IL-1-driven stromal\u2013neutrophil interactions define a subset of patients with inflammatory bowel disease that does not respond to therapies

Matthias Friedrich ,Watts Gfm ,Dharshan Sathananthan ,Alistair Easton ,A Geremia ,Holm H Uhlig ,Andreas P Frei ,Kevin Wei ,Matthew A Jackson ,Samuel J Bullers ,Mathilde Pohin ,Fiona Powrie ,Christopher D Buckley ,Moustafa Attar ,Ruchi Tandon ,Tom Thomas ,Elena Collantes ,Mark Coles ,Z Christoforidou ,Sarah Mccuaig ,Kévin Rue-Albrecht ,Hannah Sharpe ,Elizabeth H Mann ,Laurent F Thomas ,Max Brenner ,Soumya Raychaudhuri ,Ilya Korsunsky ,Rahul Ravindran ,Raphael Sanches Peres ,Francesca Barone ,Kara G Lassen ,Steven N Sansom ,Simon Travis

doi:10.1038/s41591-021-01520-5

Abstract

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.

Highlights

Inflammatory bowel diseases are a heterogeneous group of disorders characterized by inflammation throughout the gastrointestinal tract
Areas of IL-1β and FAP labeling demonstrated infiltrates of neutrophil elastase (NE)+ neutrophils (Fig. 6c,d, bottom). These results identify IL-1 receptor (IL-1R) signaling as a key driver of the inflammatory fibroblast/neutrophil recruitment phenotype that is observed in inflammatory bowel disease (IBD) tissues with a high M4/M5 pathotype
Our results identify distinct pathotypes within the heterogeneous landscape of IBD that inform on the outcome of therapies

Summary

Introduction

Inflammatory bowel diseases are a heterogeneous group of disorders characterized by inflammation throughout the gastrointestinal tract. Subsequent transcriptomic studies have associated subsets of fibroblasts, inflammatory mononuclear phagocytes (MNPs), neutrophils and pathogenic T and plasma cells with therapy nonresponse in both UC and CD6–12. It remains unknown whether the cellular and molecular hallmarks of treatment response are uniform across patients or whether several different tissular pathologies are linked to therapy failure through distinct mechanisms. Further understanding in those areas is crucial to the design of personalized treatment regimens and new therapeutics for individuals that do not respond to current options. Nature Medicine targeting of existing medications, and an alternative avenue to target inflammation in nonresponsive patients displaying ulceration with fibroblast and neutrophil remodeling

Methods

Results

Conclusion