Bacterial strains used in this study.

<div><p>Enteric pathogens navigate distinct regional microenvironments within the intestine that cue important adaptive behaviors. We investigated the response of <i>Citrobacter rodentium</i>, a model of human pathogenic <i>Escherichia coli</i> infection in mice, to regional gastrointestinal pH. We found that small intestinal pH (4.4–4.8) triggered virulence gene expression and altered cell morphology, supporting initial intestinal attachment, while higher pH, representative of <i>C</i>. <i>rodentium</i>’s replicative niches further along the murine intestine, supported pathogen growth. Gastric pH, a key barrier to intestinal colonization, caused significant accumulation of intra-bacterial reactive oxygen species (ROS), inhibiting growth of <i>C</i>. <i>rodentium</i> and related human pathogens. Within-host adaptation increased gastric acid survival, which may be due to a robust acid tolerance response (ATR) induced at colonic pH. However, the intestinal environment changes throughout the course of infection. We found that murine gastric pH decreases postinfection, corresponding to increased serum gastrin levels and altered host expression of acid secretion-related genes. Similar responses following <i>Salmonella</i> infection may indicate a protective host response to limit further pathogen ingestion. Together, we highlight interlinked bacterial and host adaptive pH responses as an important component of host–pathogen coevolution.</p></div>