THE ROLE OF AUTOPHAGY IN LIMITING IBD-ASSOCIATED AIEC-INDUCED INTESTINAL INFLAMMATION

Shai Bel © Shai Bel

Aim of research

While the aetiology underlying the development of Inflammatory Bowel Diseases (IBD) is unclear, evidence points to an interaction between host genetics, such as mutations in autophagy genes, and environmental factors, such as bacterial infections. Multiple studies have identified an adherent-invasive Escherichia coli pathotype (AIEC) that attaches to intestinal epithelial cells (IECs) in patients with IBD but not in healthy subjects. It is thought that AIEC exploits the intestinal inflammation in patients with IBD to attach to the IECs, intensifying the pre-existing inflammation. Studies in vitro have shown that functional autophagy is crucial to eliminate AIEC infection. Here, we aim to identify how, and in which compartment of the intestine, autophagy protects the host from AIEC-associated pathologies in vivo and to determine whether artificially enhancing the autophagy process is a viable therapeutic avenue for patients with IBD and intestinal AIEC colonisation.

TISSUE-ASSOCIATED MICROBIAL AND CELLULAR DRIVERS OF RESOLUTION OF INFLAMMATION AND DISEASE EXACERBATION IN A LONG-TERM COHORT OF PAEDIATRIC CD PATIENTS

Tobias Schwerd ©  Tobias Schwerd

Aim of research

Inflammatory Bowel Diseases (IBD) are characterised by episodes of disease quiescence and disease exacerbation. The microbial and molecular events that result in long-lasting resolution of inflammation or the transition from IBD quiescence (mucosal healing) to active intestinal inflammation are unknown. Intestinal inflammation arises from a dysregulated response of tissue-resident immune cells, such as T cells, towards the intestinal microbiota. We aim to study longitudinal host–microbe interactions at the mucosal level as a strategy to identify microbial and molecular events associated with the resolution or re-activation of intestinal inflammation in individual paediatric patients with IBD.

FINE DETERMINATION OF GUT TISSUE LAYERS’ INFLAMMATION EXPLORING IMMUNE-MICROBIOTA SIGNATURES: NEW BIOMARKERS OF RECURRENCE IN SURGICAL PATIENTS WITH CROHN’S DISEASE?

Francesco Giudici © Francesco Giudici

Aim of research

Up to 65% of patients with Crohn’s Disease (CD) show disease recurrence after ileocolic resection. The reasons for this high recurrence rate are still unclear, but the abnormal CD inflammatory process, against the microbiota, affects all the intestinal wall layers. We aim to explore the mutual interplay of inflammatory and microbial factors involved in CD through a systems-level study, defining the “correlation network” of mucosa-associated microbiota (and its faecal metabolites) at the time of ileocolic resection. We will evaluate whether specific microbial/inflammatory correlations are statistically associated with early postoperative endoscopic recurrence, assessed by colonoscopy at six months.

ROLE OF DNA METHYLATION AND GENE EXPRESSION ALTERATIONS IN DEVELOPMENT OF EARLY-ONSET PRIMARY SCLEROSING CHOLANGITIS IN ULCERATIVE COLITIS – DYNAMIC

Sudipto Das © Sudipto Das

Aim of research

Primary sclerosing cholangitis (PSC) is a progressive cholestatic disease and up to 80% of PSC patients have Ulcerative Colitis (PSC-UC), which presents a clinical challenge owing to the difficulty in diagnosis and increased risk for development of cancer. While several multifactorial processes, including inflammation and dysbiosis of microbiota, have been associated with PSC-UC pathogenesis, the precise molecular factors that regulate the phenotype of this disease subtype remain unknown. This research project – DYNAMIC – hypothesises that mapping the differences in DNA methylation and gene expression alterations between young PSC-UC and non-PSC-UC patients will allow us to unravel critical molecular factors that underpin this disease subtype.

De-escalation of anti-TNF therapy in adolescents and young adults with IBD with tight faecal calprotectin and trough level monitoring (free-study)

Marleen Bouhuys © Marleen Bouhuys

Aim of research

Treatment outcomes of patients with Inflammatory Bowel Disease (IBD) have improved enormously due to the use of anti-tumour necrosis factor (anti-TNF) agents, but prolonged use comes with disadvantages such as infections and skin problems. Observational studies suggest that dosing interval lengthening can reduce the risk of these adverse reactions in a relevant proportion of patients, provided that they are closely monitored.

The aim of our study is to evaluate whether, in patients with IBD in sustained remission, anti-TNF dosing interval lengthening is non-inferior compared to an unchanged dosing interval with respect to maintenance of target faecal calprotectin (FC) levels.

Dose-related differential effects of vedolizumab on leukocyte subsets

Sebastian Zundler © Sebastian Zundler

Aim of research

The anti-α4β7 integrin antibody vedolizumab is successfully used for the clinical treatment of IBD. However, some details of its mechanisms are still not clear. Moreover, whether dose intensification of vedolizumab therapy may also increase response rates is the subject of ongoing debate, as some previous studies have suggested a non-linear exposure–efficacy correlation. Since only a portion of patients benefit from vedolizumab therapy, further translational insights into these aspects are an important unmet need for therapy optimisation and the development of personalised treatment approaches.

Based on preliminary data we hypothesise that vedolizumab has a differential preference of binding to distinct leukocyte subsets (e.g. effector and regulatory T cells), resulting in specific profiles of targeted immune cells at a certain level of vedolizumab exposure. This may explain the suggested non-linear exposure–efficacy correlation.  Therefore, we aim to elucidate dose-dependent binding characteristics to leukocyte subsets and related functional aspects in vitro and in vivo.

Improving clinical outcomes for IBD patients undergoing colorectal surgery by using a clinically developed patient-centred mobile application

Sebastiaan van der Storm © Sebastiaan van der Storm

Aim of research

Enhanced Recovery After Surgery (ERAS) is a multidisciplinary and multimodal protocol focussing on perioperative care which has proved successful in improving clinical outcomes for patients undergoing colorectal resection. Adequate compliance with the ERAS protocol is associated with improved clinical outcome, but there is an additional gain in involving patients actively in their efforts towards recovery. Whether outcomes may be further improved by specifically focussing on active patient involvement has not previously been investigated. A mobile application with an integrated ERAS protocol could be of great potential. However, the integrated ERAS protocol might need adaptation to meet the specific needs of patients with Inflammatory Bowel Disease (IBD) undergoing colorectal surgery. 

The main objective of this study is to investigate whether a CE-marked, clinically developed patient-centred mobile application, which can be used for multiple colorectal surgical pathways, enhances outcomes for IBD patients by stimulating patient empowerment and actively involving patients in the ERAS care pathway.

Predictive (longitudinal) gut microbial markers for the diagnosis of fatigue in IBD patients

Emma Paulides © Emma Paulides

Aim of research

Fatigue is an important clinical problem in patients with IBD in remission and those with active disease. It results in a decrease in quality of life and impaired work productivity. However, little is known about its aetiology and pathophysiology, which impairs our ability to effectively treat this symptom. Evidence suggests that the intestinal microbiota act as a mediator in the bidirectional communication between the nervous system and the gut. Recent research by our group demonstrated a strong and statistically significant correlation between the microbiome and increasing fatigue scores. However, little is known about the changes in the composition of the intestinal microbiome and their influence on the diagnosis and course of fatigue.

Our aim is to identify the underlying biological mechanisms involved in IBD-related fatigue, especially the influence of longitudinal changes in the intestinal microbiome, and to reveal IBD fatigue-specific patterns.

The role of PTPN23 in intestinal inflammation and colitis-associated cancer

Ana Montalban-Arques © Ana Montalban-Arques

Aim of research

Inflammatory Bowel Disease with colonic involvement predisposes patients to develop colitis-associated cancer (CAC) due to chronic inflammation. Protein tyrosine phosphatases (PTP) play a critical role in the regulation of signalling cascades involved in IBD and oncogenesis. Particularly PTPN23 deletion has recently been associated with epithelial cancers. However, a role of PTPN23 in IBD and CAC/CRC has not yet been investigated. Based on previous data, our hypothesis is that PTPN23 controls intestinal epithelial cell (IEC) homeostasis and proliferation. The overarching aim of our project is to investigate the role of PTPN23 in intestinal homeostasis and inflammation.

Familial aggregation in Inflammatory Bowel Disease: a next-generation sequencing study

Ho-Su Lee © Ho-Su Lee

Aim of research

Family history of Inflammatory Bowel Disease (IBD) is the strongest risk factor for IBD. Currently, however, there is incomplete understanding of the contribution of genetic risk to familial aggregation of IBD. We aim to identify the genetic basis of familial aggregation in multiple-affected IBD families and to identify shared genetic susceptibility variants between IBD and other diseases using families suffering from IBD and concomitant diseases.