The gastrointestinal tract is the largest mucosal surface in our body. It houses diverse microorganisms that collectively form the commensal microbial community. The security of this community is kept by host-microbial interactions and is violated by foreign pathogens that induce local as well as systemic pathology. In most cases, gastrointestinal infections are caused by Gram-negative enteropathogens, which trigger host immune responses through the TLR4 signaling pathways. Although TRIF is one of the major pathways downstream of TLR4, very little is known about how the TRIF pathway contributes to intestinal defense against pathogenic infection. Recently, we reported a unique role of TRIF signaling in host response to an enterophathogen Yersinia enterocolitica, which consisted of IFN-β induction from regional macrophages followed by activation of NK cells in the mesenteric lymph nodes. In this addendum, we show distinct roles for TRIF-dependent host response in intestinal vs. systemic infection with Gram-negative enterophathogens.