Animal studies have provided a wealth of information with respect to normal and abnormal host-microbial relationships. A number of models of IBD have been described over the last decade in which chronic intestinal inflammation occurs spontaneously in mice with a specific genetic background or genetically manipulated (i.e., transgenic, knockout) mice. The importance of indigenous luminal bacteria in the development of intestinal inflammation has been revealed in those mice [27, 52, 53]. Interestingly, a sub-strain of C3H/HeJ mice develop spontaneous colitis which is dependent on luminal bacteria . At least in this model, TLR4 is not necessary for the development of colitis. Intestinal epithelial cells from IL-2-knockout mice in which colitis is initiated by exposure to commensal bacteria have shown changes in TLR responsiveness during the development of colitis, characterized by augmented TLR2 responsiveness and concomitant reduction in TLR4 responsiveness . We and others have shown that MyD88-/- and TLR4-/- mice have increased signs of colitis compared with wild-type littermates in response to DSS [46, 47]. A comparison of the histology demonstrated that TLR4-/- and MyD88-/- mice have significantly fewer neutrophils in the lamina propria and submucosa compared with control mice. The cause for decreased neutrophils in the intestine is due to diminished chemokine expression by lamina propria macrophages. The consequences of the decreased neutrophil recruitment include Gram-negative bacterial translocation to mesenteric lymph nodes in knockouts but not wild-type mice. These data demonstrate that TLR signaling in response to the presence of bacteria in the lamina propria following epithelial injury is critical for elimination of bacteria before they disseminate. The increase in bacterial dissemination is made worse by the decrease in intestinal epithelial proliferation in these mice.
On the other hand, other data implicating TLRs in the generation of a regulatory response to the commensal flora relate to the observation that oral or systemic administration of bacterial DNA ISS-ODN or CpG ODN, the ligand for TLR9, ameliorates inflammation in several animal models of colitis  but not in TLR9-/-mice . The balance however between the requirement of TLR signaling to initiate and sustain acute and chronic inflammation versus its role in healing of the epithelium is probably contextual and depends on other factors as well as the nature of the injury.
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