Defining the Role of invariant Natural Killer T (iNKT) Cells in Perianal Fistula 

Sulak Anandabaskaran © Sulak Anandabaskaran

Background & aim of research

Perianal fistulising Crohn’s Disease (pCD) is associated with poor outcomes and impaired quality of life. It remains difficult to manage despite medical and surgical advancements, likely due to poor understanding of the underlying immunology. Previous multiparameter flow cytometry work in our lab on immune cells isolated from peripheral blood and fistula curettage samples showed expansion of iNKT cells in perianal fistula compared to peripheral blood. Furthermore, iNKTs have been suggested to have a potential role in key processes in fistula pathogenesis, namely epithelial-to-mesenchymal transition and extracellular matrix degradation. The role of iNKTs in inflammation remains poorly defined and their function in human IBD is largely unexplored. Therefore, in this experiment we aim to further define their role in the pathogenesis of perianal fistula.

Intestinal epithelial cell stress modulates enteric fibroblastic and neuronal profiles in Inflammatory Bowel Disease

Celia Escudero-Hernández  © Celia Escudero-Hernández

Background & aim of research

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.

Decoding the neuroimmune crosstalk in Inflammatory Bowel Diseases

Silvia Cerantola © Silvia Cerantola

Background & aim of research

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

Margarita Papatheodoridi © Margarita Papatheodoridi

Background & aim of research

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.

Examining a novel sulphide-reducing diet As Therapy in Ulcerative Colitis (EAT-UC trial)

Robert V. Bryant © Robert V. Bryant

Background & aim of research

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

Ferdinando D’Amico © Ferdinando D’Amico

Background & aim of research

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.

JAK-STAT-driven immunometabolism as a novel principle in the pathophysiology of Ulcerative Colitis

Janus kinase (JAK) inhibition is a novel therapeutic approach in the management of Ulcerative Colitis (UC). However, the role of JAK inhibition with respect to cell-specific immunometabolic properties is not known.

The overall aim of this multi-year research proposal is to generate deeper understanding of the interplay of JAK inhibition and immunometabolic properties in the intestinal mucosa at a cellular level and thereby to open up new avenues in biomarker development and novel targeted interventions in UC. This aim is being pursued by (i) identifying immunometabolomic signatures of JAK inhibition in UC patients using multi-omics analysis of longitudinal therapy response cohorts and (ii) modelling the impact of two metabolic principles, namely amino acide (e.g. tryptophan) and short-chain fatty acids (e.g. butyrate), on the efficacy of JAK inhibition in ex vivo organisms.

A NEUROEPITHELIAL APPROACH TO INFLAMMATORY BOWEL DISEASE

Roksana Maria Pirzgalska © Roksana Maria Pirzgalska

Aim of research

Deregulation of the gut mucosa is an under-appreciated aspect of Inflammatory Bowel Disease (IBD) and metabolic syndrome. We hypothesise that brain-derived signals modulate mucosal physiology by regulating both immune responses in the gut and the absorptive capacity of intestinal cells. We aim to understand the function of this proposed brain–gut circuit and to what extent this information can be harnessed from a clinical perspective.

A SYSTEMS BIOLOGY APPROACH FOR IDENTIFICATION OF HOST AND MICROBIAL MECHANISMS AND DRUGGABLE TARGETS FOR THE TREATMENT OF PSC-IBD

M. Nabil Quraishi © M. Nabil Quraishi

Aim of research

Primary sclerosing cholangitis (PSC) is a rare hepatobiliary manifestation of Inflammatory Bowel Disease (IBD) that is associated with significant and disproportionate unmet needs and a higher all-cause mortality compared with IBD alone. Unfortunately, no medical therapy has been proven to slow disease progression in PSC-IBD, and liver transplantation is the only life-saving intervention for patients.

We recently identified distinct mucosal transcriptomic profiles in PSC-IBD with regard to bile acid metabolism, bile acid signalling and a central role of enteric dysbiosis. Data from other groups have shown that oral vancomycin attenuates colonic inflammation and improves biochemical markers of cholestasis in PSC. In our study, we hypothesise that oral vancomycin attenuates colonic mucosal inflammation in PSC-IBD by restoring gut microbiota-mediated bile acid homeostatic pathways. We aim to identify druggable gut microbial and host molecular pathways associated with bile acid-mediated colonic mucosal inflammation in PSC-IBD.

DEFINING AND SUPPORTING MUCOSAL HEALING IN INFLAMMATORY BOWEL DISEASE

Charlotte Hedin © Charlotte Hedin

Aim of research

One goal of Ulcerative Colitis (UC) treatment is complete endoscopic/histological mucosal healing (MH). The treatments currently used to achieve MH almost universally act through immunosuppression, with side-effects of infection and cancer. Therapeutic strategies that directly promote MH are lacking, partly due to poor understanding of the dynamics and different phases of MH. Better knowledge of the stages of MH may also inform optimal timing of therapeutic interventions.

The aims of this project are to generate an in-depth dynamic molecular characterisation of patients with acute, active UC and to follow the development of this profile into either MH or eventual non-response with consequent surgery. The molecular data will be linked to detailed registration of diet during inflammation and healing and to durability of remission.