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Histological evaluation of intestinal biopsies is central to diagnosis, but histological parameters that define underlying immune mechanisms are limited. We investigated histological features that distinguish individual patient immune profiles in therapy-naive pediatric IBD patients (age 6\u201318 years) using biopsy immunohistochemistry and transcriptomics and plasma proteomics across two cohorts. High colonic epithelial expression of secretory leukocyte protease inhibitor (SLPI), a microbiota-induced regulator of epithelial function, occurred in IBD patients with high clinical disease activity and more severe endoscopic and microscopic disease activity. SLPI expression was related to increased neutrophil infiltration, transcriptomic signatures of activation, and genes known to associate with therapeutic resistance. High SLPI colocalized with high densities of IL-17\u2013secreting cells and was associated with high plasma concentrations of Th17-related immune proteins. 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