Toll-like receptor (TLR) 4 is a pattern-recognition receptor (PRR) that recognizes lipopolysaccharide (LPS) from Gram-negative bacteria as a pathogen-associated molecular pattern (PAMP). TLR4 signaling activates the MyD88 (myeloid differentiation primary-response protein 88)- and TRIF (TIR domain-containing adaptor protein-inducing interferon-β)-dependent pathways to induce the production of proinflammatory cytokines and interferons (IFNs), respectively1–4. Since the discovery of TLR4 as a receptor for LPS, several non-LPS TLR4 ligands, which are mostly derived from microbes, have been identified and their roles in TLR4-mediated innate immune responses have been proposed5–8. During the onset of intestinal inflammation in response to PAMPs from colon and possibly non-LPS TLR4 ligands from diet, TLR4 signaling is likely to play an important role in intestinal epithelial cells (IECs) and immune cells, including, macrophages and dendritic cells. IFN and/or inflammatory cytokines produced in the intestine upon stimulation by these PAMPs would systemically act on virus-infected cells locally and/or far away from sites where IFN signaling was initially induced. However, TLR4 signaling in the small intestine is not well characterized9.