OBJECTIVE: A global gene expression profile of non-inflamed colonic mucosal cells from patients with Crohn's disease (CD) and of colonic mucosal cells from controls was performed. MATERIAL AND METHODS: Tissue specimens from macroscopically non-inflamed descending colon were obtained colonoscopically from 33 CD patients and from 17 control subjects. All controls and 10 CD patients were medication-free at the time of colonoscopy. The Human Genome U133 Plus 2.0 GeneChip Array was used for gene profiling. Hybridization data were analysed with dChip software. Results were confirmed by real-time reverse transcriptase polymerase chain reaction (RT-PCR). Protein product expression of selected genes was assessed by immunohistochemistry using the Envision+ visualization technique. RESULTS: The expression profile was not homogeneous with the statistical cut-point settings applied. In comparison with controls, it was found that 19 CD patients had three differentially expressed genes, two of them related to the innate immune system: dual oxidase 2 on chromosome 15 (DUOX2, fold change 4.1) and lipocalin 2 on chromosome 9 (LCN2, fold change 3.1). The third gene, regenerating islet-derived 1 alpha (REG1A, fold change 3.9), codes for a mitogenic protein; this could not be confirmed by RT-PCR. Medication-free patients had no differentially expressed genes as compared with controls. Immunohistochemistry indicated that these proteins were produced by epithelial cells (REG1A, LCN2) and leucocytes (DUOX2 and LCN2). CONCLUSIONS: As compared with controls, non-inflamed colonic mucosal cells contain two up-regulated genes related to the innate immune system. Up-regulation of these genes, known to be induced by microorganisms, suggests either increased microflora antigenicity or an altered function in mucosal barrier defence.