Peter Bossuyt © ECCO

Designing, organising and performing clinical trials in IBD is a challenge. Drug development trials often follow the well-known pathways, with established endpoints and a more or less standardised study design. Things become more complicated when the clinical researcher departs from these trusted routes.  In this context, ClinCom (the Clinical Research Committee of ECCO) organised two courses during the last ECCO Congress in Copenhagen.

Identifying biomarkers prior to IBD diagnosis from the Prospective Urban Rural Epidemiology Study (PURE-IBD)

Neeraj Narula © Neeraj Narula

Background & aim of research

The primary objective of this study is to identify novel serum biomarkers prior to IBD onset that may mediate IBD risk in PURE.

Deciphering of composition and characteristics of intra- and peritumoral immune cells in human IBD-associated dysplasia and cancer using novel spatial profiling techniques

Sofía Frigerio © Sofía Frigerio

Background & aim of research

Chronic colonic inflammation in patients with Inflammatory Bowel Disease increases the risk of colitis-associated cancer (CAC). Although mouse studies have been instrumental in understanding CAC development, the immune cell composition and the role of these immune cells in human CAC are largely unknown.

In this study, we aim to decipher the composition and characteristics of immune cells in close proximity to dysplastic pre-cancerous lesions and cancers in IBD patients, and to decipher possible interactions between epithelial cells and the underlying immune cell populations in these regions, using novel spatial profiling techniques.

Delineating an uptake-independent function of SR-BI in Paneth cells in metabolic gut inflammation

Felix Grabherr © Felix Grabherr

Background & aim of research

Dietary lipids are associated with risk of developing Inflammatory Bowel Disease (IBD). Activity of glutathione peroxidase 4 (GPX4), an anti-oxidative selenoenzyme, is impaired in intestinal epithelial cells (IECs) from patients with ileal Crohn’s Disease (CD). GPX4 controls intestinal inflammation triggered by dietary polyunsaturated fatty acids (PUFAs) and dietary PUFA uptake is associated with CD flares. SR-BI (encoded by Scarb1) is a membrane-bound receptor, mainly reported to be involved in the uptake of cholesterol, and cholesterol uptake has been described to play a role in ferroptosis induction, a cell death pathway which is regulated by GPX4. Paneth cells (PCs), specialised IECs within the small intestine, have been described to be the origin of intestinal inflammation. Preliminary data indicate that PCs sense and translate dietary PUFA stress into intestinal inflammation. 

Identification of gut microbial strains contributing to chronic inflammation in human and mice

Bahtiyar Yilmaz © Bahtiyar Yilmaz

Background & aim of research

The relationship between host and microbiota can turn negative, leading to changes in microbial composition and metabolism that result in diseases such as Inflammatory Bowel Disease (IBD). Enteropathogenic strains increase due to the presence of reactive oxygen species in an altered metabolic environment. This study aims to understand how an IBD microbiota carrying an oxidative stress signature adapts over time and how these strains contribute to the disease's trajectory and fluctuations of oxidative stress in the outer mucus layer.

Aim 1: To isolate and characterise the capacity of freshly isolated human small and large intestinal microbial members contributing to oxidative stress.

Aim 2: To colonise germ-free or defined microbiota colonised mice with isolated bacterial strains to test their contributions and resilience to inflammation/oxidative stress in the mouse intestines.

Establishment of a multi-organ-on-chip model to advance gut-brain communication research and developmentrt

Laure Maes © Laure Maes

Background & aim of research

Persistent fatigue severely affects the quality of life of IBD patients and reduces their ability to work. Although IBD patients, even when in clinical remission, report fatigue as one of the most disabling symptoms of their chronic disease, disease management is often only focused on attenuating gastrointestinal symptoms. In order to develop effective therapeutic interventions, a better understanding of what is causing IBD-associated fatigue is required. Therefore, the goal of this project is to develop a human gut-blood-brain in vitro model to explore the impact of active and extinguished gut inflammation on brain and brain barrier function.

Ascertaining the role of the appendix in inflammatory bowel disease in a population-based cohort

Manasi Agrawal © Manasi Agrawal

Background & aim of research

Appendectomy at age <20 years for appendicitis or mesenteric lymphadenitis has been associated with a lower risk of Ulcerative Colitis (UC), but this association has not been detected when appendectomy is performed at an older age or for non-specific abdominal pain. Similar findings have been reported upon combining data from Swedish and Danish registers.  However, in a Danish cohort study of familial units, individuals who had first-degree relatives with appendicitis, but no personal history of appendicitis, at age <20 years also had a lower risk of UC. This risk was even lower in those with a family history of UC. 

Interventional studies on elective appendectomy for UC therapy are underway. The impact of appendiceal inflammation on UC outcomes, including cancer, are not well understood. 

The overall aim of this study is to understand the role of the appendix (appendicitis and appendectomy) in IBD risk and IBD outcomes. 

Feeding immunity: development of a novel glycan-based dietary strategy for IBD prevention

Joana Gaifem © Joana Gaifem

Background & aim of research

Dietary interventions have been shown to ameliorate symptoms in patients with mild or moderate IBD. Nevertheless, these therapies are only effective for a subset of patients, raising the need for novel dietary intervention strategies that aim to prevent IBD development. Glycosylation is a major post-translational mechanism characterised by the addition of carbohydrate structures, called glycans, to essentially all cells. We have revealed that mucosal T cells from Ulcerative Colitis patients exhibit alterations in mucosal glycosylation, which positively correlate with T cell hyperactivity and disease severity. We have also demonstrated that mice deficient in branched N-glycosylation display increased susceptibility to severe colitis. Supplementation of these mice with glycans resulted in disease control via inhibition of Th1/Th17 immune responses.

In this research we aim to explore whether dietary supplementation with glycans promotes a superior function for nutraceutical intervention to promote IBD prevention, characterising the effect of mucosal glycosylation reprogramming in shaping the intestinal environment.

iNKT cells immunomodulation and mucosal healing by microbiota-derived lactate (OCELOT)

Francesco Strati © Francesco Strati

Background & aim of research

Invariant natural killer T (iNKT) cells are unconventional T lymphocytes that play a critical role in mucosal immunity. Although iNKT cells sense the microbiota of IBD patients, promoting pro-inflammatory responses, their rapid responsiveness to the intestinal microenvironment can be harnessed to promote immunoregulatory rather than pro-inflammatory responses. OCELOT’s central hypothesis is that iNKT cells are the primary immune cells that sense microbiota-derived metabolic signals promoting the resolution of inflammation. In particular, OCELOT argues that microbiota-derived lactate can tightly control iNKT cell function, promoting mucosal tolerance while preventing T cell-mediated inflammation and tissue injury.

Development of biomarker signatures as an alternative to endoscopy: looking beyond inflammation

Nicolas Pierre © Nicolas Pierre

Background & aim of research

In Crohn’s Disease (CD), the treat-to-target strategy has become the standard of care [1, 2]. This clinical concept consists in escalating/optimising the treatment (e.g. dose, frequency, type of drugs) until a state of remission (target) is achieved. Overall, treatment targets evolve towards a deeper level of remission and it is in this context that endoscopic remission has become a primary objective. However, endoscopy remains invasive and costly, is not well accepted by patients and does not allow tight control of disease activity. Thus, attention is turning to non-invasive biomarkers that can replace endoscopy. Our group recently made progress in monitoring disease activity with blood proteins. More precisely, we found distinct biological profiles to be associated with the risk of short-term and mid/long-term relapse in CD patients who stop infliximab [3–5]. By measuring 161 blood proteins, we captured a more complete picture of the disease activity than is achieved with classic inflammatory markers. Clearly, looking beyond inflammation is necessary in order to monitor disease activity more effectively. Based on our previous work, we aim to develop biomarker signatures as an alternative to endoscopy.