A team of scientists from the Norwich Research Park have applied network analysis to the study of cells in the gut that are crucial to health. By employing their methods to organoids grown from human gut cells, they hope to disentangle the complex gene interactions that define these cells and understand how disturbances in this regulatory network lead to conditions such as Inflammatory Bowel Disease.

The lining of the gut plays a critical role in keeping us healthy. Not only must it efficiently allow the absorption of nutrients from our food, it must also prevent bacteria and other microbes from escaping the gut and getting into our blood stream. To achieve this, a number of specialist cell types work in unison with the immune system to maintain the integrity of the gut barrier and a healthy balanced microbial population.

Disruption to this system of checks and balances has been linked to gut conditions such as Inflammatory Bowel Disease (IBD). Efforts to understand the causes of these conditions involve unpicking at the molecular level how these cells function and how they communicate with other cells, and the immune system.

3D Intestinal organoid

Studies on isolated cells don’t accurately reflect their natural environment, where different cell types in the gut lining interconnect and function in a coordinated fashion. But studying the gut lining itself is difficult and invasive. To study the role of cell populations, researchers are using three dimensional cellular masses called organoids as models for studying the organs themselves. Gut organoids, or enteroids, are particularly useful as they can recreate the relationships between different specialised cell types, as well as interactions with microbes.

In a new study published in the journal Molecular Omics, an interdisciplinary team of researchers led by Dr Tamas Korcsmaros used gut organoids to model the patterns of gene expression in two key cell types, Paneth cells and goblet cells.

Paneth cells are found at the bottom of crypts in the lining of the small intestine and produce antimicrobial peptides and other factors that contribute to defending the host. The small intestine also houses goblet cells whose function is to secrete proteins that make up a layer of mucus that coats and protects the gut lining.

Dr Korcsmaros is a joint appointment between Norwich Research Park partners the Quadram Institute and the Earlham Institute. This study combines the gut health research in QI with the Earlham Institute’s computational science expertise and the Korcsmaros group’s network analysis focus. And this integrated, interdisciplinary approach has provided valuable new insights into the regulatory networks of goblet and Paneth cells.

Gut organoids can be enriched for either of these cell types by manipulating the conditions that they are grown in. Analysing the differences that are caused by skewing the cell types in the organoids indicated the important genes needed for differentiation of these cell types and their maintenance. This provides valuable information about how the cells are “rewired” to deliver their specific functions, and the master regulatory genes that are shared, and differ, in both cell types. Many of these master regulator genes, particularly in Paneth cells, have previously been associated with IBD, so this study provides evidence that it is dysregulation of these key cell master regulators that contributes to IBD.

These findings were derived using gut organoids grown from cells taken from mice but the team now want to apply the same principles and workflow to human-derived organoids. The embedding of the Norfolk and Norwich University Hospital’s Gastrointestinal Endoscopy Centre in the Quadram Institute alongside research teams will greatly facilitate this. Biopsies taken from consenting patients, both healthy and with pre-existing conditions, provide and exciting potential source of human gut organoids for comparative regulatory network analysis that will help identify the key regulators and signalling pathways in diseased cells. This will help us understand the triggers of complex gut conditions like Crohn’s disease and ulcerative colitis and point to new targets for pharmaceuticals to help alleviate these conditions.

Reference: 

Regulatory network analysis of Paneth cell and goblet cell enriched gut organoids using transcriptomics approaches, A Treveil, P Sudhakar, Z J Matthews, T Wrzesinski, E J Jones, J Brooks, M Olbei, I Hautefort,  L J Hall, S R Carding, U Mayer, P P Powell, T Wileman, F Di Palma, W Haerty and T Korcsmáros. Molecular Omics DOI: 10.1039/c9mo00130a