An aberrant immune response to the commensal microbiota is widely hypothesized to contribute to the development of inflammatory bowel disease. Helicobacter bilis colonization of defined-flora mice has been shown to trigger host immune responses to the commensal flora. However, the magnitude of the effects on mucosal homeostasis following colonization with H. bilis has not been determined. Using microarray analysis, differential gene expression within the cecal mucosa was assessed at 15, 30, or 45 days following H. bilis colonization using Affymetrix Genechips. H. bilis colonization induced marked upregulation of genes associated with protein metabolism, immune responses, and downregulation of genes associated with fatty acid metabolism and detoxification which peaked at 15 days postinfection. A set of genes associated with glycoprotein synthesis and detoxification including Fut2, B3galt5, Ceacam12, Cyp4b1, and Ugt8a were uniquely identified and found to be similarly expressed following the induction of typhlocolitis by dextran sodium sulfate or Brachyspira hyodysenteriae. This study provides preliminary evidence as to the types of factors or changes in the intestinal mucosa that potentially predispose the host to the development of typhlocolitis.