Our current thinking in this area based upon our work and the work of others is shown in Figure 3 , in which the intensity of TLR signaling within the epithelium varies depending upon the prevailing degree of systemic stress. Under basal conditions, epithelial-bacterial interactions that may occur via TLRs are likely to play roles in the regulation of processes that regulate barrier integrity, such as epithelial migration, proliferation, and apoptosis ( Figure 3A ). However, during states of systemic stress, such as hypoxia or remote infection, we submit that the extent of TLR signaling within the epithelium becomes exaggerated in response to PAMPS and DAMPS that are encountered. This "tips the balance" in favor of mucosal barrier disruption, and adversely affects mucosal repair while worsening mucosal injury ( Figure 3B ). The extent of inflammation that develops within the local microenvironment likely is compounded further by the contribution of TLR activation on leukocytes, and the release of proinflammatory molecules. Under conditions in which the balance of TLR signaling within the epithelium can be "tipped back" to a homeostatic state, mucosal inflammation may not develop. By contrast, when the extent of TLR signaling is persistent, we propose that a "feedforward" loop develops within the mucosa, resulting in persistent TLR signaling, cytokine release, and mucosal inflammation. The evaluation of the factors that maintain the degree of TLR signaling within the mucosa in the maintenance of homeostasis and the pathogenesis of disease is a topic of intensive investigation. 