Spatial fibroblast niches define Crohn’s fistulae

Crohn's disease often presents with fistulae, abnormal tunnels that connect the intestine to the skin or other organs. Despite their profound effect on morbidity, the molecular basis of fistula formation remains unclear, largely owing to the challenge of capturing intact fistula tracts and their inherent heterogeneity<sup>1-3</sup>. Here we construct a subcellular-resolution spatial atlas of 68 intestinal fistulae spanning diverse anatomical locations. We describe fistula-associated epithelial, immune and stromal cell states, revealing abnormal zonation of growth factors and morphogens linked to establishment of tunnelling anatomy. We identify fistula-associated stromal (FAS) fibroblasts, which are assembled in concentric layers: a proliferative, lumen-adjacent zone beneath neutrophil and macrophage-rich granulation tissue, an active lesion core of FAS cells and a quiescent, pro-fibrotic outer zone. We examine the architecture of the extracellular matrix in the fistula tract and demonstrate that FAS populations associate with distinct collagen structures, exhibiting properties ranging from proliferation, migration and extracellular matrix remodelling to dense collagen deposition and fibrosis. We define niches supporting epithelialization of fistula tunnels and a FAS-like population that is detected at the base of ulcers in non-penetrating Crohn's disease. Our study demonstrates that common molecular pathways and cellular niches underpin fistulae across intestinal locations, revealing the cellular protagonists of fistula establishment and persistence. This resource will inform the development of model systems and interventions to mitigate aberrant fibroblast activity while preserving their regenerative properties in Crohn's disease.

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Publication Details

Journal
Nature
Published
2025-11-12
DOI
https://doi.org/10.1038/s41586-025-09744-y
Citations
4
Primary Topic
Inflammatory Bowel Disease
Type
article
Field-Weighted Citation Impact
7.27
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article

Spatial fibroblast niches define Crohn’s fistulae

Jan Bornschein, Michael Vieth, Nicole Cianci, Carol Erin Cheng et al.
4 citations
Nature
Inflammatory Bowel Disease
7.27
article

Spatial fibroblast niches define Crohn’s fistulae

Jan Bornschein, Michael Vieth, Nicole Cianci, Carol Erin Cheng, Colleen GC McGregor, Esther Bridges, Chloe H. Lee, Agne Antanaviciute, Paula Gomez Castro, Ruchi Tandon, Paulina Siejka-Zielińska, Johannes Lehmann, Lei Deng, Kexin Xu, Sarah Hill, Zoe Christoforidou, Vesta Lai, Mark Bignell, Katherine Baker, Maria Greco, David Fawkner-Corbett, Ling‐Pei Ho, Anna Aulicino, Renuka Teague, Marta Jagielowicz, Alison Simmons, Bruce George, Han-Sheng Chuang, Verena Lentsch, Jun Sung Park, Zinan Yin, Tarun Gupta, Xiao Qin, Jeongmin Woo, Eve Fryer, P. Gutierrez, S. Moradi, Rhea Kujawa
article en
4 citations

Abstract

Crohn's disease often presents with fistulae, abnormal tunnels that connect the intestine to the skin or other organs. Despite their profound effect on morbidity, the molecular basis of fistula formation remains unclear, largely owing to the challenge of capturing intact fistula tracts and their inherent heterogeneity<sup>1-3</sup>. Here we construct a subcellular-resolution spatial atlas of 68 intestinal fistulae spanning diverse anatomical locations. We describe fistula-associated epithelial, immune and stromal cell states, revealing abnormal zonation of growth factors and morphogens linked to establishment of tunnelling anatomy. We identify fistula-associated stromal (FAS) fibroblasts, which are assembled in concentric layers: a proliferative, lumen-adjacent zone beneath neutrophil and macrophage-rich granulation tissue, an active lesion core of FAS cells and a quiescent, pro-fibrotic outer zone. We examine the architecture of the extracellular matrix in the fistula tract and demonstrate that FAS populations associate with distinct collagen structures, exhibiting properties ranging from proliferation, migration and extracellular matrix remodelling to dense collagen deposition and fibrosis. We define niches supporting epithelialization of fistula tunnels and a FAS-like population that is detected at the base of ulcers in non-penetrating Crohn's disease. Our study demonstrates that common molecular pathways and cellular niches underpin fistulae across intestinal locations, revealing the cellular protagonists of fistula establishment and persistence. This resource will inform the development of model systems and interventions to mitigate aberrant fibroblast activity while preserving their regenerative properties in Crohn's disease.

NatureVol. 649(8097)
Oxfam (GB), Centre for Human Genetics (GB), Nuffield Orthopaedic Centre (GB), Bayreuth Medical Center (DE), John Radcliffe Hospital (GB), University of Oxford (GB), MRC Weatherall Institute of Molecular Medicine (GB), MRC Human Immunology Unit (GB), Oxford Centre for Mission Studies (GB), Oxford University Hospitals NHS Trust (GB)
Openalex Percentile: Top 3%
Inflammatory Bowel Disease
7.27
DOIOpen Access PDFOpenAlex
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