Intestinal microbiota modulate ROS‐dependent epithelial cytoprotection through Nrf2

The gut microbiota is essential for normal mucosal physiology and reparative function; yet the molecular basis for these processes is not known. Recent studies have suggested that bacterial‐host crosstalk is mediated in part by the rapid cellular generation of reactive oxygen species (ROS). In this study we describe activation of the Nrf2 signaling pathway and consequent ARE (Antioxidant Response Element)‐dependent cytoprotective antioxidant gene expression in response to microbial‐induced cellular ROS production in both murine and Drosophila models. The cytoprotective function of the Nrf2/ARE pathway is well established in many tissues, but pathway stimulation by gut bacteria is largely unrecognized. We find striking ARE‐dependent gene upregulation in conventionalized (colonized) germ‐free animals. Commensal bacteria, or constitutive Nrf2/ARE pathway activation, protects intestinal epithelia from oxidative and other exogenous stresses. However, compared to germ‐free animals, conventional animals exhibit higher tonic levels of redox responsive genes, the function of which may be to maintain the basal cytoprotective response within the mucosa. Together, these data show that the Nrf2 signaling pathway mediates gut microbiota modulation of intestinal epithelial homeostasis and cytoprotection.