Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α₄β₇ integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.

SUMMARY. Eosinophilic esophagitis (EoE) is diagnosed by symptoms, and at least 15 intraepithelial eosinophils per high power field in an esophageal biopsy. Oth

Eosinophilic gastrointestinal disorders (EGID) are characterized pathologically by excess eosinophils in mucosal biopsies of one or multiple sites in the GI tract, simultaneously or sequentially. Eosinophilic esophagitis (EoE) is the best characterized EGID, and in most patients is an abnormal immune-mediated response to food antigens. Current recommendations for diagnosis include signs and symptoms of esophageal dysfunction that do not respond to proton pump inhibitor therapy, and esophageal biopsies that exhibit at least 15 intraepithelial eosinophils in at least one high power field (HPF). Therapy consists of swallowed glucocorticoids or dietary elimination. Eosinophilic gastritis (EG) is the second most common form of EGID, but like all forms of EGID except EoE consensus recommendations for either clinical or pathologic diagnosis do not exist. EG may be associated clinically with peripheral blood eosinophilia, hypoalbuminemia, and anemia, and pathologically with marked expansion of lamina propria by dense eosinophilic infiltrates. Eosinophilic enteritis (EE) may be subdivided into eosinophilic duodenitis, eosinophilic jejunitis, and eosinophilic ileitis. Most investigators believe that EE rarely, if ever, exists as a solitary form of EGID and is encountered only in patients who have at least one other affected portion of the GI tract. Eosinophilic colitis (EC) is perhaps the most enigmatic EGID. Distinction of EC from inflammatory bowel disease may be problematic especially in children. Multiple possible etiologies for EGID include hypereosinophilic syndrome, drug reactions, etc. Currently the only etiology that can be identified histologically is parasitic infestation if a portion of an invasive parasite is found in mucosal biopsies. This review will provide guidelines for the pathologic diagnosis of the various forms of EGID.