Scientists have developed a new computational biology method to improve inflammatory bowel disease understanding and targeted treatment.
Data indicates that around 500,000 people in the UK live with inflammatory bowel disease; this terminology mainly describes two conditions: ulcerative colitis and Crohn’s disease, which involve the inflammation of the gut. Medications can treat inflammatory bowel disease; however, finding new targeted treatments is essential for improving quality of life.
Scientists at the Earlham Institute, Quadram Institute and the University of East Anglia on the Norwich Research Park set out to develop a new method to understand inflammatory bowel disease and allow for targeted clinical treatments.
Their findings were published recently in the prestigious Journal of Extracellular Vesicles, one of the leading journals covering vesicle-mediated biological communication.
The importance of gut health
The microbiome lives in the human gut and plays a crucial role in maintaining good health. A disturbed microbiome can cause a range of gut-related conditions such as inflammatory bowel disease.
People with inflammatory bowel disease often have an imbalance in their gut microbiome, especially Bacteroides and Firmicutes bacteria. Despite this knowledge, it is unclear how this translates to the progression of inflammatory bowel disease. A greater understanding of inflammatory bowel disease and the bacteria imbalance can lead to innovative research into targeted, effective treatment.
The research team, which included microbiologist and immunologist Professor Simon Carding from the Quadram Institute and UEA, with Dr Tamás Korcsmáros, a systems biologist whose expertise lies in cellular signalling networks from the Earlham and the Quadram Institutes, set out to understand how bacteria and human cells communicate.
Professor Carding and his team investigated the Bacterial Extracellular Vesicles (BEVs), which are tiny packages created by bacteria that fill with various molecules and release from the cell. They can cross the gut lining, reaching cells of the immune system where they are recognised by receptors. The contents of the BEVs are molecular signals that then trigger the immune cells to react, with that signal potentially cascading into widespread effects.
In a healthy gut, BEVs and their cargo can contribute to anti-inflammatory responses of the immune system, but in an inflamed inflammatory bowel disease patient, this response is lost. The lack of understanding of how they interact with the immune system is a research gap that the scientists set out to address.
Analysing inflammatory bowel disease
Dr Tamás Korcsmáros and his team used a previously published dataset about which genes are actively making proteins in 51 types of colon cells, from either healthy conditions or under the effect of ulcerative colitis. This dataset contained inflamed and uninflamed data from the same patients, allowing investigation into the inflammation and the complex disease. The team also analysed and characterised all of the cargo proteins obtained from BEVs made by the common gut bacterium Bacteroides thetaiotaomicron (Bt).
The research uncovered biological processes specific to one type of immune cell. This one pathway, known to be important in immunity and inflammation, allowed the team to identify differences between the same cell types in healthy and ulcerative colitis conditions. Experiments using cell cultures grown together with BEVs validated the predictions from the computational modelling.
They combined the datasets using an experimentally verified computational pipeline that predicts the interacts between microbial and host proteins, and how these trigger signalling systems. The team could utilise this data to note the differences between a healthy gut and inflammatory bowel disease. This model showcased the communication between gut bacteria and the immune system, which meant the researchers could understand the biological processes affected by microbial proteins.
“The finding that BEVs affect the immune system’s pathways in a cell-type-specific manner, and that they are altered in inflammatory bowel disease is an important step to understanding the condition, and potentially could help in developing BEVs as a therapeutic system,” said Lejla Gul, first author on the paper and an iCASE PhD student at the Earlham Institute and the Quadram Institute, supported by the BBSRC Norwich Research Park Biosciences Doctoral Training Partnership.
“Studying interkingdom connections with BEVs in a cell-type-specific resolution requires multi-disciplinary expertise and various ‘omics datasets. Then you need a computational pipeline to analyse the data from different patients. Besides the actual scientific results, in the paper, we introduce an open-source pipeline that others can use to analyse their data,” said Dr Tamás Korcsmáros. “We hope that what we have demonstrated here in this study will be applied by others for understanding the mechanisms how other bacterial species communicate with our cells, and how it may be altered in other diseases.”
“This study highlights the importance and impact of laboratory scientists working with bioinformaticians to develop the means and tools for understanding the highly complex nature of the interactions between our gut microbes and cells of our body that is central to maintaining our health,” said Professor Simon Carding. “The insights gained from studies such as this will be invaluable in developing new interventions aimed at maintaining health by promoting beneficial interactions with gut microbes and preventing harmful ones that can lead to diseases such as IBD.”