Epithelia mediate inflammation with myeloid cells in Crohn’s disease patients under treatment

Crohn’s disease (CD), a major class of Inflammatory Bowel Disease (IBD), is a chronic condition affecting millions, with >50% of the patients experiencing relapses marked by inflammation. Our cellular atlas (380,000 cells) of the terminal ileum (TI) and ascending colon (AC) mucosa from 46 CD and non-IBD donors across various clinical condition, decipher disease heterogeneity for CD relapse and refractory inflammation. We identified an inflammatory cascade mediated by follicle-associated enterocytes in the inflamed TI involving pro-inflammatory macrophage M1 that remained unresolved by given biologic treatments. Spatial transcriptomic validation confirmed this epithelial-immune crosstalk. In contrast, interactions between colonocytes, FAP+ stroma and innate immune cells were were the unresolved cascade in AC driving inflammation. In addition, we propose a transcript-based scoring method to quantify inflammation activity that can be used to compare inflammation levels across patients, with the overall aim to help disease stratification.