This gene knock-out study investigates the role of TLR4 in intestinal inflammation and microbiota recognition.

Evidence obtained from gene knock-out studies support the role of TLR4 in intestinal inflammation and microbiota recognition. Increased epithelial TLR4 expression is observed in patients with inflammatory bowel diseases (IBD). However, little is known of the effect of increased TLR4 signaling on intestinal homeostasis. Here, we examined the effect of increased TLR4 signaling on epithelial function and microbiota by using transgenic villin-TLR4 mice which over-express TLR4 in the intestinal epithelium. Our results revealed that villin-TLR4 mice are characterized by increased density of mucosa associated bacteria and bacterial translocation. Furthermore, increased epithelial TLR4 signaling was associated with impaired epithelial barrier and ion transport function, altered expression of anti-microbial peptide genes, and altered epithelial cell differentiation. The composition of the gut microbiota differed between villin-TLR4 and WT littermates. Interestingly, WT mice co-housed with villin-TLR4 mice displayed increased susceptibility towards acute colitis relative to single-housed WT mice. The results of this study suggest that epithelial TLR4 expression shapes the microbiota and affects the functional properties of the epithelium. The changes in the microbiota induced by increased epithelial TLR4 signaling are transmissible and colitogenic. Together, our findings imply that host innate immune signaling can modulate intestinal bacteria and ultimately the host susceptibility towards colitis.