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.

Induction of circadian microbial function in chronic intestinal inflammation

Silke Kiessling © Silke Kiessling

Aim of research

The body clock regulates behaviour and physiology in a circadian (24-h) manner. Circadian disruption, as occurs in shift workers, is associated with gastrointestinal (GI) pathologies, including Inflammatory Bowel Disease (IBD).                              

The intestinal epithelial cells, key regulators of barrier function and immune homeostasis, harbour a clock which may play a major role in maintaining intestinal homeostasis. In addition, the majority of the gut microbiome, including microbial metabolites, show circadian rhythmicity in both mice and humans. It remains to be addressed whether changes in microbial composition and function are regulated by the intestinal clock and influence GI diseases. Thus, we aim to test whether (i) arrhythmic microbial composition and function in IBD is caused by intestinal clock dysfunction, (ii) lost rhythmicity in microbial metabolites promotes IBD and (iii) IBD pathogenesis can be modulated by restoring circadian microbial metabolite production.

The gut mycobiome in Inflammatory Bowel Disease: addressing ITS confounders

Chloe E. Huseyin © Chloe E. Huseyin

Aim of research

The gut mycobiome refers to the community of fungi present in the human gastrointestinal tract. Surveys of the mycobiome are considerably underrepresented in the literature compared to surveys of bacteria; however, this does not imply that the mycobiome is of lesser importance. Indeed, fungi are invasive opportunistic pathogens and the human gut an internal reservoir.
Much can be learned from the abundant bacterial literature utilising next generation sequencing (NGS) technology. An ever-increasing number of exogenous and endogenous confounding factors have too often been discovered retrospectively. This both influences and complicates the ability to discern meaningful conclusions within and across studies, ultimately not only costing time and resources but also increasing research fatigue.
Several mycobiome studies have postulated that the same confounding effects are relevant to the mycobiome, especially host diet, which is complicated by the consumption of fungi used in the food and beverage industry.

The main aims of this research are to:

1. Assess the inherent effects of several methodological choices, and
2. Investigate potential confounders of importance with respect to Inflammatory Bowel Disease (IBD) mycobiome research.

STRICTuring Crohn’s disease assessment using advanced Ultrasound and magnetic REsonance imaging techniques for evaluation of inflammation and fibrosis (STRICTURE)

Krisztina Gecse © Krisztina Gecse

Aim of research

Patients with Crohn’s Disease present predominantly with inflammation; however, a significant proportion of patients already exhibit strictures at diagnosis or develop fibrostenotic complications during their disease course. Whereas predominantly inflammatory strictures are likely to benefit from medical therapy, predominantly fibrotic strictures often require a surgical approach. As strictures are rarely identified merely as fibrotic or inflammatory, identifying the predominant component of the stricture is necessary to guide clinical decision making. However, currently used imaging modalities are unable to adequately determine stricture composition.

Intestinal ultrasound (IUS) and MRI are both frequently used in the evaluation of disease activity in CD. Previous studies have shown that advanced modalities of both techniques are promising for the characterisation of stricture composition. However, data are scarce and most studies have not combined MRI and IUS parameters.

Therefore, the aim of the STRICTURE study is to evaluate the use of state-of-the-art cross-sectional imaging parameters to identify stricture composition, as defined by the histopathological degree of inflammation and fibrosis in the surgical resection specimen.

Role of PADI4 in Crohn's disease: the citrullination of proteins in the transition from inflammation to fibrosis

Gabriele Dragoni © Gabriele Dragoni

Aim of research

Citrullination is a post-translational modification of proteins, mediated by enzymes called PADs (peptidylarginine deiminases). PAD4 has recently been shown to citrullinate histone 3 (H3cit) in the nucleus, leading to the expulsion of extracellular traps from neutrophils (NETs), whose presence in Crohn’s Disease (CD) is debated.

The aim of this project is to investigate the role of PAD4 in inflammatory and fibrotic contexts of ileal CD.

Understanding the mechanisms of anti-TNF treatment failure in patients with Crohn’s Disease: a proteomic analysis of the PANTS cohort

Neil Chanchlani © Neil Chanchlani

Aim of research

In the Personalised Anti-TNF Therapy in Crohn’s Disease (PANTS) prospective cohort study, we followed 1,610 patients with Crohn’s Disease treated with infliximab or adalimumab for three years. About one in four patients experienced primary non-response and one-third of initial responders lost response, leaving only one-third in remission at one year.  

A limited number of proteomic markers have been implicated in anti-TNF treatment failure, but their relative effects and interactions have not been fully explored. We aim:

1. To identify novel protein biomarkers linked to intestinal inflammation and immunity that influence pharmacokinetic or pharmacodynamic related primary non-response and non-remission at one year, using two multiplex Olink proteomic panels.
2. Validate previously postulated protein markers associated with anti-TNF primary non-response and non-remission at one year, including TREM-1, oncostatin M, Vitamin D, ASCA, ANCA and anti-OmpC.