Abstract
The microbes in the gastrointestinal tract are separated from the host by a single layer of intestinal epithelial cells (IECs) that plays pivotal roles in maintaining homeostasis by providing a physical and immunological barrier to potential pathogens. A disruption in homeostasis could lead to an abnormal host response towards the microbiota and an imbalance in the microbial community, termed dysbiosis, eventually triggering chronic inflammation, as seen in patients with inflammatory bowel disease (IBD). One epithelial-driven innate immune mechanism that preserves homeostasis by regulating the host-microbe crosstalk involves the extracellular release of hydrogen peroxide (H2O2), a type of reactive oxygen species (ROS) that is produced via epithelial dual oxidase 2 (DUOX2). We demonstrate that murine and human dysbiosis induces DUOX2-mediated H2O2 production in IECs. We also found that DUOX2 was exquisitely dependent on TLR4 signaling and mediated the production of epithelial H2O2. TLR4-dependent tumorigenesis required the presence of DUOX2 and a microbiota. Furthermore, TLR4-shaped mucosa-associated microbiota transferred to wild-type germ-free mice caused increased production of H2O2 and tumorigenesis. Taken together, these data suggest that the local milieu imprints the mucosal microbiota and imbues it with pathogenic properties demonstrated by enhanced epithelial ROS and increased development of colitis-associated tumors. Furthermore, the microbiota and epithelial-released ROS are necessary co-conspirators in the development of colorectal cancer. Finally, we demonstrate that a low-fat high fiber diet improved dysbiosis, enhanced quality of life, and decreased biochemical markers of inflammation in patients with ulcerative colitis, a type of IBD. Future therapeutic strategies in IBD will require a two-pronged strategy involving the microbiota and the host inflammatory response, such as epithelial ROS, to reduce the risk of dysplasia in colitis patients.