P0004 Transcriptomic profiling as a tool for prediction of endoscopic inflammation in quiescent Crohn's Disease patients

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Abstract Background Biological agents have revolutionized therapy in Crohn's disease (CD), yet ~50% of patients do not respond / lose response to therapy. Therefore, patient-specific therapies are in critical need. Preliminary studies have demonstrated that transcriptomic analysis of fecal aspirates from the colon are associated with patients' inflammatory status1,2. CORE (Capsule & Omics for pRedicting Exacerbation of Crohn’s disease) is a highly defined prospective cohort of clinically non-active CD patients undergoing clinical and endoscopic serial evaluations at Sheba Medical Center (MC). Scarce data exists as to the association of small intestinal biopsies and fecal aspirates from the colon with small bowel inflammation status in quiescent CD. Methods As part of an ongoing prospective cohort study, a biobank of lower-GI biopsies and aspirates (e.g. fluids suctioned from the colon) from CD patients was established at Sheba MC between 2023-2024, along with comprehensive clinical, endoscopic and demographic data. Following RNA extraction and bulk RNA deep sequencing, transcriptomic analysis was performed for all biopsies and fecal aspirated and correlated with clinical and endoscopic data. Results 40 fecal aspirate samples and 50 biopsies were obtained and analyzed from 56 CD patients (median age: 32 years, 73% males). 63% had ileal disease, 5% had colonic disease and 32% had ileo-colonic disease. 48% were treated with Adalidumab, 7% with Infliximab, 16% with Vedolizumab, 12% with Ustekinumab and 17% were not treated with biologics. All patients were in clinical remission at time of analysis. 57% had endoscopically active disease per colonoscopy and 46% per capsule endoscopy. Figure 1 demonstrates the distinct spatial distribution of samples, demonstrating that gene expression variation is significantly associated with small bowel inflammation. 639 genes were significantly differentially expressed between fecal washes of patients with inflamed and non-inflamed small bowel (padj < 0.01). Hierarchical clustering dendrograms show distinct expression patterns that effectively separate inflamed from non-inflamed samples, underlying again a strong transcriptional signature associated with inflammation (Figure 2). The Silhouette score of 0.332, on a scale ranging from -1 to 1, demonstrates moderate clustering separation, validating our analytical approach. Conclusion Colonic fecal-aspirates yield a reliable transcriptomic profile, predicting small bowel inflammation, based on a panel of 639 genes, in quiescent CD. Further studies will enable us to build a PCR based model for prediction of small bowel inflammation in quiescent Crohn's disease.