Role of the cag island in regulating gastric acidity. The conditions of a feedback system regulating both host response and bacterial transcription are potentially fulfilled by the interaction between cag⁺ strains and humans. Gastric acidity (represented by H⁺ ions) induces transcription of cagA (40). The type IV secretion system in the cag island (20) exports the cagA product into gastric epithelial cells, where it undergoes tyrosine phosphorylation (-P*) by a host-cell kinase (10). Although the exact role of the CagA phosphoprotein is not curreVntly known, signaling of the host by cag⁺ strains induces an increased leukocytic cellular response, as well as proinflammatory cytokines, including IL-1β (42). Because such inflammatory mediators can reduce gastric acidity, at least in part by their direct effects on the specialized epithelial cells involved in acid secretion, the H. pylori–host system shifts toward a new equilibrium value (lowered acidity, thus lowering cagA transcription). Thus all the components necessary for a simple “thermostat” have been refined. However, higher degrees of regulation can be added to this simple negative-feedback (homeostatic) model. Humans are polymorphic for IL-1β expression; thus host status helps determine the level of the equilibrium, which has important disease consequences (41). Genetic variation in the cag island may offer H. pylori populations one means to respond to long-term or local environmental changes. Because H. pylori are naturally competent, genetic determinants lost by some members of the population can be regained through transformation. DNA also may be exchanged via conjugation. Thus, metastable cag islands in a population of H. pylori cells may serve as high-gain “thermostats,” governing both H. pylori and host response dynamics.