In homeostasis, it is likely that due to the mucus layer, which poses a diffusion barrier, only low concentrations of MAMPs reach the epithelial layer [59]. At these low, MAMPs seem not to elicit a proinflammatory response but still impact the epithelial cells in several ways. Mice deficient for either TLR2, 4, 5, and 9, the TLR-pathway mediator MyD88 or the NLRP6 inflammasome are highly susceptible to experimentally induced colitis [116–119]. Mice devoid of TLR2 or MyD88 show disrupted tight junctions, more apoptotic epithelial cells and higher barrier permeability [116]. NLRP6 deficiency leads to reduced mucus secretion [61]. Mice devoid of NOD2 show higher epithelial cell death rates after treatment with doxorubicin, indicating that they are more susceptible [67]. In line with this observation, patients with mutations in the NOD2 gene are predisposed to develop IBDs especially CD [120]. While these studies clearly point to the importance of innate immune signalling for epithelial homeostasis, it is unclear whether the observed impact is due to the innate immune signalling in epithelial cells or in professional immune cells. To disentangle the interplay of professional immune cells and epithelial cells, several studies have used epithelium-specific knockouts, or more recently, epithelial organoids. In mouse models, none of the epithelial-specific deletions of PRRs leads to spontaneous inflammation. However, mice with epithelial-specific knockout of MyD88 are more susceptible to experimental colitis and show severe barrier disruption, impaired goblet and Paneth cell responses [121] and reduced production of mucin and antimicrobial peptides [121, 122]. Small intestinal organoids do not mount an inflammatory response to several purified PRR ligands [55], although this cannot be generalized and depends on the species, location and age of the tissue the organoids are generated from [44, 45]. The absence of a spontaneous inflammatory phenotype in epithelial cell-specific PRR knockout models does support the hypothesis that factors other than a general inflammatory response of the epithelium have an impact on epithelial homeostasis. For example, stimulation with the NOD2 agonist muramyl dipeptide (MDP) increased the number of organoids growing out of isolated stem cells, indicating that the innate immune signalling supported survival of the stem cells [67, 84]. Furthermore, data from mice highlight the importance of the anti-apoptotic effects of NF-κB signalling in response to other stimuli, such as TNF-α [123]. Interestingly, in humans, polymorphisms in innate immune genes including NOD2 and TLR4 are associated with an increased risk to develop IBD [124] and blockage of TNF-α is currently the most efficacious treatment for IBD in some patients (reviewed in [125]). A picture emerges, in which a low level of innate immune stimulation is important for mucus secretion, barrier integrity and epithelial cell survival. Its impairment may allow translocation of intestinal bacteria from the lumen into the subepithelial tissue, leading to inflammation.