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.

TIGIT+CD38+ effector cells: New players in suppressing inflammation in IBD?

Janneke N. Samsom  © Janneke N. Samsom

Background and Hypothesis

In Inflammatory Bowel Disease (IBD), T-cell reactivity against harmless microbial antigens drives chronic inflammation. After induction of remission, patients receive T-cell-suppressing maintenance treatment, which is effective in maintaining remission in some patients but not others. “T-cell immunoglobulin and ITIM domain” (TIGIT) is a novel inhibitor of T-cell activation. Preliminary experiments show that human circulating TIGIT-expressing CD38+ effector T cells are concomitantly enriched in the inhibitory molecules IL-10, PD-1 and CTLA-4. Crucially, frequencies of these cells were much reduced in a subgroup of paediatric IBD patients at disease onset and associated with reduced duration of clinical remission during follow-up.

We hypothesise that TIGIT+CD38+ effector T cells are functionally involved in immune regulation of microbial responses in the gastrointestinal tract.

Regulation of intestinal epithelial homeostasis by Cyclin Y

Stefan Koch © Stefan Koch

Aim of Research

Genetic predisposition contributes to the development of Inflammatory Bowel Diseases (IBD). Prior GWAS studies have identified numerous IBD risk loci, but most of them have no assigned function to date. The aim of this study is to explore the role of the IBD risk gene CCNY, encoding the Wnt signalling activator Cyclin Y, in intestinal homeostasis and wound repair.

Because Wnt signalling is essential for the maintenance of intestinal epithelial stem cells, we anticipate that CCNY mutations impair intestinal Wnt signalling and thereby reduce epithelial regeneration during colitis.

The regulation and function of epithelial Glutathione Peroxidase 4 in Inflammatory Bowel Disease  

Timon Adolph © Timon Adolph

Aim of Research

Glutathione peroxidase 4 (GPX4) controls a specialised regulated form of cell death termed ferroptosis. Research supported by this ECCO Grant aims at investigating the regulation and function of GPX4 in intestinal epithelial cells (IECs) from patients with Crohn’s Disease (CD) and Ulcerative Colitis (UC). This project aims to establish a role for ferroptosis and lipid peroxidation in IBD and to clarify the function of GPX4 in Crohn’s Disease.

Using exosomes to gain insights into the early phase of Crohn’s Disease  

Sare Verstockt © Sare Verstockt

Aim of Research

Crohn’s Disease (CD) is characterised by chronic inflammation of the gut. Treatment usually involves drug therapy or surgery with the goal of reducing inflammation and inducing and maintaining steroid-free remission and mucosal healing. A more intensive treatment early in the disease course leads to better outcomes. However, the time between symptoms and diagnosis is often years.

The aims of this project are to identify (a) the triggers present at the onset of CD, allowing (pointers for) new therapies, and (b) molecular markers that can help diagnose CD as early as possible. Given that exosomes provide a rich genetic profile reflecting their cellular origin, we are focussing on exosomal markers.

Innate lymphoid cells in Paediatric Inflammatory Bowel Disease  

Aline van Acker © Aline van Acker

The incidence of paediatric IBD (PIBD) is on the rise. However, the underlying aetiology of PIBD remains largely unknown, indicating the dire need for more knowledge on the mechanisms driving this disease. Innate lymphoid cells (ILCs) constitute an important component of the mucosal immune system. Recent years have seen an increase in ILC knowledge, with numerous publications highlighting the importance of ILCs in murine and adult IBD development and progression.

In this project, we aim to elucidate ILC heterogeneity and function specifically in PIBD. In practice, single-cell suspensions are isolated from blood and colon biopsies of PIBD and non-PIBD patients admitted to the Paediatric Gastroenterology, Hepatology and Nutrition Unit at Karolinska University Hospital, Stockholm, Sweden or the Department of Clinical Research and Education at Södra Hospital, Stockholm.

Francesca Maria Onidi © Francesca Maria Onidi

The award of an N-ECCO Travel Grant, organised by ECCO, enabled me to spend time as an intern in the prestigious Inflammatory Bowel Diseases Centre at Humanitas Research Hospital, the largest IBD centre in Italy. The Centre provides the most innovative treatments and therapeutic strategies for IBD patients in accordance with current scientific evidence and offers a multidisciplinary approach to IBD with the help of industry experts and novel technologies. At the Humanitas outpatient clinic dedicated to IBD, patients are followed by IBD nurse Simona Radice. In addition to the provision of medical assistance to patients, the Centre is strongly engaged in research activities aimed at developing new treatments and diagnostic and/or therapeutic strategies. Participation in clinical trials is subject to a preliminary clinical evaluation during a specialist visit to the Centre.