Abstract
Enterohepatic Helicobacter species infect the intestinal tracts and biliary trees of various mammals, including mice and humans, and are associated with chronic inflammatory diseases of the intestine, gallstone formation, and malignant transformation. The recent analysis of the whole genome sequence of the mouse enterohepatic species Helicobacter hepaticus allowed us to perform a functional analysis of bacterial factors that may play a role in these diseases. We tested the hypothesis that H. hepaticus suppresses or evades innate immune responses of mouse intestinal epithelial cells, which allows this pathogen to induce or contribute to chronic inflammatory disease. We demonstrated in the present study that the innate immune responses of intestinal epithelial cells to lipopolysaccharide (LPS) via Toll-like receptor 4 (TLR4) and to flagellin-mediated activation via TLR5 are reduced by H. hepaticus infection through soluble bacterial factors. In particular, H. hepaticus lysate and the soluble component LPS antagonized TLR4- and TLR5-mediated immune responses of intestinal epithelial cells. H. hepaticus lysate and LPS inhibited development of endotoxin tolerance to Escherichia coli LPS. Suppression of innate immune responses by H. hepaticus LPS thus may affect intestinal responses to the resident microbial flora, epithelial homeostasis, and intestinal inflammatory conditions.