Hyperbaric Oxygen Therapy for the Treatment of Perianal fistulas in Crohn’s Disease (HOT-TOPIC trial)

Nina Lansdorp © Nina Lansdorp

Aim of Research

Perianal fistulas are a debilitating complication of Crohn’s Disease (CD). Current treatment options have a relatively low success rate and a high recurrence risk. The role of hyperbaric oxygen (HBO) therapy in Inflammatory Bowel Disease (IBD) is increasingly appreciated, and positive outcomes for fistulising CD have been reported in animal studies and small case series. The aim of the HOT-TOPIC trial is to investigate the therapeutic efficacy and feasibility of HBO in patients suffering from therapy-refractory perianal fistulising CD.

Exploring the heterogeneity of macrophages in Crohn's Disease

Gareth Rhys-Jones © Gareth Rhys-Jones

Aim of Research

To identify the biological processes underpinning the macrophage (Μφ) contribution to the pathogenesis of Crohn’s Disease (CD) by:

• Investigating gut mucosal Μφ heterogeneity in newly diagnosed, treatment-naïve CD patients
• Investigating Μφ subset specific dysregulation using a combination of new flow cytometry approaches and transcriptome and chromatin analysis.

Fungal feelings: Abdominal pain during remission

René van den Wijngaard © René van den Wijngaard

Aim of Research

In the absence of ongoing inflammation, a significant proportion of IBD patients in remission continue to suffer from irritable bowel syndrome (IBS)-like symptoms such as pain and diarrhoea (IBD-IBS). Abdominal pain in IBD-IBS is an under-treated problem with a negative impact on quality of life. In IBS, we recently provided evidence that abdominal pain may arise due to immune recognition of an aberrant gut mycobiome. The possible relevance of the gut mycobiome in IBD-IBS has never been studied previously. We aim to perform (1) a descriptive study to establish faecal mycobiome differences when comparing IBD patients in remission with and without IBS complaints and (2) a functional study to show the relevance of the IBD-IBS mycobiome for abdominal pain in a human-to-rat faecal microbiota transfer (FMT) model of post-inflammatory colitis.

Brain circuits controlling intestinal inflammation

Giuseppe D'Agostino © Giuseppe D'Agostino

Aim of Research

The caudal brainstem, and particularly the nucleus of the solitary tract (NTS), is of critical importance for pathophysiological signals reaching the brain from the gastrointestinal tract. During inflammation, signals from the gut can be integrated in the NTS to initiate a peripherally directed anti-inflammatory response. However, the neuronal circuits underlying this response are unknown, with no genetic, neurochemical and anatomical information available. This gap in knowledge prevents the development of novel anti-inflammatory strategies. Our team has identified discrete subsets of genetically identified neurons in the NTS that are responsive to microbial and inflammatory stimuli.

Host–microbiota crosstalk through tryptophan metabolism in Inflammatory Bowel Diseases (IBD)

Harry Sokol © Harry Sokol

Aim of Research

The aim of this work is to study the communication between host cells and microbiota through tryptophan (Trp) metabolism and particularly: (i) the effects of microbes on Trp metabolism in host cells, (ii) the effects of Trp metabolites on host cell response to microbes and (iii) the interaction between epithelial and immune cells through Trp metabolism and the consequences for inflammatory responses.

An integrative analysis of DNA methylation and RNA-Seq data in human adipose stem cells of Crohn’s Disease patients with different clinical activity

Carolina Serena © Carolina Serena

Aim of Research

1. To identify an epigenetic signature in human adipose stem cells (hASCs) isolated from CD patients with different clinical activity, and to compare this signature with that of hASCs from healthy donors (study of epigenetics).
2. To explore the effects of DNA methylation on the regulation of gene expression in hASCs isolated from the same cohort (study of transcriptomics).
3. Integration of data to identify the interplay between differentially methylated DNA sites and the transcriptome profile of hASCs from healthy and CD subjects that could be involved in the dysregulation of hASCs associated with CD.

Sarcopenia as a Predictor of Anti-TNF Non-Response in Crohn’s Disease

Nik Ding © Nik Ding

Aim of Research

• To demonstrate that sarcopenia, myopenia and body composition parameters are associated with lower anti-TNF drug levels and primary non-response in patients with moderate to severe Crohn’s Disease who are anti-TNF naive.
• To demonstrate that sarcopenia is a biomarker of primary non-response (PNR) and secondary loss of response (SLR) to anti-TNF therapy.
• To demonstrate that sarcopenia/myopenia is a biomarker of primary non-response (PNR) to anti-TNF therapy due to inadequate anti-TNF dosing by use of therapeutic drug monitoring.
• To demonstrate that improvement of sarcopenia/myopenia increases anti-TNF drug levels and clinical response to anti-TNF drugs.

The hypothesis is that sarcopenia is predictive of low anti-TNF drug levels and possible primary non-response to anti-TNF therapy, and, in addition, that sarcopenia is a predictor for primary non-response and loss of response to anti-TNF therapy which correlates with anti-TNF levels at weeks 4 and 12.

The immune repertoire of microbe-reactive T cells in blood and tissue of IBD patients

Petra Bacher © Petra Bacher

Aim of Research

Dysregulated T cell reactions against intestinal antigens are considered to be a causal or driving factor for Inflammatory Bowel Diseases (IBD). So far, technical limitations concerning the detection and characterisation of microbiota-reactive T cells have prevented determination of the exact contribution of specific T cell subsets against individual microbes to the intestinal balance and its dysregulation in IBD. Analysing the phenotype, function and T cell receptor (TCR) repertoire of microbe-specific T cells in blood and intestinal mucosa of IBD patients will therefore provide important insights to fundamental questions on the clonal expansion of pro- and anti-inflammatory microbe-reactive T cells, their clonal relation and stability and the sites (blood and/ or intestinal tissue) at which the relevant T cell subsets are located.

Infliximab in Paediatric Crohn’s Disease; in whom to start (ImProve)

Lissy de Ridder © Lissy de Ridder

Aim of Research

Crohn’s Disease (CD) is a heterogeneous chronic immune-mediated inflammatory disease. To improve management, precision medicine is urgently needed to target the underlying pathogenic immune response that is driving disease. There is a key unmet need to identify biomarkers that will predict the need for, and the response to, anti-tumor necrosis factor (TNF) treatment, including in paediatric CD. This constitutes the aim of the present project. The use of such predictive biomarkers will help to avoid delay in effective treatment, complications due to ongoing inflammation and exposure of non-responders to anti-TNF. We hypothesise that genetic expression profiling, in combination with thorough patient characterisation, will lead to such biomarkers and thereby improve targeted anti-TNF use in paediatric CD.

The role of fibroblasts in the pathogenesis of Crohn’s Disease-associated fistulas and in mesenchymal stem cell therapy  

Ramona Bruckner © Ramona Bruckner

Aim of the research

Perianal fistulas are a severe and frequent complication in Crohn’s Disease (CD) patients, significantly affecting their quality of life. High recurrence rates, incomplete fistula healing and non-responding patients make the treatment challenging. Despite some novel insights, current knowledge about the pathogenesis of fistula formation is still limited. Fibroblasts are abundantly present in fistulas and were recently reported to regulate Th1 cell activity in Inflammatory Bowel Disease (IBD). Our hypothesis is that fibroblasts act as the key drivers of this disease complication by regulating inflammatory cell recruitment. We will investigate which pro-inflammatory cytokines and chemoattractants are produced by fistula-derived fibroblasts and how they influence recruitment of immune cells, leading to sustained inflammation. Our second hypothesis is that mesenchymal stem cells (MSCs) can normalise this fibroblast-driven pro-inflammatory environment.