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. Single cell suspensions of colonic biopsies from eight patients were stained with antibodies and sorted by FACS. Single cell 5’ gene expression libraries were prepared for CD45+CD3+CD19- (HB1), CD45+CD3-CD19+ (HB2), CD45+CD3-CD19- (HB3-1) and CD45- (HB4) cells obtained from pooled cells of 4 patients. Single cell 5’ gene expression library was prepared for CD45+CD3-CD19- (HB3-2) cells from pooled cells of 2 patients. Single cell 3’ gene expression libraries were prepared for CD45+ (S279 and S280) cells obtained from 2 patients respectively. All libraries were constructed according to the 10X Chromium instructions and sequenced on Illumina Hiseq X Ten instrument.