NIHRDataInsights/HRCSData huggingface dataset:
Title: The causes of constipation. Reclassifying constipation using MRI and high resolution manometry to define mechanism of disease and target treatment.
Funder: Medical Research Council

Abstract: Chronic constipation is characterised by abdominal discomfort, pain and difficult or infrequent defaecation. The current clinical criteria subdivide patients based on symptoms into painful irritable bowel syndrome with constipation (IBS-C) or painless functional constipation (FC). However the current classification system fails to predict treatment response, which is unsatisfactory in 50%. While in some cases colonic hypomotility is the underlying problem this does not explain the abdominal pain which we hypothesize is due to abnormally increased retrograde/ uncoordinated colonic motility. Our recently developed cine MRI technique can noninvasively quantify colonic motility in response to distension of the ascending colon by means of the osmotic laxative, Moveprep. This shows that a subgroup of IBS-C have increased motility compared to FC. We wish to develop this observation using recent advances in high resolution manometry (HRM) made by our collaborator Dr Dinning (Adelaide) which have demonstrated the importance of cyclical retrograde propagated contractions (CRPCs) and/ or uncoordinated motility in the sigmoid colon in constipation. We will validate the MRI assessment of colonic motility in constipation against the manometry gold standard and test the hypothesis that constipated patients with normal/hypermotility of either the right or left colon shown by MRI will show normal/increased CRPCs or uncoordinated motility in the left colon shown by manometry. We will then perform an RCT comparing an antispasmodic with a prokinetic to test the hypothesis that a) constipated patients with paradoxical normal/increased motility will respond better (in terms of reduced pain) to a smooth muscle relaxant than to a stimulant prokinetic and b) that patients with hypomotility will do better with a prokinetic. We will thus develop a simple MRI test to predict response to treatment in patients with constipation resistant to simple laxative treatment.


Research activity codes: 4.2 EVALUATION OF MARKERS AND TECHNOLOGIES;6.1 PHARMACEUTICALS;7.3 MANAGEMENT AND DECISION MAKING
Health categories: ORAL AND GASTROINTESTINAL
Title: MICA: Novel approaches in optimising steatotic livers for transplantation
Funder: Medical Research Council

Abstract: Steatotic livers derive poor outcomes following transplantation due to their increased susceptibility to ischaemia-reperfusion injury (IRI) and therefore many are discarded. With an increasing incidence of fatty liver disease, an increase of hepatic steatosis in the donor pool is inevitable. This project aims to optimise steatotic livers for transplantation through normothermic machine perfusion (NMP) and de-fatting agents. The first objective is to determine changes in hepatocyte structure and function in human steatotic livers undergoing NMP. Liver biopsy samples from the biobank of a randomised controlled trial (RCT) comparing static cold storage (SCS) with NMP as a preservation technique will be examined. The fat content of pre-perfusion biopsies will be compared with those at the end of perfusion and after re-perfusion in the NMP and SCS groups through histological analysis. The second objective is to establish the impact of NMP on improving viability of human steatotic livers by reducing IRI. Post-reperfusion biopsies of steatotic livers preserved via NMP and SCS from the same biobank will be analysed for evidence of IRI by investigating the presence of key cytokines, neutrophil infiltration and Kupffer cell activation. Thirdly, I will compare recipient outcomes in the form of peak asparate aminotransferase and early allograft dysfunction from steatotic livers preserved via SCS and NMP using RCT data. Finally, I will perfuse discarded human livers ex vivo via NMP and compare metabolic and histological changes when de-fatting agents are added through serial analysis of biopsy and perfusate samples. De-fatting agents previously successful in reducing lipid content of steatotic rat hepatocytes in vitro will be refined and validated for human steatotic liver cells in vitro before being applied to whole livers through the NMP circuit. Stable isotope tracers will be added to the circuit to investigate pathways involved in glucose and fatty acid metabolism.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Insulin protects pancreatic acinar cells during pancreatitis
Funder: Medical Research Council

Abstract: Acute pancreatitis is a serious and sometimes fatal inflammatory disease whereby the pancreas digests itself. This is caused by bile acids and ethanol/fatty acid metabolites. Recently, impaired metabolism and cytotoxic calcium overload have been suggested to be the cardinal events that trigger the disease regardless of the cause. There is strong clinical evidence linking diabetes (both type-1 and type-2) and the severity of pancreatitis. Moreover, using two distinct experimental animal models (caerulein and fatty acid/ethanol-induced), our pilot data show that pancreatitis is worse in type-1 diabetic and PACIRKO mice, in which the insulin receptor has been genetically deleted. Furthermore, we have shown that insulin directly protects pancreatic acinar cells from cellular injury induced by pancreatitis agents, including; ATP depletion, inhibition of the plasma membrane Ca2+ pump (PMCA), cytotoxic Ca2+ overload and necrosis. This was due to a metabolic switch towards glycolysis, sufficient to maintain ATP to fuel the PMCA and thus prevent Ca2+ overload, even in the face of impaired mitochondrial function. The over-arching aim of this project is to test the hypothesis that insulin directly protects pancreatic acinar cells during pancreatitis. This will be directly and unambiguously tested in PACIRKO mice using cellular and in vivo models of pancreatitis, in which exogenous insulin is administered using a hyperinsulinaemic-euglycaemic clamp. In addition, the molecular mechanism for this insulin protection will be determined by investigating the signalling pathways and metabolic phenotype induced by insulin. The successful outcome of this project will further corroborate insulin, and related agents, as possible treatments for acute pancreatitis, regardless of the precise causative factor. It is hoped that this multidisciplinary approach from molecular mechanism to whole organism disease state will have major clinical implications for the treatment of acute pancreatitis.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Impact of an Enterobacteriaceae-rich microbial community on gut health
Funder: Medical Research Council

Abstract: Aim I: To investigate the impact of an Enterobacteriaceae-rich microbial community on the colon. Enterobacteriaceae-rich microbiota derived from RYGB-operated rats will be transplanted into non-operated rat recipients. We will analyse faecal samples collected weekly to monitor the microbial colonisation over 20 weeks post-transplant using qPCR. Microbial composition of luminal content and mucosa will be characterised using 16S rRNA gene-based sequencing. Metabolites in biofluid, luminal content and tissue samples will be measured using proton nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS)-based metabolic profiling. MicroRNAs and cytokines will be measured using an Illumina microRNA deep sequencing platform and a Meso Scale Discovery platform, respectively. Mucosal proliferative biomarker (e.g. Ki67) and inflammation biomarkers (CD3+ intraepithelial lymphocyte and CD68+ lamina propria macrophages) will be assessed using immunohistochemical staining. Aim II: To investigate the mechanisms by which an Enterobacteriaceae-rich microbial community regulates the host phenotype We will investigate whether an Enterobacteriaceae-rich microbial community regulates the host colonic physiology and metabolism via microbial metabolites. The luminal microbial metabolites that are found to be associated with Enterobacteriaceae and alterations of host phenotype in Aim I will be tested in the isolated colonic crypt culture. Ki67 will be measured to evaluate the impact of the metabolites on cell proliferation. Cell microRNA profiles will be obtained to predict the pathways which the microbial metabolites regulate. The mRNA targets of the microRNAs will be further confirmed using transfection and inhibition experiments in IEC-6 cells.


Research activity codes: 1.1 NORMAL BIOLOGICAL DEVELOPMENT AND FUNCTIONING
Health categories: ORAL AND GASTROINTESTINAL
Title: USE OF LOW-DOSE IL-2 TO EXPAND ENDOGENOUS REGULATORY T CELLS AND ACHIEVE TRANSPLANTATION TOLERANCE
Funder: Medical Research Council

Abstract: Transplantation remains the most successful treatment for end-stage organ failure, but the need to administer life-long immunosuppression (IS) to prevent rejection limits patient survival. Liver transplantation is the only transplantation setting in which a sizeable proportion of patients spontaneously develop "operational tolerance", a phenomenon defined by the maintenance of stable graft function in the absence of destructive immune responses without the need of IS. Unfortunately this phenomenon preferentially develops in elderly recipients and several years after transplantation. To maximize the benefit derived from IS discontinuation there is a need to find strategies to intentionally induce tolerance in young recipients in whom accumulated IS toxicity has not yet occurred. Our studies have revealed that successful IS discontinuation is associated with a transient intra-graft immune regulatory response with preferential accumulation of regulatory T cells (Tregs). This suggests that short-term enhancement of Treg numbers and/or function at the time of IS withdrawal may facilitate the acquisition of tolerance in patients who are not predisposed to spontaneously develop it. IL-2 is a cytokine that is essential for the optimal development, survival and function of Tregs. Several clinical studies have shown that low-dose IL-2 preferentially expands Tregs and is safe and efficacious in patients with autoimmunity or GVHD. In these studies, Treg frequency increased up to 2 to 8-fold without significant changes in the number of effector T cells. Our objective is to investigate if administration of a short-course of low-dose IL-2 to liver transplant recipients facilitates the discontinuation of IS. We propose to conduct a prospective, phase II, efficacy, single-arm clinical trial in which liver recipients <50 years old and 2-6 years after transplantation will receive IL-2 and gradually discontinue their IS medication.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: ORAL AND GASTROINTESTINAL
Title: Diagnosing chronic liver disease in primary care: developing a cost effective care pathway
Funder: Medical Research Council

Abstract: Rationale: CLD is one of the few diseases with an increasing incidence/prevalence both in the UK and internationally. Three independent UK reports have highlighted the need for the early detection of liver disease including the Chief Medical Officer report (2012), the All-Party Parliamentary Hepatology Group Inquiry and the Lancet commission in 2014. Overall aim: To develop a cost-effective diagnostic strategy for CLD in primary care in the UK. Methodology: -The Clinical Practice Research Datalink (CPRD) will be used to phenotype CLD using easily available abnormal liver fibrosis/cirrhosis measures (AST/ALT ratio, APRI, FIB4, NAFLD Fibrosis Score) and to determine high risk target groups. -Rates of CLD related complications over 5 and 10 years will be determined as relative and attributable risks associated with the non-invasive measure phenotyped CLD compared to the general population. -Through primary data collection the Nottingham Community Cohort (NCC) Study will be used to collect and analyse health related quality of life data, pre- and post CLD diagnosis. -Finally all components will be brought together in a cost-effectiveness assessment of different diagnostic strategies for CLD. The costs and benefits of alternative primary care pathways for identifying CLD against current practice will be modelled. A number of patient and societal effects are anticipated and data will be collected for analysis including: HRQoL, productivity, disease burden and health service costs and savings Scientific and medical opportunities: This research will improve the applicability and reliability of clinical guidelines for the diagnosis of CLD in primary care. It will identify the most cost-effective strategy for integration into clinical care, with the intension of improving quality of care and outcomes for patients.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: ORAL AND GASTROINTESTINAL
Title: The role of the transfer RNA repertoire in generating secretory phenotypes during epithelial homeostasis
Funder: Medical Research Council

Abstract: Much work has focussed on how regulation of mRNA translation can drive protein synthesis to support cell growth. However, less attention has been devoted to the role played by translational control during differentiation - when the protein synthesis machinery tends to reduce production of cellular components, and switches its attention to generation of large quantities of secreted proteins. For example, certain differentiated lineages of the intestinal epithelium produce copious quantities of anti-microbial proteins and the extracellular matrix (ECM) that constitutes the intestinal basement membrane. There are differences in the transfer RNA (tRNA) repertoires of proliferating and differentiated cells - and it has been proposed that this might contribute to changing landscapes of protein synthesis during differentiation. We are interested in how tRNA repertoires might influence translational control, and have recently discovered that a transgenic animal with a defined alteration to its tRNA repertoire displays marked alterations to its translational landscape which are largely restricted to secreted proteins. Indeed, fibroblasts from mice with extra copies of the initiator methionine tRNA gene produce a markedly different profile of ECM components which leads to altered tumour angiogenesis. This project is focussed on experimentally determining the tRNA repertoires that are associated with acquisition of secretory phenotypes in vivo, and to what extent these are responsible for dictating the complex secretomes of differentiated cells. We will characterise alterations to the tRNA repertoire and secretory translational landscape as intestinal stem cells differentiate in vivo and ex vivo. From this, we will investigate how genetic alterations to the tRNA repertoire influences intestinal homeostasis - in particular the generation of secretory phenotypes associated with differentiated intestinal lineages.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Dissecting the steroid metabolome in the pathogenesis and treatment of metabolic liver disease
Funder: Medical Research Council

Abstract: The global burden of metabolic disease, including its hepatic manifestation, non-alcoholic fatty liver disease (NAFLD), continues to escalate and contribute significantly to morbidity and mortality. NAFLD is a spectrum of disease ranging from simple steatosis through to inflammation (non-alcoholic steatohepatitis, NASH), scarring, fibrosis and cirrhosis with a risk of development of hepatocellular carcinoma (HCC). Within 5 years, NAFLD will become the leading indication for liver transplantation. Steroid hormones are potent regulators of metabolic phenotype and have been implicated in the pathogenesis of obesity, diabetes and NAFLD. Using computational analysis of the urinary steroid metabolome, we have identified unique profiles that distinguish patients with cirrhosis from healthy controls. We will define the changes in these profiles that occur across the spectrum of NAFLD correlated with biopsy-proven stage of disease. This approach offers potential as a sensitive and specific non-invasive marker of disease stage, and has allowed us to identify a specific molecular target (AKR1D1, 5beta-reductase) that may drive the pathogenesis of NAFLD and metabolic disease. AKR1D1 is highly expressed in the liver generating all 5beta-reduced dihydro-steroid metabolites as well as having a crucial role in bile acid synthesis. We have generated a rodent model with global deletion of AKR1D1 that has a sexually dimorphic phenotype; female mice resist diet-induced obesity and glucose intolerance. We will define the metabolic and hepatic phenotype of this model using state-of-the-art imaging and molecular biology techniques, generating conditional models with liver-specific deletion and transgenic over-expression. In addition, in vitro experiments will examine the role of AKR1D1 in human hepatocyte models. AKR1D1 may represent a therapeutic target and we have begun to develop a high throughput assay to screen >350,000 compounds to identify specific and potent AKR1D1 inhibitors.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Dysbiosis and Rebiosis of the Periodontal Microbiome
Funder: Medical Research Council

Abstract: Dysbiosis of the oral microbiome in periodontal disease is a hallmark of this condition. Understanding the mechanism of dysbiosis, its functional relevance to disease and strategies to achieve reversal of dysbiosis to restore health have been hindered by the lack of a suitable animal model. Our recent investigations using the mouse model of this disease have demonstrated that the human periodontal bacterium Porphyromonas gingivalis acts as a keystone pathogen in manipulating the normal commensal microbiome into a dysbiotic condition even when present at low abundance. Furthermore we have also shown that this dysbiotic microbiome is causative of disease rather than a consequence of the altered environment in this inflammatory condition. We aim to build upon these finding using this tractable model system in this application. The specific aims are: 1. Determine the mechanism of P. gingivalis induced dysbiosis of the periodontal microbiome by assessment of the dysbiotic potential of P. gingivalis genetic mutants in candidate genes with particular reference to the role of the Type IX secretion system and the production of outer membrane vesicles 2. Functional characterisation of the dysbiotic periodontal microbiome compared to the symbiotic microbiome characteristic of health through metagenomic and meta-transcriptomic analyses 3. Reversal of dysbiosis: Rebiosis of the periodontal microbiome. Informed by the findings of the preceding aims we will identify organisms or consortia of organisms whose presence/ transcriptional activities are consistent with symbiosis and periodontal health and apply these in bacterial replacement investigations in order to reverse dysbiosis and restore health in this model system. These investigations will form the basis for the design of future translational investigations in humans with the overall aim of the development of novel treatment approaches to periodontal disease.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL
Title: Defining the regenerative capacity of ductular cells from non-transplantable human liver
Funder: Medical Research Council

Abstract: Hepatocyte transplantation has successfully been used to: bridge patients to whole liver transplantation; support paediatric patients in acute liver failure and correct metabolic liver disease. However, hepatocytes are usually sourced from discarded livers not suitable for transplantation that are significantly steatotic, meaning high quality hepatocytes are rarely obtained from these discarded livers. These same steatotic livers have abundant ductular reactions. Ductular reactions are activated in chronic liver disease and are thought to contain putative hepatic progenitor cells (HPCs), with the potential to regenerate hepatocytes and cholangiocytes. We have shown that mouse HPCs can: be frozen/defrosted without harm, be cultured and expanded in vitro without change of phenotype, repopulate and regenerate liver upon transplantation in a mouse model of induced hepatocyte injury and senescence, differentiate in vivo into hepatocytes and cholangiocytes. We aim to develop human ductular cells/HPCs for liver disease therapy by: 1. refining our methods for isolating ductal cells/HPCs from human cadaveric livers discarded from transplantation using ex-situ normothermic perfusion prior and during cell isolation. HPCs will be purified using defined FACS protocols and their phenotype, gene expression profiles, clonogenicity, and phenotypic stability will be assessed. 2. to assess ductular cell/HPC biliary and hepatocyte regeneration potential, we will transplant defined populations of human HPCs into our immunodeficient mouse models of induced (i) hepatocyte or (ii) biliary senescence and injury, and assess histological and functional repopulation capacity. 4. Develop protocols to isolate, purify and expand ductular/HPCs in a GMP compatible manner as a potential clinical cell product. 5. Assess long term stability and safety of the transplanted ductular/HPCs. 6. If the above components are successful we will apply for MHRA approval to use the cells as an ATMP.


Research activity codes: 5.2 CELLULAR AND GENE THERAPIES
Health categories: ORAL AND GASTROINTESTINAL
Title: Optimising an oral health intervention delivered by health visitors and establishing robust outcomes to measure its impact
Funder: Medical Research Council

Abstract: Preventing dental caries is a key public health priority. UK guidance strongly supports Parental Supervised Toothbrushing (PSB) using fluoride toothpaste twice-daily from first tooth eruption (around 6 months). Infrequent brushing is associated with higher caries prevalence in young children especially those living in deprived areas. We have identified many barriers to PSB and, using MRC guidance, developed a complex intervention to maximize PSB adoption by parents. The Healthy Child Programme with universal home visits by health visitors mandates a discussion of oral health behaviours with parents of infants. There is limited evidence to support the effectiveness of this discussion and significant variation in practice. There are no standard materials or frameworks for this discussion and inconsistent training for health visitors. Work Package A- AIM:(1)To co-produce training and materials with health visitors and parents to maximise PSB adoption. METHOD: Detailed specification of the PSB intervention will be developed through an iterative process with mixed groups of health visitors and parents. Work Package B- AIMS:(1)To explore acceptability and feasibility of the PSB intervention to health visitors and parents of infants; (2)To develop an objective measure(s) of PSB adoption. METHOD: 30 parents of infants aged 12 months will be recruited. The research team will collect self-reported and objectives measures of PSB at baseline. Parents will then receive their health visitor home visit including the PSB intervention. The research team will then collect further PSB adoption data at 2 weeks and 3 months. ACCEPTABILITY of the PSB intervention and measurement of PSB adoption will be explored with parents through qualitative interviews. ACCEPTABILITY and FEASIBILTY of delivering the PSB intervention will be examined with health visitors through focus groups. UTILITY of 3 objective PSB measures will be compared with each other and with parental-self reports.


Research activity codes: 3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: ORAL AND GASTROINTESTINAL