Ileal Enterocyte Brush Border Abnormalities Associate with Progressive Disease Course in Pediatric Crohn's Disease

Objective: There is a critical need for biomarkers to predict prognosis and guide clinical care in pediatric Crohn's disease (CD). Our previous studies of adult CD indicated ileal microvillus length as a potential prognostic biomarker for therapy response. Here, we tested if short microvillus length predicted progression of disease behavior or bowel resection surgery in pediatric CD. Design: We obtained H&E-stained ileal histology samples from 3 pediatric CD cohorts. Average microvillus length was determined for 59 Control and 377 CD samples and tested for associations with patient demographic and clinical data, RNA-seq molecular profiles, histological inflammation scores, and clinical outcomes. Results: Relative to Controls, the average microvillus length was shorter in CD samples collected at diagnostic or follow-up colonoscopy procedures. Microvillus length was generally not associated with demographic data or clinical activity indices. The CD molecular signature was functionally enriched for transporter activity and brush border membrane among the genes positively associated with microvillus length and for extracellular matrix, inflamed macrophages, and fibroblasts among the genes negatively associated with microvillus length. Microvillus length negatively correlated with histologic inflammation score, but short microvillus length phenotype could cooccur with low histologic inflammation. There was a higher likelihood of stricturing disease behavior or bowel resection surgery, but not fistulizing disease behavior, in follow-up CD samples with short microvillus length. Conclusion: Short microvillus length can predict the development of stricturing disease behavior and bowel resection surgery in pediatric CD, further supporting the potential use of this histological phenotype as a biomarker for CD prognosis. Overall design: 138 Crohn's disease (CD) and 14 control human ileum biopsies