Genetic studies have implicated the autophagy gene ATG16L1 and the endoplasmic stress (ER) gene XBP1 in the pathogenesis of Inflammatory Bowel Disease (IBD). Indeed, spontaneous inflammation develops in mice lacking ATG16L1 or XBP1 expression in intestinal epithelial cells (IEC). Because of the dominant role of failing autophagy and ER stress in IBD, we hypothesise that IEC stress contributes to intestinal fibrosis, gut dysmotility and pain during colitis.
This project aims, for the first time, to thoroughly comprehend the role of crucial IBD epithelial stress factors (i.e. ATG16L1 and XBP1 impairments) in enteric fibroblasts and neurons and to explore potential future intervention points.
Inflammatory Bowel Disease (IBD) results from an anomalous interaction between genetic, environmental, immunoregulatory and microbial-derived factors. IBD- associated specific mutations include genes involved in microbial recognition, such as mutations in the Toll-like receptor 4 (TLR4). Beside controlling host defence responses, TLR4 modulates enteric nervous system (ENS) activity, gut motility and repair processes following an insult. TLR4 deficiency in mice leads to significant ENS alterations, characterised by modified gut motility and susceptibility to inflammation. The findings of decreased gut catecholamine levels in IBD patients and the onset of milder experimental colitis after sympathectomy highlight the role of the nervous system as a key regulator of immune responses. Therefore, our research project aims to decode the neuroimmune interactions between the catecholaminergic system and innate immune sensor TLR4 in dinitrobenzene sulphonic acid (DNBS)-induced ileitis.
Deciphering the bioactive role of extracellular matrix fragments (matrikines) in Crohn's Disease (CD) fibrostenosis as potential therapeutic targets and biomarkers
We have pioneered in studying ex vivo extracellular matrix (ECM) remodelling, which is known for its key role in Crohn’s Disease (CD) fibrostenosis. By adding disease-relevant enzymes on the ECM of CD patients’ intestine, we identified numerous matrikines (specific ECM peptide fragments) unique in CD fibrostenosis. Peptidomics software analysis showed specific likelihood for bioactivity for 19 of those matrikines (Giuffrida et. al, unpublished data) ().
This project aims to explore the bioactivity of matrikines in CD fibrostenosis in vitro.
It is currently unknown whether diet influences inflammation in Ulcerative Colitis (UC). Observational and experimental data suggest that modulating sulphide within the luminal environment may have therapeutic potential for UC. The aim of this trial is therefore to determine whether a sulphide-reducing diet, designed to attenuate excess microbial production of potentially noxious gases in the colon, can induce remission in UC.
Comparative accuracy of TransPerineal UltraSound (TPUS) versus Magnetic Resonance Imaging (MRI) for the assessment of perianal fistulae in patients with Crohn’s Disease: a prospective observational longitudinal cohort study
Magnetic resonance imaging (MRI) is the first-line imaging modality for monitoring of perianal disease in patients with Crohn’s Disease (CD). However, its use depends on local availability, costs and expertise. Few studies are available on the role of transperineal ultrasound (TPUS). Performing MRI alone in all patients would impose a substantial expense on the health service and would represent a limitation for the many patients who cannot tolerate the procedure (e.g. owing to claustrophobia). For this reason, we urgently need a painless, non-invasive, cost-effective and widely available modality to assess perianal disease and predict disease outcomes. In this observational prospective study, we investigate the accuracy of TPUS versus pelvic MRI in the diagnosis and monitoring of medical and surgical treatment of perianal fistulae in CD patients.
Y-ECCO Interview Corner gives us the opportunity to gain insights into members of the IBD Community, what they do and how they got to where they are. For this edition, I caught up with Dr. Karen Edelblum , a scientist who has a unique and important perspective.
Karen Edelblum combines cell biology and mucosal immunology, with some stunning time-lapse microscopy. She aims to understand how we might harness immune–epithelial interactions in the treatment of Inflammatory Bowel Disease. Having trained at Vanderbilt University and the University of Chicago, she is now assistant professor at Rutgers New Jersey Medical School. We met (over an internet connection) to get her insights into IBD and the science that will move it on.
Traditionally, treatment of Crohn’s Disease (CD) has focused on symptomatic, clinical and corticosteroid-free remission. However, more recent studies have shown that endoscopic remission is associated with more favourable patient long-term outcomes [1, 2]. It has been hypothesised that more intense treatment regimens may increase the likelihood of endoscopic remission in CD patients. Previous studies (such as that performed by the DIAMOND study group) have indicated that adalimumab trough levels are higher in CD patients who achieve an endoscopic response and mucosal healing at weeks 26 and 52 [3]. Further to that, the personalised anti-TNF therapy in Crohn's Disease study (PANTS) demonstrated that low drug levels were predictive of anti-tumour necrosis factor (anti-TNF) treatment failure [4].
Various methods of dose optimisation have been postulated, such as higher induction doses, therapeutic drug monitoring (TDM) to guide dose optimisation during the maintenance phase or a clinically adjusted (CA) dose optimisation strategy.
Vedolizumab (VDZ) was the first biologic to be approved for Ulcerative Colitis (UC) and Crohn’s Disease (CD) after the age of anti-tumour necrosis factor antagonists (anti-TNF). The role of thiopurines in combination with anti-TNFs in the management of IBD is well recognised. However, the role for combination of VDZ with thiopurines is uncertain [1, 2]. This study aimed to investigate the comparative effectiveness of VDZ in combination with a thiopurine versus VDZ monotherapy in the management of both UC and CD.
We are living through challenging times; the pandemic is evolving but is not yet over and conflict in Europe occupies all our minds. Many training programmes and research projects have had to be delayed or adapted over the last two years, but now that restrictions are less onerous much of our clinical and research work is back on track. I therefore hope that you all got your abstracts in to the UEG before the deadline at the end of April. Bear in mind also that the ECCO'23 abstract submission is open. We are looking forward to reading your contributions and selecting the best abstracts for the Y-ECCO Awards and the Basic Science Workshop.
The H-ECCO Committee is saying goodbye to Monika Tripathi and would like to thank her for all her work on behalf of the Committee in recent years.
At the same time, as chairman of the Committee, I am very happy to welcome our new member, Aart Mookhoek. Aart currently works as a pathologist at the Institute of Pathology, University of Bern, Switzerland. He is, however, Dutch originally, and developed his passion for gastrointestinal pathology during a residency and subsequent fellowship at the University of Amsterdam, the Netherlands. Aart and I trained together on histological scoring systems for disease activity in Ulcerative Colitis and Crohn’s Disease, and we participated in a research project on this topic.
Robin Dart
Charlotte Hedin