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Research Article: A single-cell atlas of ulcerative colitis reveals neutrophil–stromal circuits linked to biologic therapy resistance

Date Published: 2026-06-11

Abstract:
Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by immune cell infiltration, crypt erosion, and severe ulceration. In phase 3 studies with etrolizumab, the results of a transcriptional analysis of colonic biopsies revealed that etrolizumab-mediated integrin ?7 blockade, but not adalimumab (a TNF-blocking antibody), reduced genes associated with integrin ?E?7+ intraepithelial lymphocytes (IELs). Both treatments significantly reduced stromal and myeloid cell-related genes linked to Mayo Clinic Score (MCS) remission status. A single-cell atlas from UC biopsies identified 36 distinct cell populations, including myeloid cells. This atlas enabled cell-specific signatures and cellular deconvolution of the phase 3 data, showing reductions in neutrophils, monocyte-derived macrophages, and inflammatory fibroblasts, along with increases in epithelial cells common to both treatments. Pseudo-time analyses identified four neutrophil subsets, transitioning from PADI4hi, OSMhi, and MX1hi to CXCR4hi populations. PADI4hi and OSMhi neutrophils exhibited high protease, cytokine (CXCL1, IL1B, OSM), and chemokine receptor (CXCR1, CXCR2) levels, while MX1hi expressed markers of IFN exposure. CXCR4hi neutrophils showed elevated CXCL2, TNF, and VEGFA levels. Notably, interactions between PADI4hi and OSMhi neutrophils and inflammatory fibroblasts, such as OSM and IL1B, were associated with MCS remission with both drugs. CXCR4hi neutrophils showed only minor changes unrelated to clinical outcomes. These findings suggest that neutrophils are highly heterogeneous, with abundant interactions in inflamed colonic tissue, potentially perpetuating chronic disease. Disrupting neutrophil interactions with myeloid and resident cells like inflammatory fibroblasts could reduce inflammation, possibly enhancing clinical remission rates.

Introduction:
Inflammatory bowel disease (IBD), including ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract that has emerged as a globally relevant disease with increasing incidence worldwide and is associated with significant morbidity and healthcare utilization ( 1 – 3 ). Although biologic therapies with diverse mechanisms of action (e.g., anti-TNF, anti-integrin, anti-cytokines, JAK inhibitors) have expanded the therapeutic armamentarium of IBD, only approximately 30%–40% of patients…

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