The discovery of an inner mucus layer normally impervious to bacteria has changed our way of understanding the interaction between commensal bacteria and the host epithelial cells. This inner colon mucus layer is rapidly renewed and converted into the outer mucus layer by host controlled endogenous proteolytic processing. The mucus characteristics esteem from the properties of the main protein component of these layers, the MUC2 mucin. This forms an enormously large net-like structure that builds the laminated inner mucus layer that largely acts as a size exclusion filter excluding bacteria. In the absence of MUC2 mucin, there is no inner mucus layer and bacteria reach the epithelial cell surface, penetrate the crypts and are also found inside epithelial cells, something that leads to severe inflammation. Other mouse models that spontaneously develop colitis due to different defects, like an absent ion channel (Nhe3) or immunological mediators (Tlr5, IL-10), all also have a defective inner colon mucus layer. Human patients with active ulcerative colitis have this layer penetrable to bacteria and beads the size of bacteria. Some of the ulcerative colitis patients in remission have a normal mucus layer whereas others have a penetrable inner mucus layer. Together, this suggests that the inner mucus layer and its integrity is important for the protection of the colon epithelium and inhibiting activation of the immune system as in ulcerative colitis.