Current inflammatory bowel disease (IBD) therapies are ineffective in a high proportion of patients. Combining bulk and single-cell transcriptomics, quantitative histopathology and in situ localization across three cohorts of patients with IBD (total n = 376), we identify coexpressed gene modules within the heterogeneous tissular inflammatory response in IBD that map to distinct histopathological and cellular features (pathotypes). One of these pathotypes is defined by high neutrophil infiltration, activation of fibroblasts and vascular remodeling at sites of deep ulceration. Activated fibroblasts in the ulcer bed display neutrophil-chemoattractant properties that are IL-1R, but not TNF, dependent. Pathotype-associated neutrophil and fibroblast signatures are increased in nonresponders to several therapies across four independent cohorts (total n = 343). The identification of distinct, localized, tissular pathotypes will aid precision targeting of current therapeutics and provides a biological rationale for IL-1 signaling blockade in ulcerating disease.

目前的炎症性肠病 (IBD) 疗法对很大一部分患者无效。结合大容量和单细胞转录组学、定量组织病理学和原位定位三个 IBD 患者队列（总n = 376)，我们在 IBD 的异质性组织炎症反应中识别出共表达的基因模块，这些模块映射到不同的组织病理学和细胞特征（病理类型）。其中一种病理类型定义为中性粒细胞高度浸润、成纤维细胞活化和深度溃疡部位的血管重塑。溃疡床中活化的成纤维细胞显示出依赖于 IL-1R 而不是 TNF 的中性粒细胞趋化特性。在四个独立队列（总n = 343）中，对几种疗法无反应的患者中与致病型相关的中性粒细胞和成纤维细胞特征增加 。识别不同的局部组织病理类型将有助于精确靶向当前疗法，并为溃疡性疾病中的 IL-1 信号传导阻断提供生物学原理。