Research

Our aim: To further our understanding of human gut health and related diseases particularly those affecting children.

By translating findings derived from laboratory-based research back into clinical care, we strive to improve the health and wellbeing of patients. We believe that successful translational research can only be achieved by working closely with affected patients and the wider public.

We therefore place major emphasis on patient and public engagement to ensure our efforts are aligned and we fully benefit from their unique insight. With research becoming increasingly complex, it is of critical importance to collaborate with other research groups across the globe, clinicians, and related healthcare professionals. Most importantly, applying novel findings to clinical care and ultimately making them widely available requires interaction with and support from industry partners.

Our research

A major focus of our research lies on the role of epigenetic mechanisms in regulating intestinal epithelial cell function. More specifically, we are investigating how DNA methylation (DNAm), one of the major epigenetic marks operative in mammalian cells, impacts on gene transcription and cell function of the human intestinal epithelium in healthy gut development, at homeostasis as well as related diseases such as Inflammatory Bowel Diseases (IBD). Epigenetic mechanisms can be influenced by environmental factors such as diet, microbial colonisation, lifestyle factors (e.g. smoking) and exposure to medical treatment (e.g. antibiotics). As such they could provide the link between changes in our environment and the major increase in the incidence of many multi-factorial disease such as IBD.

As one of the main experimental models, we use human mucosa derived intestinal epithelial organoids. Over the past 8 years, we have generated a large living biobank containing >1000 frozen organoid lines that form the basis for future translational research efforts. In addition to organoids derived from intestinal mucosal samples, induced pluripotent stem cells (iPSCs) can be differentiated into intestinal epithelium.

Current projects focus on the development of clinical biomarkers to guide treatment of children diagnosed with Inflammatory Bowel Diseases, test novel treatments targeting the intestinal epithelium using our organoid model and further develop 2D and 3D culture systems which allow complex co-culture of the intestinal epithelium with other cell types (e.g. immune and stromal cells) as well as the intestinal microbiota.

**Figure 1:** Generation and downstream applications of human, mucosa derived intestinal epithelial organoids (hIEOs).

**Figure 2:** Use of human intestinal epithelial organoids as translational research tools for the development of novel treatment approaches.

**Figure 3:** Brightfield images of Human Intestinal Epithelial Organoids (IEOs) derived from A) Terminal Ileum B) Duodenum C) Sigmoid Colon. D) Fluorescent image of organoid derived from Terminal Ileum and stained for Nuclei (blue), LGR5 (green) and E-cadherin (red)

Research themes

Epigenetics

in gut health and disease

Investigating disease pathogenesis

of Inflammatory Bowel Diseases (IBD)

Human gut organoids

as translational research tools

Single cell RNA sequencing

of the human gut in health and disease

Development of clinical biomarkers

using novel computational approaches

Plain english

The intestinal epithelium forms the most inner layer of the human intestine. In addition to playing an important role in helping to digest and absorb nutrients and water, the epithelium also provides a crucial barrier that protects us from potentially harmful bacteria or toxins contained in our daily diet. Impaired function of the epithelium can lead to disease for example chronic gut inflammation (Crohn’s Disease and Ulcerative Colitis). Such chronic inflammatory bowel diseases increasingly affect small children and have a devastating impact on their lives. Although we do not understand why more and more people are diagnosed with these conditions, it seems clear that changes in our environmental play a key role. That is why we are studying the potential role of ‘epigenetic mechanisms’ in gut diseases. These ‘epigenetic mechanisms’ can switch genes on or off and thereby allow our cells to adapt to changes in our environment. This is important to allow our body to function, but it can also lead to disease if something goes wrong.

If we understand the epigenetic changes in the gut epithelium of patients suffering from gut diseases we can find ways to ‘reset’ the epigenome or use medications to prevent the consequences causing damage to the gut.