL-10 signaling loop between immune cells and the intestinal epithelium after E. coli colonization that modulates intestinal inflammation and CRC. Importantly, these pathways can be protective or pathogenic depending on timing of activation. Supported by 2021 Ludwig Center Basic and Translational Research Award
Published Version
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