Studying immune-epithelial-microbial interactions in Inflammatory Bowel Disease using mini-guts

The maintenance of intestinal homeostasis depends on the interactions between several compartments including the gut epithelium, the intestinal microbiota and the gut-associated immune system. Disrupting this delicate balance results in intestinal inflammation, which is associated with several diseases such as Inflammatory Bowel Disease (IBD), cancer and neurodegenerative diseases. We developed a novel system of lymphocyte cultures in intestinal organoids (“mini-guts”) that mimics the intestinal environment. Intestinal organoids are generated from intestinal stem cells that differentiated into the several types of intestinal epithelial cells forming intestinal crypts. We can add bacteria and bacterial metabolites to our innovative culture system to determine how these microbial components influence immune and epithelial cell phenotype and function (Figure-1). This is disease relevant as IBD patients present altered metabolite composition in their gut due to due to differences in composition of their microbiota.

This pioneer system led us to identify novel roles for innate lymphoid cells (ILC) (Jowett et al, under revision) in regulating intestinal epithelial cells and fibroblast proliferation and function. To facilitate the translation of our discoveries our co-culture system is established with human cells allowing us to use patients’ cells to test the importance of our novel pathways in the clinical setting and the potential to modulate these pathways to promote health.

The overall aim of this project is to identify key pathways responsible for the crosstalk between intestinal epithelial cells, lymphocytes and bacteria in the context on intestinal associated diseases. IBD patients have alterations in the composition of their gut microbiota, with less diversity and accumulation of pathogenic strains. However, the cellular and molecular mechanisms associated with such changes are still being elucidate and using our novel reductionist system we aim to pinpoint the effect of specific bacteria on the epithelial and immune compartments.

During this project the student will acquire a wide range techniques such as flow cytometry, imaging, molecular biology (including CRISPR), microbiology, transcriptomics, single cell RNAseq, epithelial, lymphocyte and stem cell biology and mucosal immunology techniques.