Understanding Gut Disease with a Network Approach

Diseases of the gut are notoriously difficult to diagnose, let alone understand. Because of this, scientists are working on developing a more network-based approach to study them. Rather than trying to understand individual symptoms or the role of individual genes, we can use computational methods to get a deeper understanding of how genes work together in complex systems, and how, in disease, these can fail.

In a study published today in Molecular Omics, Earlham Institute researchers pioneered a combined experimental and computational pipeline that tells us what genes are the important ‘master regulators’ in the gut and which of these genes overlap with those associated with IBD, presenting new angles for future research.

In the gut, Paneth cells release antimicrobial peptides that protect the gut from pathogens, and goblet cells release mucus to create a protective barrier. Dysregulation of these cells’ function is implicated in diseases such as IBD. However, a promising new method for understanding the role of these cells has recently been introduced.

Stem cells can be cultured from either mouse models or patients to make a small model of a human gut, known as an organoid. Using this model system, the effects of different treatments can be explored—opening avenues for precision medicine, among others. These organoids can also be modified to study the relative importance of different cell types within the system and to explore interactions between different genes in healthy or diseased cells.

The new pipeline allowed the researchers to compare gene expression in organoids that were enriched for either Paneth cells or goblet cells with those that were not. These could then be compared with a growing database of known gene interactions.

Essentially, the researchers were able to tag the genes that regulate others, highlighting, in particular, those genes that regulate many processes and are important for goblet and Paneth cell function. The finding that many of these genes overlap with inflammatory processes both confirms the important role of Paneth cells in IBD and also opens another route to understanding these illnesses.

“Now we have a pipeline that we can use to investigate organoids generated from IBD patients and analyze drug compound or probiotic effects on these key cell types,” says senior author Tamas Korcsmaros.