Short Ileal Microvillus Length Phenotype Associates with Progression from Inflammatory to Complicated Disease Behavior in Pediatric Crohn's Disease.

BACKGROUND AND AIMS: Our previous studies of adult Crohn's disease (CD) suggested ileal microvillus length (MVL) as a prognostic biomarker for therapy response. We investigated if ileal MVL also differed in pediatric CD versus controls and tested for associations with stricturing or penetrating disease behavior outcomes. METHODS: We determined the average ileal MVL of 412 CD and 88 control H&E-stained ileal histology samples from a subset of the RISK cohort and 2 validation cohorts. The RISK sub-cohort had an average follow-up of >60 months and was used to test for associations between ileal MVL and clinical data, RNA-seq molecular profiles, and histopathological scores. RESULTS: Ileal MVL was shorter in CD relative to control (median of 1.396 µm vs. 1.598 µm, respectively). Ileal MVL generally did not associate with demographics or clinical disease activity indices. However, there was a significant association between shorter ileal MVL and increased risk of development of complicated disease behavior. Furthermore, CD samples with shorter ileal MVL showed a significantly shorter time to development of complicated disease behavior. Ileal MVL positively associated with a gene signature enriched for brush border membrane and negatively associated with a gene signature enriched for extracellular matrix, inflamed macrophages, and fibroblasts. Accordingly, ileal MVL was negatively correlated with histopathological scores. CONCLUSIONS: Short ileal MVL is associated with the development of complicated disease behaviors in pediatric CD, supporting the potential use of this histological phenotype as a biomarker for CD prognosis.