Researchers at the University of Oxford have mapped the cellular makeup of Crohn’s disease fistulas, providing new insights that could lead to targeted treatments. Crohn’s disease is a chronic condition affecting about one in every 650 people, causing inflammation and ulcers in the gut. Fistulas, which are abnormal tunnels that can form when ulcers do not heal properly, are a particularly difficult complication to treat.
The study, published in Nature by scientists at the MRC Weatherall Institute of Molecular Medicine, used advanced single-cell and spatial analysis techniques to examine thousands of individual cells from Crohn’s fistulas and compare them with healthy gut tissue. The research team identified concentric rings of fibroblasts—cells usually responsible for maintaining tissue structure—that had become reprogrammed to behave like those found during early fetal gut development.
“These fibroblasts have essentially switched on developmental programmes that should only be active before birth,” said Dr Agne Antanaviciute, one of the senior authors. “This reawakening makes them highly destructive. They erode tissue at the surface and lay down fibrotic scar deeper in the tract, helping the tunnels form and persist.”
The researchers also detected small numbers of these abnormal fibroblasts at ulcer bases in Crohn’s patients who had not yet developed fistulas. This suggests that early intervention targeting local cell signaling might prevent tunnel formation.
Professor Alison Simmons, senior author and Director of the MRC Translational Immune Discovery Unit, commented: “Current medicines for Crohn’s, and other types of inflammatory bowel disease (IBD), focus on suppressing inflammation, but do little to promote tissue repair. By pinpointing the cell types and pathways that actually drive fistula formation, we now have more of the vital information required to design and test preventatives and novel wound healing approaches.”
The Oxford team compiled what they describe as the largest dataset integrating single-cell, spatial, and molecular imaging data across diverse patient samples. This data has been made publicly available for further research into complications from Crohn’s disease.
Clinical researcher Dr Colleen McGregor, co-first author of the study, said: “As a clinician who sees firsthand the burden of this debilitating complication, I’m thrilled to have helped define key aspects of fistula biology - an area where data have long been limited.
“This work exemplifies the power of interdisciplinary analysis at the interface of clinical medicine and science - the foundation of high-quality IBD care.”
The paper is titled ‘Spatial Fibroblast Niches Defining Crohn’s Fistulae’ and appears in Nature. The research received support from several organizations including UKRI Medical Research Council (MRC), Leona M. and Harry B. Helmsley Charitable Trust, National Institute for Health and Care Research (NIHR) Oxford Biomedical Research Centre, and Wellcome Trust.