An update on our current funded project of just over £130,000 over two years
We wanted to share an update on a research project we have funded to a group of investigators at the University of Oxford (Dr Khalid Shamiyah, Dr Matthias Friedrich, Dr Katharine Baker, Dr Bruce George, Dr Mathilde Pohin, Prof Fiona Powrie).
Crohn’s Disease (CD) is a chronic inflammatory bowel condition that significantly impacts quality of life, with most patients requiring surgery at some point. Recent discoveries suggest that the enteric nervous system (ENS) may hold critical insights into the disease’s progression and potential new treatment pathways.
Our ground-breaking research study, spearheaded by Fellow Dr Shamiyah and coordinated by Dr Friedrich, aims to unravel the architectural, cellular, and molecular alterations of the ENS in individuals with CD. By analysing tissue samples from CD-affected bowel regions and comparing them with healthy adjacent tissues, we strive to construct a comprehensive ENS map in the context of CD. This map will guide us in identifying specific changes associated with the disease, providing a deeper understanding of its pathogenesis.
The prevalence of CD continues to increase in industrialised countries. CD predominantly affects young people and is a chronic inflammatory disease with a relapsing remitting course and without any available cure.
It can affect any part along the entire length of the gastrointestinal tract, with most patients presenting with inflammation of the small intestinal bowel wall. Research into the aetiology of Crohn’s disease has focused on the interaction between the gut immune system, the gut microbiome, genetic predispositions, and environmental influences such as smoking. Despite recent advances in revealing disease pathogenesis and the development of several approved medical therapies, the majority of patients requires at least one abdominal surgical
procedure during their lifetime.
The intestine is a highly innervated organ, but the importance of the enteric nervous system (ENS) in Crohn’s disease remains largely unexplored.
The cellular ENS components comprise neurones, interstitial cells of Cajal and enteric glial cells which are predominantly located in the submucosa (Meissner’s plexus) and also between the circular and longitudinal muscle layers (Auerbach’s (myenteric) plexus) of the bowel. Extensions of the ENS however also reach into the layer that is directly underneath the epithelial barrier shielding the bowel wall from the intestinal lumen (mucosa).
Given historic evidence of changes in the ENS observed in CD, the team of investigators working with Dr Friedrich and Dr Khalid Shamiyah are conducting a comprehensive study and quantification of ENS changes in CD, with the eventual aim of exploring how these could be targeted by medical therapy. During the last six months, the investigators completed mapping of the enteric nervous system in 2D tissue sections in CD and control cases. This analysis demonstrated clear changes in ENS structures in CD compared with controls, including more extensive ENS networks in the intestinal layers underneath the epithelial barrier in CD. The investigators have now moved on to formally quantifying these on a greater number of samples using expert pathologist scoring.
Although the 2D imaging has revealed valuable information, it is possible that 2D imaging might miss pathologic changes that occur in the 3D network of the ENS. Therefore, the team is now collaborating with Dr Fränze Progatzky (Kennedy Trust Group Leader in Tissue Biology & Wellcome Trust Career Development Fellow) and has successfully labelled the ENS in 3D in CD patient tissues.
Our multi-tiered approach includes advanced histopathologic assessments, innovative immunofluorescent profiling, and cutting-edge spatial transcriptomics (molecular profiling), alongside establishing primary nerve cultures for mechanistic studies. By delineating the alterations in the ENS, we seek to uncover the mechanisms by which it influences the immune system and intestinal integrity in CD patients.
This research holds the promise of identifying new biomarkers for CD prognosis and advancing our understanding of ENS involvement in gut diseases. Our ultimate goal is to pioneer ENS-targeted therapies that could revolutionise CD management, offering hope for improved patient outcomes and quality of life.
Below is a video of Crohn’s patient Cian sharing her journey and experience.