New Spotlight: Patient-derived organoids reveal molecular subtypes of Crohn’s disease
A living organoid biobank of patients with Crohn’s disease reveals molecular subtypes for personalized therapeutics
Introduction
Crohn’s disease (CD) is a chronic condition characterised by intestinal inflammation that progressively leads to bowel destruction involving fistulas and stricturing fibrosis, along with other extra-intestinal complications. Disease triggers are likely to be multifactorial, but are thought to include interactions between environmental insults, genetic background and the intestinal immune system and microbiome. Disease management can be complex, is not curative, and can fail to maintain remission. In a recent report, Tindle et al descibe how the study of patient-derived organoids offers insights into the molecular basis for differing Crohn’s subtypes and potential methods for delivering more personalised, relevant treatments to patients.
Main Points
- Patient-derived organoids (PDOs) were derived from colon biopsies taken from a cohort of inflammatory bowel disease (IBD) patients and healthy subjects. Comparison of differentially expressed genes in PDOs from Crohn’s disease vs healthy subjects with publically available datasets of laser microdissected colonic epithelium in IBD affected patients revealed that the PDO gene expression changes reproduced those found in the tissue-derived epithelium.
- Principal component analysis of the PDO gene expression data revealed that the CD PDOs clustered into 2 distinct groups, identified as distinct molecular subtypes of CD. One, whose gene expression patterns identified an infectious disease-like state, but with reduced inflammatory/cytokine response termed immune-deficient infectious CD (IDICD) and one characterised by cellular stress, senescence and reduced anti-fibrotic signalling named stress and senescence-induced fibrostenotic CD (S2FCD).
- Futher analysis of genomic DNA from the PDOs appeared to reconcile the transcriptomic data with known genomic risk factors for CD including SNPs in NOD2 and ATG16L1 (bacterial clearance – ICICD subtype) and YAP1-IL-18 (proinflammatory pathway – S2FCD PDOs). These finding were matched by measurements of impaired bacterial clearance and cytokine insufficiency in ICICD PDOs and increased cellular senescence and genotoxic stress in S2FCD PDOs, indicating a convergence of transcriptome, genome and phenome.
- To determine if the PDOs from the CD subtypes could function as a platform for testing personalised interventions by reversing the established phenotypic differences in each subtype, a proof of concept study indicated that the senescence associated with the S2FCD subtype could be reversed with a JAK1/2 kinase inhibitor and that the impaired bacterial clearance in ICICD PDOs could be improved by an dual agonist of PPARα/γ.
Conclusion
The authors report the indentification of two distinct molecular subtypes of CD combining transcriptomic, genomic and phenotypic characterisation of a bank of PDOs. Critically, the two groups in the molecular classification cut across the established clinical subtypes (from the Montreal classification) suggesting that including a diagnostic test based on these new subtypes might improve a stratification of CD patients with colonic involvement.
EPISTEM SERVICES
Epistem offer a range of models that allow researchers to look at the importance of different cell types for the development and maintenance of inflammatory bowel disease. Models of both acute and chronic colitis are available. Key cell populations can be identified by immuno-labelling techniques and can be administered to control disease, or isolated for phenotyping and/or short-term culture and functional assays. A range of analytical platforms are available to support this work, including histology and quantitative image analysis, flow cytometry, luminex-based multiplex analysis of cytokines and chemokines and gene expression analysis
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