Abstract
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.
Highlights
Shapiro−Wilk normality test was used on the continuous clinical parameters, and on specific gene expression, and PC1
If the data were normally distributed unpaired t test was used to compare two groups, and ANOVA with FDR was used for comparison of more than two groups. *All two-sided P < 0.05, **P < 0.01, ***P < 0.001
All statistical analyses were performed in SASv9.3 or GraphPad Prism v7.04
Summary
Children aged 4–17 years with a diagnosis of UC based on accepted clinical, endoscopic, and histological parameters[5], disease extent beyond the rectum, a baseline Pediatric Ulcerative Colitis Activity Index (PUCAI) score of at least 10, no previous therapy for colitis, and stool culture negative for enteric bacterial pathogens and Clostridium difficile toxin were included. A central pathologist blinded to clinical data examined a single rectal biopsy from each patient and assessed histological features of chronicity and quantitated acute inflammation. The description of eosinophilic inflammation included the peak number of eosinophils per high-power field relative to a cut-point (>32 cells per high-power field) derived from a study of normal rectal biopsies in children[3,5]
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