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.

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.

PTPN2 and TiO2 in the pathogenesis of Inflammatory Bowel Disease  

Aim of the research

Titanium dioxide (TiO2) may play a pivotal role in the onset and perpetuation of chronic intestinal inflammation. These effects may be genetically triggered, and variations in IBD risk genes, such as PTPN2, may contribute critically to the detrimental effect of TiO2 in vivo. For these reasons, we will study the combined effects of the presence of disease-associated genetic PTPN2 variations and TiO2 microparticles on the development of chronic intestinal inflammation and on inflammasome activity, as well as the subsequent consequences for the host immune system, in particular innate immune responses. The study will demonstrate the relevance of TiO2 in the pathogenesis of intestinal inflammation in vivo. To address the aforementioned aims, we will:

1. Analyse whether PTPN2-mediated inflammasome activation can control TiO2-induced intestinal inflammation.
2. Demonstrate whether the presence of the disease-associated PTPN2 variant affects NLRP3 inflammasome activation and intestinal inflammatory responses to TiO2 in IBD patients.

Definition of IBD-associated gut virome via next-generation sequencing: Novel insights for disease onset and treatments

Federica Ungaro © Federica Ungaro

Aim of Research

Viral infections have been reported to be the primary trigger in many diseases. Preliminary results from RNA-seq analysis performed on mucosal biopsies of patients with active Crohn’s Disease (CD) or Ulcerative Colitis (UC) and healthy controls revealed indicated an IBD-specific viral signature, characterised by increased levels of viral RNAs, especially in patients with UC.

Although analyses on gut virome composition are available, to date nobody has described which viruses are involved in IBD onset. We propose characterising the viral composition of gut mucosal samples from early-diagnosed patients with IBD and healthy subjects by exploiting transcriptomic analysis. Moreover, through RNA silencing experiments, we will investigate whether the inhibition of viral-specific RNAs may be beneficial in mucosal biopsies from patients with active IBD. Results obtained from this study are expected to lead to the unveiling of a novel concept depicting IBD aetiopathogenesis as related to specific viral infections. This will arguably offer new therapeutic insights and promote the search for antiviral drugs for the treatment of IBD.

Identification of the functional role of NLRP6 in human Crohn’s Disease

Dina Danso-Abeam © Dina Danso-Abeam

Aim of Research

The introduction of biological therapies such as anti-TNF has led to a decrease in surgery in IBD. However, many patients do not benefit from this treatment: One-third of patients do not respond to induction therapy (primary non-responders) and about half of primary responders lose response over time (secondary non-responders). This is in part due to therapeutic targeting of generalised inflammation rather than specific targeting of well-defined molecular mediators of IBD pathogenesis.

Most recently, the nod-like receptor NLRP6 has come to light for its potential role in local inflammation driven by gut microbial dysbiosis, albeit almost all data are emerging from mouse models. Our preliminary data from a patient harbouring a novel NLRP6 mutation show significant dysregulation in multiple immune cells, providing strong evidence for the role of NLRP6 in immune homeostasis. Taking into account the high expression of NLRP6 in human intestine, this project aims to decipher the role of NLRP6 in the pathology of Crohn’s Disease (CD).

Neuro-immune interactions in gut macrophages

Holm Uhlig © Holm Uhlig

Inflammatory Bowel Diseases (Crohn’s Disease and Ulcerative Colitis) are polygenic and multifactorial disorders caused by aberrant responses to the intestinal microbiota. Crohn’s Disease in particular is associated with defective bacterial handling in phagocytes (i.e. monocytes and macrophages), which digest bacteria by the process known as autophagy/xenophagy. Monocyte/macrophage function is modulated by the surrounding microenviroment, in which pathogens, metabolites, chemokines and cytokines are present.

Identification of rare genetic variants contributing to the development of childhood-onset IBD-PSC using parent-offspring trios

Patrick van Rheenen © Patrick van Rheenen

Primary Sclerosing Cholangitis (PSC) is a rare and severe disease leading to fibrotic destruction of the bile ducts. The majority of childhood-onset cases are associated with Inflammatory Bowel Disease, Ulcerative Colitis in particular.