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.

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.

Arshdeep Singh © Arshdeep Singh

ECCO-AOCC Travel Grant Awardee

I accepted the ECCO AOCC Travel Grant 2020 with great pleasure and in all humility. The grant enabled me to visit Helsinki University Central Hospital in Finland between January 13 and March 6, 2020. This gave me the opportunity to increase my knowledge on the management of IBD patients and to gain insight into the faecal microbiota transplant and human microbiome research programme in Finland. At the Hospital District of Helsinki and Uusimaa (HUS), I attended the IBD clinics and IBD inpatient rounds, which greatly enriched my experience. Further, I learned more about IBD endoscopy, including double-balloon enteroscopy and capsule endoscopy for Crohn’s Disease and faecal microbiota transplant (FMT). I intend to deploy this knowledge at our IBD centre to foster further professional growth.