Objective: The clinical presentation and course of Crohn’s disease (CD) is highly variable. We sought to better understand the cellular and molecular mechanisms that guide this heterogeneity, and characterize the cellular processes associated with disease phenotypes.

Design: We examined both gene expression and gene regulation (chromatin accessibility) in non-inflamed colon tissue from a cohort of adult CD and control patients. To support the generality of our findings, we analyzed previously published expression data from a large cohort of treatment-naïve pediatric CD and control ileum.

Results: We found that adult CD patients clearly segregated into two classes based on colon tissue gene expression—one that largely resembled the normal colon and one where certain genes showed expression patterns normally specific to the ileum. These classes were supported by changes in gene regulatory profiles observed at the level of chromatin accessibility, reflective of a fundamental shift in underlying molecular phenotypes. Further, gene expression from the ilea of the treatment-naïve pediatric CD patient cohort could be similarly subdivided into colon- and ileum-like classes. Finally, expression patterns within these CD subclasses highlight large-scale differences in the immune response and aspects of cellular metabolism, and were associated with multiple clinical phenotypes describing disease behavior, including rectal disease and need for colectomy.

Conclusion: Our results strongly suggest that these molecular signatures define two clinically relevant forms of CD irrespective of tissue sampling location, patient age or treatment status.

Data

Differentially expressed genes in colon between colon-like and ileum-like adult Crohn’s disease patients (RNA-seq). All genes are included. FDR < 0.05 considered significant (last column, padj).
Weiser_Colon-like_vs_Ileum-like_DE_Analysis_All_Genes.txt

Significantly (p < 0.05) differentially accessible regions (DARs) of chromatin in colon between colon-like and ileum-like adult Crohn's disease patients (FAIRE-seq).
Weiser_DARs_Colon-like_More_Accessible.bed
Weiser_DARs_Ileum-like_More_Accessible.bed