The landscape of immune dysregulation in Crohn’s Disease revealed through single-cell transcriptomic profiling in the ileum and colon

Lingjia Kong, Vladislav Pokatayev, Ariel Lefkovith, Grace T. Carter, Elizabeth A. Creasey, Chirag Krishna, Sathish Subramanian, Bharati Kochar, Orr Ashenberg, Helena Lau, Ashwin N. Ananthakrishnan, Daniel B. Graham, Jacques Deguine, Ramnik J. Xavier

Published in Immunity, 2023

Crohn’s disease (CD) is a chronic gastrointestinal disease, increasing in prevalence worldwide. CD is multifactorial, involving the complex interplay of genetic, immune, and environmental factors, necessitating a systems-level understanding of its etiology. To characterize cell type-specific transcriptional heterogeneity in active CD, we profiled 720,633 cells from terminal ileum and colon of 71 donors with varying inflammation status. Our integrated datasets revealed organ and compartment-specific responses to acute and chronic inflammation; most immune changes were in cell composition while transcriptional changes dominated among epithelial and stromal cells. These changes correlated with endoscopic inflammation, but small and large intestines exhibited distinct responses, particularly apparent when focusing on IBD risk genes. Finally, we mapped markers of disease-associated myofibroblast activation, and identified CHMP1A, TBX3, and RNF168 as regulators of fibrotic complications. Altogether, our results provide a roadmap for understanding cell type- and organ-specific differences in CD and potential directions for therapeutic development.