biostudies-literatureFriedrich MMedical Research CouncilNational Institute for Health Research (NIHR)NIAMS NIH HHSKennedy TrustWellcome Trust1970-1981https://www.ebi.ac.uk/biostudies/studies/S-EPMC8604730biostudies-literatureUnknown27(11)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 Nature medicineIL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies.PMC8604730K08 AR077037KENN161701095688/Z/11/ZMR/N02690X/1212240/Z/18/ZKENN192004KENN202101KENN161703ACF-2017-13-008MR/V001949/1Korsunsky IFrei APUhlig HHSathananthan DSharpe HMann EHRue-Albrecht KWatts GFMRaychaudhuri SOxford IBD Cohort InvestigatorsLassen KGThomas LRavindran RPowrie FMThomas TBarone FEaston ATandon RWei KJackson MAAttar MPeres RSBuckley CDBullers SJTravis SPMcCuaig SSansom SNChristoforidou ZFriedrich MGeremia AColes MCollantes EPohin MRoche Fibroblast Network ConsortiumBrenner MfalseIL-1-driven stromal-neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies.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 2021-01-01T00:00:00Z2021 Nov2026-05-08T14:24:06.45Z2022-02-11T13:29:12.397ZS-EPMC86047303467538310.1038/s41591-021-01520-5