Colonoids From Patients With Pediatric Inflammatory Bowel Disease Exhibit Decreased Growth Associated With Inflammation Severity and Durable Upregulation of Antigen Presentation Genes.

BACKGROUND: Defining epithelial cell contributions to inflammatory bowel disease (IBD) is essential for the development of much needed therapies for barrier repair. Children with very early onset (VEO)-IBD have more extensive, severe, and refractory disease than older children and adults with IBD and, in some cases, have defective barrier function. We therefore evaluated functional and transcriptomic differences between pediatric IBD (VEO and older onset) and non-IBD epithelium using 3-dimensional, biopsy-derived organoids. METHODS: We measured growth efficiency relative to histopathological and clinical parameters in patient enteroid (ileum) and colonoid (colon) lines. We performed RNA-sequencing on patient colonoids and subsequent flow cytometry after multiple passages to evaluate changes that persisted in culture. RESULTS: Enteroids and colonoids from pediatric patients with IBD exhibited decreased growth associated with histological inflammation compared with non-IBD controls. We observed increased LYZ expression in colonoids from pediatric IBD patients, which has been reported previously in adult patients with IBD. We also observed upregulation of antigen presentation genes HLA-DRB1 and HLA-DRA, which persisted after prolonged passaging in patients with pediatric IBD. CONCLUSIONS: We present the first functional evaluation of enteroids and colonoids from patients with VEO-IBD and older onset pediatric IBD, a subset of which exhibits poor growth. Enhanced, persistent epithelial antigen presentation gene expression in patient colonoids supports the notion that epithelial cell-intrinsic differences may contribute to IBD pathogenesis.

The Unique Disease Course of Children with Very Early onset-Inflammatory Bowel Disease.

BACKGROUND: Insight into the pathogenesis of very early onset-inflammatory bowel disease (VEO-IBD) has expanded through the identification of causative monogenic defects detected in a subset of patients. However, the clinical course of this population remains uncertain. The study objective is to determine whether VEO-IBD is associated with more severe disease, defined as increased surgical intervention and growth failure, than older pediatric IBD. Secondary outcomes included therapeutic response and hospitalizations. METHODS: Subjects with IBD diagnosed younger than 6 years old (VEO-IBD) were compared with children diagnosed 6 to 10 (intermediate-onset) and older than 10 years of age (older-onset IBD). Metadata obtained from the medical record included age of onset, disease phenotype and location, surgeries, medical therapy, and comorbid conditions. Length of follow-up was at least 1 year from diagnosis. RESULTS: There were 229, 221, and 521 subjects with VEO, intermediate-onset, and older-onset IBD, respectively. Very early onset-inflammatory bowel disease subjects underwent more diverting ileostomies (P < 0.001) and colectomies (P < 0.001) than the older children. There was less improvement in weight- and height-for-age Z scores during the follow-up period in subjects with VEO-IBD. Additionally, subjects with VEO-IBD had higher rates of medication failure at 1 year and were more frequently readmitted to the hospital. Targeted therapy was successfully used almost exclusively in VEO-IBD. CONCLUSION: Patients with VEO-IBD can have a more severe disease course with increased surgical interventions and poor growth as compared with older-onset IBD patients. Further, VEO-IBD patients are more likely to be refractory to conventional therapies. Strategies using targeted therapy in these children can improve outcome and, in some cases, be curative.