Dr Debbie Shawcross
Professor Alberto Sanchez Fueyo
Dr Mark McPhail
King’s College London Institute of Liver Studies is a world-leading academic liver research centre completely integrated with the Liver Clinical Services at King’s College Hospital, with a track record of delivering high-quality translational research, developing novel medicinal products with a direct impact on clinical care, and carrying out innovative research and innovation activities in partnership with the MRC, NIHR and industry. The Institute of Liver Studies’ academic strengths include liver immunobiology, gut microbiome manipulation, transplantation, cell therapy and the management of complex acute and chronic liver diseases.
King’s College Hospital runs one of the largest adult and paediatric liver transplantation programmes in Europe and on a yearly basis performs between 200 and 250 adult and paediatric transplant procedures per year. The total volume of liver transplantation activity at King’s is in excess of 4500 transplants. We are a globally renowned tertiary liver centre offering high quality adult and paediatric liver services. We have a dedicated 15-bed liver intensive care unit and a further 4 level 2 high dependency beds offering state-of-the-art care for patients presenting with acute and acute-on-chronic liver failure as well as those undergoing liver transplantation and complex hepatobiliary surgery.
In terms of clinical training, our IATs will rotate between General Hepatology, Transplant Assessment and Liver Transplantation blocks in the Liver Unit. This will be balanced with training opportunities in the liver outpatient clinics and gastrointestinal endoscopy sessions. Altogether, the clinical rotation covers all elements of the core and advanced hepatology curriculum. ACFs and CLs will join the Higher Specialist Training Programme in Gastroenterology and General Internal Medicine in South Thames spread across South London within the M25.
Our Integrated Academic Trainees (IAT) will be offered the opportunity to develop a research project in one of three areas. These areas have been chosen on the basis of their novelty and likelihood to deliver the type of high quality data that would be required for a successful application for a research council PhD fellowship. Either Prof. A. Sanchez-Fueyo, Prof. D. Shawcross or Dr M. McPhail and members of their teams will provide close research supervision and mentorship.
a) Regulatory T cell immunotherapy in liver autoimmunity and liver transplantation [Prof Sanchez Fueyo and Dr Nilou Safinia]
Regulatory T cells are a lymphocyte subset that plays a key role in preventing autoimmunity, maintaining immune tolerance and promoting tissue repair and regeneration. Prof. Sanchez-Fueyo’s laboratory is interested in investigating how liver failure influences the function of regulatory T cells and in developing regulatory T cell-based immunotherapies to control inflammatory liver damage and induce tolerance following liver transplantation. The IAT will have the opportunity to gain familiarity with a variety of lymphocyte biology and immunomonitoring assays and to study the link between adaptive immunity and clinical outcomes in patients with liver diseases. Following one or more research placements, ACFs will be encouraged to submit fellowship applications to complete a PhD in this area.
b) Therapeutically modulating Immuno-metabolism in liver failure syndromes [Dr Mark McPhail]
Liver failure is a high mortality condition where both profound metabolic and immune defects predispose to high risks of sepsis, multi-organ failure and death. Immuno-metabolism is a novel area of investigation that explores how metabolism affects immune cells and promotes phenotypical and functional change. In this project the IAT will have the opportunity to characterise the metabolic abnormalities in bio-fluids in patients with acute or acute-on-chronic liver failure and to therapeutically modulate immunity ex vivo in Dr McPhail’s laboratory. For example, recent work in this area has focussed on metabolically phenotyping lipid dysregulation in plasma of liver failure patients and then modulating lipid receptors on CD14+ monocytes to promote immune activation and cytokine production. The IAT will have the opportunity to learn metabolomics (1H NMR and LC-MS), multivariate analysis, flow cytometry, ELISA and pathway analysis as part of a rich area of investigation of novel pathways of immunotherapy via an experimental medicine approach. A common approach is to learn one of these skills in a 3-month research placement as part of a metabolite pathway analysis and then utilise further techniques during later research blocks or during a PhD.
c) Gut microbiome manipulation to improve outcomes in chronic liver disease [Prof Debbie Shawcross]
There is an evolving crisis of chronic liver disease in the UK with the prevalence and mortality increasing exponentially. End-stage chronic liver disease, termed cirrhosis, is the third biggest cause of mortality and loss of working life behind ischaemic heart disease and self-harm. Cirrhosis is associated with an increased incidence of infection resulting in hospitalisation. Infection can lead to worsening liver function and precipitate complications including variceal bleeding, hepatic encephalopathy, acute kidney injury and multi-organ failure, contributing to high mortality. Patients with cirrhosis have enteric bacterial dysbiosis and translocation of bacteria across the gut epithelial barrier. This culminates in systemic inflammation and endotoxemia, inducing innate immune dysfunction, predisposing to bacterial infection which influences the progression to terminal liver failure. As the gut microbiome plays a key role in the natural history of cirrhosis, unlocking the potential of the microbiome and developing antibiotic-free therapies becomes a research priority.
The programme comprises three main work streams (WS) working within a robust collaborative framework with the goal of improving outcomes for patients with cirrhosis and reducing the burden of managing cirrhosis within the NHS.
WS 1: MICROB-PREDICT: MICROBiome-based biomarkers to PREDICT decompensation of cirrhosis and treatment response. This 5-year Horizon 20:20 funded consortium has access to data and samples from the major microbiome initiatives in the field of hepatology from 12 international studies enrolling >10,000 patients. Prof. Shawcross’ is a partner in this consortium leading a team of 7. The consortium provides a rich network for collaboration and clinical and academic training and offers mentorship and opportunities to visit other institutions across Europe offering unique research opportunities such as the Max Planck Institute in Germany.
WS 2: NIHR EME funded PROMISE Trial: A PROspective double-blind placebo-controlled multicentre trial of faecal MIcrobiota tranSplantation to improve outcomEs in patients with cirrhosis.
WS 3: Replacement of animal models with ‘organ-on-a-chip’ technology for interrogating the gut-microbiota-liver axis in health and chronic liver disease. Human Gut-liver-Chip technology has the potential to provide significant advances over animal models. Recapitulating 3D structures with differentiated cell types and multiple physiological functions of normal human intestinal villi coupled with primary liver cells enables investigation of the gut-liver axis. This provides a novel ex vivo system for drug development aimed at targeting the gut microbiome.