TLR-independent intestinal epithelial TRAF6 signaling protects mice from DSS-induced colitis

Multiple studies in mice demonstrated that the gut microbiota modulates host susceptibility to intestinal inflammation. However, the cell types and the signaling pathways orchestrating this bacterial regulation of intestinal homeostasis remain poorly understood. Here we investigated the function of epithelial TLR responses in the Dextran Sodium Sulfate (DSS)-induced mouse model of colitis. Blocking epithelial TLR signaling by simultaneous deletion of MyD88 and TRIF specifically in intestinal epithelial cells (IECs) did not alter DSS-induced colitis severity, unequivocally showing that microbiota-driven epithelial TLR signaling does not influence inflammation in this model. In contrast, mice lacking the downstream ubiquitin ligase TRAF6 in IECs showed exacerbated DSS-induced inflammatory responses that were driven by the gut microbiota and that resulted in the development of chronic colitis. Together, these results reveal that epithelial TRAF6-dependent but MyD88/TRIF- and thus TLR-independent signaling pathways are critical for preventing propagation of DSS-induced colon inflammation by the gut microbiota.