There is an order of magnitude more bacterial cells in the colon than human cells in the body. Our laboratory became interested in how intestinal bacteria were recognized by the innate immune system. We reasoned that in disorders such as inflammatory bowel disease, where the patient is afflicted by chronic intestinal inflammation, aberrant recognition of bacteria could be playing a role. Toll-like receptors (TLRs) are pattern-recognition receptors that recognize molecular patterns expressed by broad categories of microbes. As a model for how TLRs are regulated in the intestine we have focused our efforts on TLR4. TLR4 recognizes lipopolysaccharide (LPS) derived from the wall of Gram-negative bacteria. We found that TLR4 and its co-receptor MD-2 were expressed in the epithelial cells lining the colon but their expression was normally low. IFN-gamma increases expression of TLR4 and MD-2 through transcriptional activation of their promoters. We have uncovered a critical role for TLR4 in repair of epithelial injury. If animals deficient in TLR4 undergo intestinal injury, they cannot induce COX-2 or EGF family growth factors, and have blunted proliferation. We have also found that TLR4 is required for development of colitis-associated neoplasia. Patients with ulcerative colitis and cancer have increased expression of TLR4 in their tumors. We are now studying how TLR4 plays a role in sporadic colorectal cancer in which inflammation may also play a role. By understanding these mechanisms, we may be able to manipulate TLR signaling to prevent or treat colitis-associated cancer in patients with inflammatory bowel disease.