Defining the Intestinal Epithelial Defects in Crohn's Disease

Intestinal epithelial defects are likely critical to Crohn's disease (CD) pathogenesis; however, molecular targets have been elusive due to varying degrees of inflammation in the tissue specimens typically used for expression screens. To circumvent this problem, we generated transcriptional profiles of CD patients (n=38) and non-IBD controls (n=33) by both RNA-seq and microarray using unstained, formalin-fixed, paraffin-embedded tissue sections of surgical resection margins. Histological scoring of serial tissue sections was used to subdivide the CD patients into two additional groups: no inflammation and mild chronic inflammation (but no active disease). We identified three principal gene networks with significant, differential expression between the CD and non-IBD groups. The most prominent was an epithelial cell-associated network present in ~75% of the CD patients that was independent of mild inflammation and contained 418 down-regulated transcripts (compared to controls) with both known and novel disease-relevant functions. We validated this network in biopsy tissue from CD patients who had not undergone resection. Two additional networks, the inflammatory and Paneth cell networks, exhibited a coordinated increase in transcript abundance in CD patients who had mild chronic inflammation and elevated Paneth cell numbers detected histologically. This study uncovered an epithelial signature that represents a partial inhibition of differentiation in most adult CD patients. This signature will be a critical tool to uncover novel aspects of CD pathogenesis and is a potential therapeutic target.