CCR6 blockade as novel therapeutic strategy against inflammatory bowel disease

Simona Bertoni © Simona Bertoni

Aim of research

CCL20 and its cognate receptor CCR6 are dysregulated in the colonic mucosa and serum of IBD patients; their genes have been identified as susceptibility genes for IBD and an anti-CCL20 neutralizing antibody has been reported to be beneficial in TNBS-induced colitis.
Our working hypothesis is that blocking the CCL20-CCR6 axis represents a novel and promising approach to IBD therapy by limiting neutrophil recruitment to the inflamed tissues and by restoring the balance of effector/regulatory T cells.
Accordingly, our aim is the preclinical validation of small-molecule CCR6 antagonists as potential drug candidates for the treatment of IBD.

Unraveling the immunoregulatory effects of local mesenchymal stromal cell therapy in patients with IBD

Marieke Barnhoorn © Marieke Barnhoorn

Aim of research

Local mesenchymal stromal cell (MSC) therapy is approved for the treatment of Crohn’s Disease-associated perianal fistulas. However, little is known about the mechanism(s) of action of local MSC therapy. In this project we intend to unravel the engraftment and immunoregulatory effects of local MSC therapy in patients with refractory IBD.

Comparative accuracy of the standard Lémann index versus the simplified Lémann index for Crohn’s Disease: a prospective observational cohort study

Ferdinando D'Amico © Ferdinando D'Amico

Aim of research

Crohn's Disease (CD) is an idiopathic Inflammatory Bowel Disease (IBD) characterised by transmural inflammation of the affected tracts. The uncontrolled inflammation can lead to bowel damage, defined as the onset of strictures, abscesses or fistulas negatively impacting patients' quality of life and outcomes. The Lémann index (LI) is a recently validated tool that was specifically designed to assess the presence of penetrating or stenosing lesions and to quantify their severity. LI is a complex and time-consuming score which is based on imaging [magnetic resonance imaging (MRI)] and endoscopic procedures. Of note, it is mainly used in clinical trials, while its use in clinical practice is limited. Our aim was to develop a simplified LI and to compare the correlation between this simplified LI and the standard LI in assessing bowel damage.

Targeting CD4+ T-cell plasticity in Inflammatory Bowel Diseases

Andres Machicote © Andres Machicote

Aim of research

Inflammatory Bowel Diseases (IBD) are devastating diseases induced by a breakdown of gut homeostasis, in which CD4⁺ effector T cells are major mediators of the inflammatory response. Interestingly, CD4⁺ effector T cells can convert into regulatory T cells, thereby controlling inflammation. However, the forces driving this T-cell plasticity remain largely unexplored, especially in IBD patients. In this regard, changes in the microbiota that can induce different T-cell profiles are commonly observed during IBD. The present proposal aims to elucidate how CD4⁺ T-cell plasticity can be modulated from a pro-inflammatory towards an anti-inflammatory profile in IBD patients. Our hypothesis is that the microbiota may modulate T cells towards an anti- or pro-inflammatory profile. To address this issue, we aim to analyse T-cell plasticity in IBD patients and mouse IBD models, and to correlate our findings with the microbiota composition. Furthermore, we will study whether antibiotics commonly used to treat IBD affect T-cell plasticity through microbiota-dependent processes.

Stopping Aminosalicylate Therapy in Inactive Crohn’s Disease (STATIC) study: a randomized, open-label, non-inferiority trial

Gordon Moran © Gordon Moran

Aim of research

Oral 5-ASA agents have proven effective for inducing and maintaining remission in mild-to-moderate Ulcerative Colitis (UC) and thus are commonly used as first-line agents. However, in contrast to UC, there is uncertainty regarding their effectiveness in Crohn’s Disease (CD). For induction of remission in CD, a Cochrane review of randomised controlled trials (RCTs) and meta-analysis found no evidence that low/high dose 5-ASA was superior to placebo. Several studies originating from North America and Europe indicate that 5-ASA agents are the most commonly prescribed drug class for patients with CD. Therefore, there is discordance between clinical prescribing practice and evidence from RCTs.

Integrative analysis of the intestinal epithelium and the mucosal environment in paediatric versus adult-onset Crohn’s Disease

Azucena Salas © Azucena Salas

Aim of Research

Inflammatory Bowel Diseases (IBDs), including Crohn’s Disease (CD) and Ulcerative Colitis, can manifest from childhood to late adulthood. However, IBD presents age-dependent differences related to phenotype, location and behaviour. Recent studies have revealed that functional alterations in the epithelial layer and in its interplay with the intestinal environment can contribute to IBD pathogenesis. Our research aims to explore the crosstalk between the epithelial barrier, the underlying mucosa and the microbiota in patients with CD using an intestinal epithelial organoid culture system to identify potential mechanisms driving early disease onset.

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.