Examining intestinal fibrosis in patients with Chron's disease using organoid models
Fibrosis is commonly associated with high morbidity and mortality, indeed, nearly 45% of all deaths in the developed world are attributed to chronic fibroproliferative diseases. Strong evidence indicates that chronic inflammation triggers fibrosis that, once established, may progress independently.
Serious complications of Crohn¿s disease (CD), a form of Inflammatory Bowel Disease (IBD), involves the formation of intestinal fibrotic stenosis followed by obstruction.
Currently, a comprehensive understanding of the pathogenesis of gut fibrosis in CD remains uncertain hampering the development of effective therapeutic strategies.
Patient-derived organoids represent a promising novel platform for the study of the development and progression of fibrosis (fibrostenosis) in CD patients.
In the present project, we aim: 1) to induce the inflammation-mediated fibrosis in human intestinal organoids (colonoids), whose generation has been recently set up in our laboratory, from intestinal stem cells originated from isolated intestinal crypts of the colon of CD patients, by exposing them to pro-inflammatory (TNFalpha) and pro-fibrotic (TGFbeta) agents; 2) to confirm in colonoids the role of the transcription factor ZNF281 as a promoter of gut fibrosis, previously shown in established intestinal cell lines; 3) to explore in colonoids the potential of non-pharmacological agents, in particular the beta 18-glycirrethic acid, the main metabolite of glycyrrhizin obtained from licorice root, and the extracts from Scutellaria baicalensis Georgi and Boswellia serrata, alone or in combination, as anti-fibrotic drugs.
This is a translational and innovative research project that will lead to remarkable advances in the scientific knowledge of CD fibrosis and management. The novelty of this study lies in the set-up of fibrotic colonoids as a novel tool to investigate the role of new protagonists of the intestinal fibrotic process and the identification of novel therapies for its treatment.