Mucosal Profiling of Pediatric-Onset Colitis and IBD Reveals Common Pathogenics and Therapeutic Pathways

Pediatric-onset colitis and inflammatory bowel disease (IBD) have significant effects on the growth of infants and children, but the etiopathogenesis underlying disease subtypes remains incompletely understood. Here, we report single-cell clustering, immune phenotyping, and risk gene analysis for children with undifferentiated colitis, Crohn’s disease, and ulcerative colitis. We demonstrate disease-specific characteristics, as well as common pathogenesis marked by impaired cyclic AMP (cAMP)-response signaling. Specifically, infiltration of PDE4B- and TNF-expressing macrophages, decreased abundance of CD39-expressing intraepithelial T cells, and platelet aggregation and release of 5-hydroxytryptamine at the colonic mucosae were common in colitis and IBD patients. Targeting these pathways by using the phosphodiesterase inhibitor dipyridamole restored immune homeostasis and improved colitis symptoms in a pilot study. In summary, comprehensive analysis of the colonic mucosae has uncovered common pathogenesis and therapeutic targets for children with colitis and IBD. [Display omitted] •Defective cAMP response underlies mucosal immune defects in pediatric colitis or IBD•Platelets are activated at colonic mucosae in pediatric colitis or IBD•Dipyridamole promoted mucosal healing in nine children with colitis in a pilot study•Candidate risk genes are differentially enriched in mucosal cellular subsets Single-cell and risk gene analysis of children with undifferentiated colitis, Crohn’s disease, and ulcerative colitis identifies common underlying mechanisms of pathogenesis and reveals the potential therapeutic benefit of modulating cAMP signaling via the drug dipyridamole.