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Cellular changes lead to childhood-onset Crohn's Disease

Tuesday December 8th 2020

Key cellular changes have been identified that are linked to the development of Crohn’s Disease in children, British researchers have reported.

A new study, published yesterday (7 December 2020) in Developmental Cell, revealed that researchers from the University of Cambridge and the Wellcome Sanger Institute tracked very early stages of human foetal gut development and found specific cell functions that appear to be reactivated in the gut of children with Crohn's Disease.

Study leader Dr Matthias Zilbauer, from the Department of Paediatrics at the University of Cambridge and honorary consultant in paediatric gastroenterology at Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, said identifying intricate cellular mechanisms of how the gut develops could help in the management and treatment of the condition.

“Crohn's Disease can be particularly aggressive and more treatment-resistant in children, so there's a real need to understand the condition when it affects them and perhaps come up with childhood-specific treatments,” he added.

The researchers used single-cell RNA sequencing to look at gene expression in individual cells of the developing human gut, six to ten weeks after conception.

Focusing on the intestinal epithelium, they found cells dividing constantly even at this early stage, guided by messages from other cell types. This allows the gut to grow and form the structures needed for good gut function later in life.

When the team analysed the tissues from the guts of children aged four-12 with Crohn's Disease, they detected some of the cellular pathways active in the epithelium of the foetal gut seemed to be reactivated in Crohn's Disease.

These pathways were not active in healthy children of a similar age.

Dr Zilbauer said: “Our results indicate there might be a reprogramming of specific gut cell functions in Crohn's Disease. We don't know whether this is the cause of the disease or a consequence of it, but either way it is an exciting step in helping us to better understand the condition.”

The team also found that lab-grown 'mini-guts' undergo similar individual cellular changes to those inside a developing foetus, which could demonstrate that lab-grown models are an accurate tool for future research into very early gut development and associated diseases.

The study forms part of the global Human Cell Atlas effort, which aims to create a map of the human body.

Dr Sarah Teichmann, of the Wellcome Sanger Institute and co-chair of the Human Cell Atlas Organising Committee, said: “With single-cell RNA sequencing we can look at any tissue and identify the individual cell types it's made up of, the function of those cells, and even identify new cell types.

“A complex tissue like the gut contains different cell types, and these 'talk' to each other - the function of one cell affects the function of another. That's particularly important in the early stages of gut development, and something we can interrogate using computational analyses of single cell RNA sequencing data.”

Although this study focused specifically on the dynamics of intestinal epithelial cells, it generated information on about 90,000 primary human intestinal cells of all types. These data have been available at: http://www.gutcellatlas.org

Elmentaite R, Ross A, Roberts K et al. Single-cell sequencing of developing human gut reveals transcriptional links to childhood Crohn’s disease. Developmental Cell 7 December 2020.

Tags: Child Health | Gastroenterology | UK News

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