Vibrio cholerae is a noninvasive enteric bacterium that causes the severe diarrheal disease cholera. Candidate cholera vaccines have been engineered by deleting genes encoding known virulence factors in V. cholerae; however, many of these attenuated strains were still reactogenic in human volunteers. In this study, DNA arrays were utilized to monitor the transcriptional responses of human intestinal epithelial cells (T84) to eight strains of V. cholerae, including attenuated, toxigenic, and environmental isolates. cDNA probes generated from host RNA samples were hybridized against low-and high-density gene arrays. V. cholerae induced the transcription of a variety of host genes and repressed the expression of a lower number of genes. Expression patterns were confirmed for certain genes by reverse transcriptase PCR and enzyme-linked immunosorbent assays. A core subset of genes was found to be differentially regulated in all experiments. These genes included genes involved in innate mucosal immunity, intracellular signaling, and cellular proliferation. Reactogenic vaccine strains induced greater expression of genes for certain proinflammatory cytokines than nonreactogenic strains. Wild-type and attenuated derivatives induced and repressed many genes in common, although there were differences in the transcription profiles. These results indicate that the types of host genes modulated by attenuated V. cholerae, and the extent of their induction, may mediate the symptoms seen with reactogenic cholera vaccine strains.The human diarrheal disease cholera results from infection with pathogenic strains of the gram-negative enteric bacterium Vibrio cholerae. Many serogroups of V. cholerae have been identified, but only two of these (O1 and O139) are important for epidemic disease. The O1 serogroup is further subdivided into the classical and El Tor biotypes, as well as the Inaba, Ogawa, and Hikojima serotypes. After ingestion, pathogenic V. cholerae bacteria colonize the small intestine and produce a number of virulence factors, notably cholera toxin (CT). This toxin targets and activates the adenylate cyclase within host epithelial cells, provoking the net secretion of chloride ions and water into the intestinal lumen, resulting in the extensive diarrhea that is characteristic of this disease (25). As such, the pathology of cholera has traditionally been considered noninflammatory (5). However, several reports provide evidence for an inflammatory response in cholera disease. Lymphocytes and mononuclear cells have been observed in the intestinal lamina propria in biopsy specimens from cholera patients (16, 40), and increased levels of lactoferrin, myeloperoxidase, and prostaglandins have been measured in stool samples from infected humans (43, 50). Leukocytes and erythrocytes were also detected in the stools (48), and elevated concentrations of nitric oxide metabolites were observed in urine and serum samples (22,43,44) from cholera patients. Finally, and of most relevance for this study, V. cholerae vaccine strains caused...