Introduction
The below has been written on behalf of the Study Team, Khalid Shamiyah, Anna Ladach, Luca Verger, Mathilde Pohin, Fiona Powrie, Fränze Progatzky, Katherine Baker, Bruce George and Matthias Friedrich.
We would like to thank the Oxford Colon Cancer Trust once again for their generous support of this project. We are looking forward to the exciting findings this project will reveal, which may ultimately help improve treatment of Crohn’s disease, and are grateful for your generosity.
Crohn’s disease (CD) is a chronic relapsing inflammatory condition that can affect any part of the gastrointestinal tract. There is currently no cure for CD. Less than half of the patients treated with standard-of-care medication enter or remain in remission long-term1-2.
Even if effective in ameliorating inflammation, immunosuppressive therapy for CD does not significantly affect the progression of fibrosis. This is evidenced by rates of surgery remaining high, despite the introduction of biologics and other advanced medical therapies in CD3-5.
As a result, current medications may not sufficiently target the key drivers of this established disease. Stromal cells of mesenchymal origin have long been hypothesised as a key cellular driver of fibrosis due to their capacity to deposit extracellular matrix and remodel connective tissue6-7. We and others have associated fibroblasts with tissue inflammation and non-response to medical therapy in inflammatory bowel diseases (IBD), including CD8-14. Very recently, the enteric nervous system (ENS), comprising neurons and glial cells, has been revealed as a key structure in maintaining a healthy intestinal barrier15.
During this project, we mapped the pathological changes in the ENS that occur in CD. Reversing these changes and thereby re-establishing healthy gut homeostasis may represent a novel therapeutic target for refractory Crohn’s.
We mapped changes in the ENS in CD from three different angles: Immunofluorescence-based labelling of protein ENS structures in 2D (Figure 1); 3D sections (Figure 2); and transcriptional changes in the ENS by spatial transcriptomics technology (Figure 3). In addition to 2D (Figure 1) changes in the ENS, the 3rd dimension (Figure 2) proved pivotal in appreciating changes in the ENS network that couldn’t be detected in 2D. We also learned that studying the ENS in the context of changes in surrounding immune cell niches (Figure 3) enables a comprehensive description of pathologic ENS changes in CD; dissection gene expression (transcriptional) changes within cells (neurons, glia) using spatial transcriptomics will allow us to design therapies specifically targeting these processes. We are now in the final phase of our research where we are generating:
- A comprehensive 2D and 3D map of the ENS in health and disease, including pathologic
changes in CD; - Candidate pathways and ENS cellular subsets that may serve as therapeutic targets;
- Patient tissue-derived ENS in vitro cultures for perturbation studies (pre-clinical platform).
Looking ahead
The 3D mapping and spatial transcriptomics-based characterisation of ENS changes has proven particularly insightful. As this project nears completion, we are now seeking funding to build upon this important work and expand this profiling in two ways:
1) Sampling over 100 tissues from patients with CD and controls, in order to be powered to
detect even the smallest changes in disease;
2) Not only describing changes in the ENS, but also the changes in the immune system,
epithelial barrier and other stromal components in CD.