Work at the Milner Therapeutics Institute in collaboration with Professor Matthias Zilbauer has made a promising step toward identifying more precise and personalised treatments for patients with Crohn’s disease.
The research published today in Gut reports how Milner Research Associate Thomas Dennison and colleagues grew and analysed more than 300 mini-guts – also known as gut organoids – in the lab to investigate changes in the gut epithelium that were found in Crohn’s disease, but not in organoids from healthy donors. Specifically, the authors looked at changes to a modification on the DNA known as methylation: they looked for differences in the DNA isolated from healthy versus diseased gut organoids. One of the differences identified could contribute to the increased gut inflammation commonly seen in patients with Crohn’s disease and has identified potential pathways that could be therapeutically relevant.
The MTI’s collaboration with the Zilbauer lab was formed in 2021. The Target Discovery Team, led initially by Rebecca Harris and more recently by Erica Bello, worked with the Zilbauer lab to investigate whether patient derived gut organoids established using protocols shared by the Zilbauer group could be adapted for high throughput experiments to examine the impact of drugs and genome editing on the biology of Crohn’s disease. The Zilbauer lab also collaborates with the Milner’s Computational and AI team, led by Namshik Han, to analyse large RNA and DNA datasets generated by the wet lab teams and thereby prioritise potential therapeutic targets and pathways to investigate.
The collaborations between the Zilbauer lab and the teams at the MTI are ongoing and are likely to result in more publications reporting potential new therapeutic routes for patients with inflammatory bowel disease.
Click here to read the University of Cambridge press release.
It’s exciting to have shown for the first time that stable epigenetic changes can identify problems in the gut epithelium in patients with Crohn’s disease. This marks an exciting step toward creating more personalised treatments for patients with Crohn’s disease and IBD.
Reference:
Patient-derived organoid biobank identifies epigenetic dysregulation of intestinal epithelial MHC-I as a novel mechanism in severe Crohn’s disease.
Dennison, T et al.. Gut; 11 Jun 2024; 10.1136/gutjnl-2024-332043
Abstract from the paper:
Epigenetic mechanisms, including DNA methylation (DNAm), have been proposed to play a key role in Crohn’s disease (CD) pathogenesis. However, the specific cell types and pathways affected as well as their potential impact on disease phenotype and outcome remain unknown. We set out to investigate the role of intestinal epithelial DNAm in CD pathogenesis.
We generated 312 intestinal epithelial organoids (IEOs) from mucosal biopsies of 168 patients with CD (n=72), UC (n=23) and healthy controls (n=73). We performed genome-wide molecular profiling including DNAm, bulk as well as single-cell RNA sequencing. Organoids were subjected to gene editing and the functional consequences of DNAm changes evaluated using an organoid-lymphocyte coculture and a nucleotide-binding oligomerisation domain, leucine-rich repeat and CARD domain containing 5 (NLRC5) dextran sulphate sodium (DSS) colitis knock-out mouse model.
We identified highly stable, CD-associated loss of DNAm at major histocompatibility complex (MHC) class 1 loci including NLRC5 and cognate gene upregulation. Single-cell RNA sequencing of primary mucosal tissue and IEOs confirmed the role of NLRC5 as transcriptional transactivator in the intestinal epithelium. Increased mucosal MHC-I and NLRC5 expression in adult and paediatric patients with CD was validated in additional cohorts and the functional role of MHC-I highlighted by demonstrating a relative protection from DSS-mediated mucosal inflammation in NLRC5-deficient mice. MHC-I DNAm in IEOs showed a significant correlation with CD disease phenotype and outcomes. Application of machine learning approaches enabled the development of a disease prognostic epigenetic molecular signature.
Our study has identified epigenetically regulated intestinal epithelial MHC-I as a novel mechanism in CD pathogenesis.