ORIGINAL RESEARCH article
Front. Immunol.
Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders
This article is part of the Research TopicInnovations in targeting intestinal immunity for chronic inflammatory disordersView all 21 articles
A Single-Cell Atlas of Ulcerative Colitis Reveals Neutrophil–Stromal Circuits Linked to Biologic Therapy Resistance
Provisionally accepted
Shadi Eshghi1
John Mark Gubatan2
Parisa Mazrooei1
Luis Quintanilla1Allen Nguyen1
Amelia Au-Yeung1
Derek Holman2
Chikara Takahashi1Courtney Schiffman1
William Edward O'Gorman1Mary Keir1Saroja Ramanujan1
Stephan Rogalla2*
Jason Hackney1*
Jacqueline M McBride1*- 1Genentech Inc, South San Francisco, United States
- 2School of Medicine, Stanford University, Stanford, United States
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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, transcriptional analysis of colonic biopsies revealed that etrolizumab-mediated integrin β7 blockade, but not adalimumab (a TNF-blocking antibody), reduced genes associated with integrin ɑEβ7+ 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. 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.
Keywords: cell-cell comminication, inflammatory fibroblasts, neutrophil heterogeneity, single cell RNA-sequencing (scRNA-seq), therapy resistance, Transcriptomic profiling, ulcerative colitis
Received: 14 Sep 2025; Accepted: 02 Jan 2026.
Copyright: © 2026 Eshghi, Gubatan, Mazrooei, Quintanilla, Nguyen, Au-Yeung, Holman, Takahashi, Schiffman, O'Gorman, Keir, Ramanujan, Rogalla, Hackney and McBride. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Stephan Rogalla
Jason Hackney
Jacqueline M McBride
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