Researchers identify cellular drivers of gut scarring in Crohn’s disease

As inflamed regions of the gut form scar tissue, the space within the gut lumen becomes smaller and more restricted, leading to symptoms of gut obstruction. There is currently no drug treatment available for this complication – eventually as fibrosis worsens, surgery becomes the only option.

The researchers discovered that the biggest build up of scar tissue takes place in the submucosa (a layer of tissue beneath the inner lining of the bowel) – this indicates that the submucosa could be the starting point where the scarring begins. 

Inflammation, the hallmark of Crohn's Disease, brings clusters or aggregates of immune cells into the submucosa. Using single-cell RNA sequencing (scRNA-seq) to study fibrosis in Crohn's Disease, the researchers uncovered an unusual clustering of endothelial cells - cells which usually line blood vessels - around these groups of immune cells (known as Crohn's lymphoid aggregates or CLAs). These clusters of blood vessel cells signal to scar building cells (fibroblasts/myofibroblasts) either directly or through macrophages, to start producing excessive collagen or scar tissue. This suggests that these Crohn's lymphoid aggregates may have a significant role in driving the process of fibrosis. 

Pathologists, gastroenterologists, biomedical scientists and computer experts at the University of Edinburgh and Heriot-Watt University in Edinburgh worked together with researchers at the Earlham Institute and Sanger Institute for over 6 years, to study the cellular and molecular mechanisms of the process of fibrosis in Crohn's Disease, in order to try to identify new therapeutic targets that can be used to treat patients to try to slow down or reverse fibrosis, to help such Crohn's patients."

Professor Mark Arends, Professor of Pathology and Head of Edinburgh Pathology, University of Edinburgh

This study demonstrates the value of single-cell transcriptomics to complement histological analysis of clinical samples. By linking tissue pathology to cell and signalling mechanisms we can gain greater resolution of disease associated sub-populations of cells which are typically challenging to separate morphologically. 

The paper is generated from an international consortium of researchers collaborating to create a 'gut cell atlas' - a research tool that identifies and characterizes gut cells - enabling greater insight and faster resolution for diseases impacting the digestive system. 

At Earlham Institute, scientists in the Papatheodorou Group are combining their computational expertise in single-cell genomics with cutting-edge data science and AI to develop tools and methodology needed to integrate data, standardize metadata, build cell atlases, and analyze these atlases across different species.

Dr Gregory Wickham, Postdoctoral Researcher in the Papatheodorou Group and joint first author at the Earlham Institute said: "Fibrostenosis remains a significant and unaddressed source of morbidity in Crohn's disease and this work represents an important contribution to understanding its progression. This collaboration allowed us to combine detailed pathological analysis with single-cell RNA sequencing to characterise how lymphoid aggregates accumulate alongside fibrosis and reveal how cells may be coordinating their behaviour to drive this process. 

"These insights will support our continuing research into Crohn's disease with the aim of identifying candidates for novel therapeutics in order to better manage fibrostenotic complications."

Professor Irene Papatheodorou, Head of Data Science at Earlham Institute, said: "The power of single-cell transcriptomics coupled with computational analysis lies in its ability to reveal cellular interactions that aren't discernible otherwise. By integrating our computational frameworks with clinical pathology, we have been able to map the specific cellular neighborhoods within the submucosa where inflammation transforms into permanent scarring. This study is paving the way to understand Crohn's disease progression trajectories and in the future identify new targets for intercepting the molecular mechanisms of fibrosis."

Further analysis is needed to confirm these interactions, and therefore, the next steps for this research will involve increasing the number of gut samples analyzed using the same methodology. 

Funded by The Leona M. and Harry B. Helmsley Charitable Trust, the largest private philanthropy focused on Crohn's Disease, this research is vital for the discovery of new therapeutic targets to find better treatments for the hundreds of thousands of Crohn's Disease patients suffering from this painful complication – severely impacting their quality of life.

Dr Michael Glinka, Postdoctoral Research Fellow at the University of Edinburgh's Institute of Genetics and Cancer, and joint first author said: "The fundamental necessity to understand the driving forces that lead to the late-stage fibrostenosing lesions in Crohn's Disease is what led to this collaboration and work between University of Edinburgh, Heriot-Watt University, Sanger Institute and Earlham Institute. 

"Without proper characterization and understanding, novel approaches and treatments cannot be developed, so we hope that with this work and the follow-up studies, we will be able to help aid the generation of better treatments in future."

The paper 'Crohn's lymphoid aggregates with endothelial clusters colocalize with submucosal fibrosis in fibrostenosing Crohn's disease' is published in The Journal of Pathology.