Gut

Researchers study two gut areas: the intestinal epithelium, seeking therapies to speed repair after IBD damage, and the enteric nervous system, developing treatments for Hirschsprung's disease.

Intestinal epithelium

We have recently determined that excessive epithelial cell shedding from the villus tip in the human terminal ileum results in loss of intestinal barrier function, and surprisingly that this phenomenon is able to predict whether inflammatory bowel disease (IBD) is likely to relapse in the near future.

Additionally, we have shown that epithelial cell specific gene regulation modulates their susceptibility to immune cell-derived inflammatory mediators. Further exploration of these interactions is necessary to develop both cellular and molecular therapeutics that will stimulate the rapid regeneration of the intestinal epithelium following intestinal barrier breakdown during active IBD.

Key areas of research

Identifying key regulators of the intestinal stem cell niche, epithelial cell proliferation, differentiation and cell shedding

This is in order to understand the processes that maintain intestinal barrier function and modulate an organism’s susceptibility to both intestinal and systemic diseases such as IBD and sepsis.

Understanding the mechanisms of IBD pathogenesis

This is in order to enable the development of novel therapies that target the rapid re-epithelialisation of the intestine to prevent bacterial invasion, inflammation and the breakdown of intestinal barrier function (features that are also present in Hirschsprung-associated enterocolitis).

Generating 3D intestinal organoid co-culture models to determine signalling mechanisms between intestinal compartments

We aim to determine the bidirectional signalling mechanisms in co-cultures involving epithelial, immune, bacterial and ENS components in order to elucidate novel mechanisms to be targeted using regenerative medicine therapy approaches for IBD, Hirschsprung’s disease, short bowel syndrome and sepsis.

Key investigators

• Dr Carrie Duckworth
• Professor Mark Pritchard
• Professor Barry Campbell.

Cross-disciplinary collaborators

• Dr Janine Coombes
• Professor Chris Probert.

Gastrointestinal researchers at Liverpool participate in the FP7 Sysmed IBD Research Programme.

Enteric nervous system

Hirschsprung's disease is a potentially life-threatening condition resulting from the congenital absence of ENS ganglion cells (aganglionosis) in the distal gut. We propose that transplantation of ENS progenitor cells into aganglionic bowel has the potential to provide a novel treatment for Hirschsprung’s disease.

ENS progenitor cells can be isolated from the postnatal human gut and they proliferate in tissue culture as neurospheres, subsequently differentiating into neural cells by a Notch-dependent mechanism. We have shown that transplanted neurosphere neurons can regulate gut contractility.

We have recently made the surprising discovery that ENS progenitors can be derived from the glial cells of extrinsic (non-ENS) nerve fibres present in Hirschsprung’s aganglionic gut.

Areas of focus

Why do ENS progenitor cells not develop normally in Hirschsprung’s disease in vivo?

We are following up new lines of research into the mechanisms involved in ENS development and the pathogenesis of Hirschsprung’s disease.

ENS progenitor cells for autologous transplantation

These can be isolated from the patient’s own tissue normally discarded at surgery.

Existence of progenitor cells in the aganglionic gut

This raises the novel possibility of inducing their differentiation in situ to treat Hirschprung’s disease.

Key investigators

• Dr David Edgar
• Professor Simon Kenny
• Dr Bettina Wilm.