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.

THE ROLE OF AUTOPHAGY IN LIMITING IBD-ASSOCIATED AIEC-INDUCED INTESTINAL INFLAMMATION

Shai Bel © Shai Bel

Aim of research

While the aetiology underlying the development of Inflammatory Bowel Diseases (IBD) is unclear, evidence points to an interaction between host genetics, such as mutations in autophagy genes, and environmental factors, such as bacterial infections. Multiple studies have identified an adherent-invasive Escherichia coli pathotype (AIEC) that attaches to intestinal epithelial cells (IECs) in patients with IBD but not in healthy subjects. It is thought that AIEC exploits the intestinal inflammation in patients with IBD to attach to the IECs, intensifying the pre-existing inflammation. Studies in vitro have shown that functional autophagy is crucial to eliminate AIEC infection. Here, we aim to identify how, and in which compartment of the intestine, autophagy protects the host from AIEC-associated pathologies in vivo and to determine whether artificially enhancing the autophagy process is a viable therapeutic avenue for patients with IBD and intestinal AIEC colonisation.

TISSUE-ASSOCIATED MICROBIAL AND CELLULAR DRIVERS OF RESOLUTION OF INFLAMMATION AND DISEASE EXACERBATION IN A LONG-TERM COHORT OF PAEDIATRIC CD PATIENTS

Tobias Schwerd ©  Tobias Schwerd

Aim of research

Inflammatory Bowel Diseases (IBD) are characterised by episodes of disease quiescence and disease exacerbation. The microbial and molecular events that result in long-lasting resolution of inflammation or the transition from IBD quiescence (mucosal healing) to active intestinal inflammation are unknown. Intestinal inflammation arises from a dysregulated response of tissue-resident immune cells, such as T cells, towards the intestinal microbiota. We aim to study longitudinal host–microbe interactions at the mucosal level as a strategy to identify microbial and molecular events associated with the resolution or re-activation of intestinal inflammation in individual paediatric patients with IBD.

FINE DETERMINATION OF GUT TISSUE LAYERS’ INFLAMMATION EXPLORING IMMUNE-MICROBIOTA SIGNATURES: NEW BIOMARKERS OF RECURRENCE IN SURGICAL PATIENTS WITH CROHN’S DISEASE?

Francesco Giudici © Francesco Giudici

Aim of research

Up to 65% of patients with Crohn’s Disease (CD) show disease recurrence after ileocolic resection. The reasons for this high recurrence rate are still unclear, but the abnormal CD inflammatory process, against the microbiota, affects all the intestinal wall layers. We aim to explore the mutual interplay of inflammatory and microbial factors involved in CD through a systems-level study, defining the “correlation network” of mucosa-associated microbiota (and its faecal metabolites) at the time of ileocolic resection. We will evaluate whether specific microbial/inflammatory correlations are statistically associated with early postoperative endoscopic recurrence, assessed by colonoscopy at six months.

ROLE OF DNA METHYLATION AND GENE EXPRESSION ALTERATIONS IN DEVELOPMENT OF EARLY-ONSET PRIMARY SCLEROSING CHOLANGITIS IN ULCERATIVE COLITIS – DYNAMIC

Sudipto Das © Sudipto Das

Aim of research

Primary sclerosing cholangitis (PSC) is a progressive cholestatic disease and up to 80% of PSC patients have Ulcerative Colitis (PSC-UC), which presents a clinical challenge owing to the difficulty in diagnosis and increased risk for development of cancer. While several multifactorial processes, including inflammation and dysbiosis of microbiota, have been associated with PSC-UC pathogenesis, the precise molecular factors that regulate the phenotype of this disease subtype remain unknown. This research project – DYNAMIC – hypothesises that mapping the differences in DNA methylation and gene expression alterations between young PSC-UC and non-PSC-UC patients will allow us to unravel critical molecular factors that underpin this disease subtype.