Integrated multimodel analysis of intestinal inflammation exposes key molecular features of preclinical and clinical IBD
Miguel González-Acera, Jay V. Patankar, Lena Erkert, Roodline Cineus, Reyes Gámez‐Belmonte, Tamara Leupold, Marvin Bubeck, Li-Li Bao, Martin Dinkel, Ru Wang, Laura Schickedanz, Heidi Limberger, Iris Stolzer, Katharina Gerlach, Leonard Diemand, Fabrizio Mascia, Pooja Gupta, Elisabeth Naschberger, Kristina Koop, Christina Plattner, Gregor Sturm, Benno Weigmann, Claudia Günther, Stefan Wirtz, Michael Stürzl, Kai Hildner, Anja A Kühl, Britta Siegmund, Andreas Gießl, Raja Atreya, Ahmed N. Hegazy, Zlatko Trajanoski, Markus F. Neurath, Christoph Becker
Abstract
BACKGROUND: IBD is a chronic inflammatory condition driven by complex genetic and immune interactions, yet preclinical models often fail to fully recapitulate all aspects of the human disease. A systematic comparison of commonly used IBD models is essential to identify conserved molecular mechanisms and improve translational relevance. OBJECTIVE: We performed a multimodel transcriptomic analysis of 13 widely used IBD mouse models to uncover coregulatory gene networks conserved between preclinical colitis/ileitis and human IBD and to define model-specific and conserved cellular, subcellular and molecular signatures. DESIGN: We employed comparative transcriptomic analyses with curated and a priori statistical correlative methods between mouse models versus IBD patient datasets at both bulk and single-cell levels. RESULTS: We identify IBD-related pathways, ontologies and cellular compositions that are translatable between mouse models and patient cohorts. We further describe a conserved core inflammatory signature of IBD-associated genes governing T-cell homing, innate immunity and epithelial barrier that translates into the new mouse gut Molecular Inflammation Score (mMIS). Moreover, specific mouse IBD models have distinct signatures for B-cell, T-cell and enteric neurons. We discover that transcriptomic relatedness of models is a function of the mode of induction, not the canonical immunotype (Th1/Th2/Th17). Moreover, the model compendium database is made available as a web explorer (http://trr241.hosting.rrze.uni-erlangen.de/SEPIA/). CONCLUSION: This integrated multimodel approach provides a framework for systematically assessing the molecular landscape of intestinal inflammation. Our findings reveal conserved inflammatory circuits, refine model selection, offering a valuable resource for the IBD research community.