ABSTRACTStressor exposure has been shown to enhance host susceptibility and the severity of a plethora of illnesses, including gastrointestinal disease. In mice, susceptibility toCitrobacter rodentiumhas been shown to be dependent on host genetics as well as the composition of the intestinal microbiota, but the effects of stressor exposure on this gastrointestinal pathogen have not been elucidated fully. Previously, our lab showed that exposure to the prolonged-restraint stressor prior to a challenge withC. rodentiumalters the intestinal microbiota community structure, including a reduction of beneficial genera such asLactobacillus, which may contribute to stressor-enhancedC. rodentium-induced infectious colitis. To test the effects of stressor exposure onC. rodentiuminfection, we exposed resistant mice to a prolonged-restraint stressor concurrent with pathogen challenge. Exposure to prolonged restraint significantly enhancedC. rodentium-induced infectious colitis in resistant mice, as measured by increases in colonic histopathology, colonic inflammatory mediator gene production, and pathogen translocation from the colon to the spleen. It was further tested if the beneficial bacteriumLactobacillus reutericould reduce the stressor-enhanced susceptibility toC. rodentium-enhanced infectious colitis. WhileL. reuteritreatment did not reduce all aspects of stressor-enhanced infectious colitis, it did significantly reduce pathogen translocation from the colon to the spleen. Taken together, these data demonstrate the deleterious effects that prolonged stressor exposure can have at the onset of a gastrointestinal infection by its ability to render a resistant mouse highly susceptible toC. rodentium. Probiotic treatment ameliorated the systemic manifestations of stress on colonic infection.