Psychosocial factors are important determinants of disease manifestations, treatment efficacy, and prognosis of functional and inflammatory bowel disorders. Isolation of C57BL/6J mice from their 4 brothers growing in the same cage reduced goblet cells and MUC2 expression with a peak on day 8 in the rectum, but not in the colon. Gene expression analysis using a whole mouse genome microarray showed that the stress induced a 10-fold larger change in the gene expression in the rectum (722 genes) than in the colon (72 genes). The Ingenuity Pathway Analysis (IPA) application organized the rectum-specific 711 genes into stress response-related pathways. Nuclear factor-kappaB-related cytokine networks constructed with IPA showed selective up-regulation of interleukin (IL)-18 mRNA expression, which was also confirmed by real-time polymerase chain reaction. The stress produced active forms of caspase 1, IL-18, and a negative regulator for goblet cells, Notch 1, only in the rectum. IL-18-knockout mouse rectum had significantly increased goblet cells and MUC2 mucin, compared with wild-type mouse rectum. The absence of IL-18 completely blocked the stress-induced changes in gene expression and the goblet cell responses in the rectum. Thus, IL-18 may be a crucial determinant for the vulnerability of the rectum to psychosocial stress.