Enterohepatic Helicobacter species are emerging infectious disease agents. Infection of the enterohepatobiliary tract of several mammals by these bacteria results in various pathological disorders. The adaptation of Helicobacter hepaticus to human factors such as bile was investigated using proteomics and transcriptomics. Ninety-one different proteins were identified in the responses of H. hepaticus to human, porcine and bovine bile. These proteins participate in several key cellular processes including DNA replication; protein transcription, translation and folding; oxidative stress response; motility; virulence; and metabolism. In particular, the bacteria deployed several strategies such as inhibition of the TCA cycle and the electron transport chain as well as iron sequestration to ensure control of the levels of hydroxyl radicals. The responses of human HEp-2 and Huh7-derived cell-lines to H. hepaticus and Helicobacter bilis, respectively, were also investigated.