P062 Characterization of UC1 and UC2 patients: towards personalized medicine in Ulcerative Colitis

Abstract

Abstract Background Ulcerative colitis (UC) is a highly heterogeneous chronic inflammatory bowel disease (IBD) that primarily affects the colon. Although there are some available classifications, mostly based on clinical parameters, the lack of a molecular stratification prevents full comprehension of the diagnostic and prognostic heterogeneity of patients, and thus from correctly predicting their response to available treatments. We have recently developed an unbiased stratification of UC patients (UC1/UC2) based on their transcriptomic profiles (Czarnewski P; et al. Nature Communications, 2019), which holds great potential for the design of personalized medicine in IBD. However, further characterization is necessary to validate it and consolidate its clinical application. Methods To achieve this goal, we used bulk and single-cell RNA sequencing (sc-RNAseq) datasets from a prospective cohort of Swedish IBD patients to understand whether UC1 and UC2 are different diseases or states of the same disease, and to deeply characterize the cellular composition of UC1 and UC2 patients. In addition, we took advantage of murine spatial transcriptomics datasets of colonic tissues at steady state or during mucosal healing, to get insights into the spatiotemporal dynamics of UC1/UC2 transcriptional profiles. Results A longitudinal analysis of UC1/UC2 transcriptomic profiles as well as gene module analysis revealed that UC1 and UC2 profiles are fluctuant during the course of disease, eventually representing different stages of the same disease. scRNAseq analysis allowed us to identify specific cell types characterizing UC2 patients.[FC1] Finally, while genes defining UC2 patients distributed homogenously within the murine mouse colon at steady state and during mucosal healing, UC1 genes primarily mapped within damage/regeneration regions. Conclusion This study details the differences in immune cell composition and molecular pathways in UC1 and UC2 patients, contributing to a more comprehensive understanding of the new molecular stratification system we have developed for ulcerative colitis patients.