Mucosal Inflammatory and Wound Healing Gene Programmes Reveal Targets for Stricturing Behaviour in Paediatric Crohn’s Disease

Abstract

Background and Aims Ileal strictures are the major indication for resective surgery in Crohn’s disease (CD). We aimed to define ileal gene programs present at diagnosis linked with future stricturing behavior during five year follow-up, and to identify potential small molecules to reverse these gene signatures. Methods Antimicrobial serologies and pre-treatment ileal gene expression were assessed in a representative subset of 249 CD patients within the RISK multicenter pediatric CD inception cohort study, including 113 that are unique to this report. These data were used to define genes associated with stricturing behavior and for model testing to predict stricturing behavior. A bioinformatics approach to define small molecules which may reverse the stricturing gene signature was applied. Results 19 of the 249 patients developed isolated B2 stricturing behavior during follow-up, while 218 remained B1 inflammatory. Using deeper RNA sequencing than in our prior report, we have now defined an inflammatory gene signature including an oncostatin M co-expression signature, tightly associated with extra-cellular matrix (ECM) gene expression in those who developed stricturing complications. We further computationally prioritize small molecules targeting macrophage and fibroblast activation and angiogenesis which may reverse the stricturing gene signature. A model containing ASCA and CBir1 serologies and a refined eight ECM gene set was significantly associated with stricturing development by year five after diagnosis (AUC (95th CI) = 0.82 (0.7-0.94)). Conclusion An ileal gene program for macrophage and fibroblast activation is linked to stricturing complications in treatment naïve pediatric CD, and may inform novel small molecule therapeutic approaches.

Mucosal Genomics Implicate Lymphocyte Activation and Lipid Metabolism in Refractory Environmental Enteric Dysfunction

“…These include up-regulation of an innate antimicrobial DUOX2 and LCN2 gene signature coupled with reduction of metallothioneins (MT family) that buffer against toxic metals, and aldo-keto NADPH-dependent reduction genes (AKR1C family) involved in detoxification of environmental compounds. Those features widely overlap with the intestinal Crohn's disease transcriptome, 17,23 suggesting similar pathogenic mechanisms involving altered gut microbiota. 5 In fact, the antimicrobial gene signature detected in SEEM is quite consistent with the recent report of duodenal microbiota, and host defense proteins, associated with stunting in children in Bangladesh 5 and Zambia.…”

Mechanism of fibrosis and stricture formation in Crohn's disease

“…A recent paper addressed this intriguing question by analysing gene expression in biopsies from a large cohort of newly diagnosed paediatric Crohn's patients. 47 Gene expression patterns in those who developed strictures at their 5-year follow-up were compared to those who maintained a purely inflammatory disease behaviour. Over 500 differentially expressed genes were identified and revealed an inflammatory signature associated with extracellular matrix genes and future stricture development.…”

“…Over 500 differentially expressed genes were identified and revealed an inflammatory signature associated with extracellular matrix genes and future stricture development. 47 This suggests that gene expression changes occur in the intestinal tissue of patients prone to develop strictures early in the process. It also identifies genes associated with stricture development to aid in classification of patients and facilitate research to identify targets to prevent stricture development.…”

“…If so, this could be a means to predict patients that will develop strictures with time. A recent paper addressed this intriguing question by analysing gene expression in biopsies from a large cohort of newly diagnosed paediatric Crohn's patients 47 . Gene expression patterns in those who developed strictures at their 5‐year follow‐up were compared to those who maintained a purely inflammatory disease behaviour.…”

“…Gene expression patterns in those who developed strictures at their 5‐year follow‐up were compared to those who maintained a purely inflammatory disease behaviour. Over 500 differentially expressed genes were identified and revealed an inflammatory signature associated with extracellular matrix genes and future stricture development 47 . This suggests that gene expression changes occur in the intestinal tissue of patients prone to develop strictures early in the process.…”