NIHRDataInsights/HRCSData huggingface dataset:
Title: The role of the gut microbiota in regulating mucosal macrophage homeostasis and inflammation
Funder: Wellcome Trust

Abstract: Inflammatory bowel diseases (IBD) represents a significant economic and public health burden, and are caused by an inappropriate immune response against the microbiota. Broad-spectrum antibiotic use in childhood has been linked with susceptibility to IBD, but the mechanisms are not understood. Macrophages are crucial components of the intestinal immune system where they usually recognize the microbiota without provoking an inflammatory response. My preliminary data indicate that antibiotic treatment in vivo dysregulates intestinal macrophage behaviour, inducing them to become overactive after microbial re-colonization, driving long-lived pro-inflammatory T-cell responses. Here, I will investigate the cellular and molecular mechanisms underlying the effects of antibiotics on intestinal macrophages and inflammation, examining if there is a specific developmental window early in life when effects are most potent. I will identify which bacterial strains are involved in driving inflammation after re-colonization, and will explore the role of short-chain fatty acids. Additionally, due to strong evidence that antibiotic use can predispose to asthma, I will also test the hypothesis that the effects of antibiotics on macrophages will extend beyond the intestine into the lung. Together, these experiments will determine how antibiotic use might induce immune dysfunction and generate important new insights into how mucosal macrophages are controlled.

Lay abstract: Our immune system must fight harmful pathogens, but remain silent against harmless substances such as the trillions of bacteria found in the gut that are beneficial for health. If our immune system attacks these bacteria (the “microbiota”), inflammatory bowel diseases (IBD) such as Crohn’s disease can occur. These are painful, debilitating conditions affecting millions worldwide, and although the causes are poorly understood, there is mounting evidence that previous antibiotic use may be important, especially if used in early life. However, why antibiotics increase IBD risk is unknown. My preliminary results indicate that antibiotic use causes immune cells called macrophages to become over-active in the gut, resulting in long-lived inflammation. Here, I will examine how antibiotics cause changes in gut macrophages that may lead to IBD. As it is now known that antibiotic use in childhood also predisposes to asthma, I will explore if antibiotics also make lung macrophages more active and if this contributes to inflammatory disease in the lung. Together, my project will determine how gut and lung macrophages control the immune system in health and how antibiotic use might disrupt this process, allowing inflammation to develop, with the potential for identifying new drug targets.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Deciphering host microbial interactions in the intestine in health and disease
Funder: Wellcome Trust

Abstract: Host microbe interactions in the intestine promote health and when deranged can lead to chronic inflammatory diseases such as inflammatory bowel disease (IBD). Manipulation of these pathways is limited by a lack of understanding of the molecular interactions that underpin host microbial cross-talk. We will examine the reciprocal relationship between the host and the microbiota to uncover how host factors contribute to microbial regulation and its impact on downstream innate and adaptive immune responses. Specifically, we will investigate how the immune-regulatory factors IL10 and a novel kinase govern microbial community function and colitogenicity. We will further investigate how specific microbial products such as short chain fatty acids (SCFA) and CREB-inducing polysaccharides interact with these pathways to promote tolerance and host defence mechanisms in macrophages and the effects of microbiota modulation and host maladaptations on the differentiation and regulation of intestinal T cells. Further understanding of the molecular and cellular pathways that control the host microbial dialogue in the intestine may provide novel therapies to prevent and treat inflammatory diseases such as IBD.

Lay abstract: Trillions of bacteria live in our intestines. These tiny microbes promote healthy immune function in the gut that in turn keeps these bacteria in check. We will study the beneficial interactions between bacteria and immune cells in the gut and how things go wrong in inflammatory bowel disease (IBD), a chronic debilitating disease of the gastrointestinal tract. By measuring bacterial DNA and proteins in healthy and diseased tissue, we will be able to pinpoint the types of bacteria – and their secreted products – that associate with inflammation. Using this information together with data already generated in the lab, we will examine precisely how bacteria and the molecules they produce act on different immune cell types in the gut to boost protective immunity or elicit damaging inflammation. This may uncover new targets for interventions that promote health or prevent or treat inflammatory or infectious disease.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL;INFECTION;INFLAMMATORY AND IMMUNE SYSTEM
Title: Tissue-resident macrophage activation and regulation in injury and recovery
Funder: Wellcome Trust

Abstract: In this project, we hypothesise that there exist a tight regulation of macrophage activation following tissue injury to create environments permissive to different stages of tissue repair. Making use of human iPSC-derived macrophages (iMacs), we aim to gain insight into how they become activated after tissue damage, particularly through scavenger receptors in collaboration with other pattern recognition receptors. By studying knockout iMac models, we will then seek to understand how the IL-10/PGE2 axis and regulatory T cells limit excessive activation. Lastly, we aim to deliver in vivo evidence that some of these pathways are involved in promoting either organ inflammation or homeostasis restoration by using carbon tetrachloride (CCl4)-induced acute liver injury mouse model. A full understanding of these mechanisms will guide the development of potential therapeutic targets that harness specific macrophage properties for clinical benefit.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL;INFLAMMATORY AND IMMUNE SYSTEM
Title: Intestinal epithelial cells: at the interface of the microbiota and mucosal immunity
Funder: Wellcome Trust

Abstract: Intestinal infections affect billions of people worldwide, resulting in nearly 1.4 million deaths each year. The commensal microbiota can prevent pathogenic infection, as demonstrated by increased susceptibility to infection upon antibiotic use; however, the precise mechanisms of microbiota-mediated protection are not well-characterized. I have recently discovered that colonization of mice with commensal Enterococcus faecium leads to improved intestinal barrier function and decreased Salmonella and Clostridium difficile pathogenesis. I went on to uncover a mechanism by which a unique enzyme, SagA, from these bacteria activates intestinal epithelial cells (IECs) to increase anti-microbial peptide (AMP) expression and mucin distribution. These studies revealed several host and microbiota factors involved in pathogen tolerance. My proposed independent research will identify the mechanisms by which commensal bacteria modulate IECs and intestinal immunity. Utilizing advance microscopy, proteomics and sequencing approaches, I will characterize the effects of E. faecium, SagA and other microbiota metabolites on IEC gene expression and function and subsequent pathogen resistance. Using proteomics-based bioorthogonal reporters and intersectional genetics, I will then dissect how microbial modulation of IECs affects the differentiation and function of intraepithelial lymphocytes. Elucidating the IEC programs triggered by commensal bacteria will enable better strategies to prevent and treat intestinal infections.

Lay abstract: Intestinal infections affect billions of people worldwide and result in nearly 1.4 million deaths each year. Normal intestinal bacteria, known as the microbiota, can prevent pathogenic infections, as demonstrated by increased susceptibility to infection upon antibiotic use; however, the mechanisms of microbiota-mediated protection are not well-characterized and therefore cannot be employed to engineer effective therapies. I have recently shown that Enterococcus faecium, normally found at low abundance in the human gut, is able to reduce disease caused by the pathogens Salmonella and Clostridium difficile when administered as a probiotic. This protection was elicited by cues from E. faecium that are able to activate the intestinal epithelium. My proposed research will utilize advanced approaches and cutting-edge technologies to dissect the mechanisms by which normal intestinal bacteria activate and prepare the intestinal epithelium and the vast network of underlying immune cells to fight infections. Revealing the mechanisms of defense triggered in the intestinal epithelium by the microbiota will enable better strategies to prevent and treat intestinal infections and inflammation.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL;INFLAMMATORY AND IMMUNE SYSTEM;INFECTION
Title: 2014 Cochrane Fellowship: Dr Sharon Millen -Psychosocial Interventions for Liver Transplant Patients
Funder: Health and Social Care Research and Development Division (HSC R&D) of Public Health Agency, Northern Ireland

Abstract: Following work by the Organ Donor Taskforce there has been a 30.5% increase in the number of organ transplants conducted in the UK between 2008 and 2013.1 Last year, the number of liver transplants in UK increased by 4.5% to 817 compared with 782 in 2012.2 With this number increasing annually, it is important that we identify the most effective interventions to improve patient outcomes. Research indicates that although liver transplantation offers improved quality and length of life, the transplant experience extends far beyond hospital discharge. It is evident that liver recipients experience numerous stressors which can lead to maladaptive coping and significant psychological distress particularly in the early post-operative phase.3,4,5 These negative emotional states can lead to immune dysregulation and adverse health behaviours such as nonadherence to the transplant regimen (including lifelong medication). This can result in rehospitalisation and retransplantation due to rejection.6 Despite current evidence7,8,9,10 indicating that various psychosocial interventions are effective in improving health states for liver recipients, we do not know which of these strategies (or indeed which specific components of these) are most effective. This review aims to assess the effectiveness of psychosocial interventions available for liver transplant recipients. Participants= liver recipients (of any age). Interventions= psychosocial interventions currently in place for liver recipients. Interventions of any duration, intensity, or frequency, and delivered in any setting in a variety of ways (e.g. web-based, by a facilitator, delivered individually/in groups, by phone). Comparisons= no intervention or treatment as usual. Primary Outcomes= 1) Health-Related Quality of Life; 2) psychological well-being (e.g. Post Traumatic Stress Disorder, depression, anxiety, coping and optimism); 3) adherence (e.g. intake of medication, clinic attendance, alcohol, tobacco or illicit drug use). Secondary outcomes= Educational outcomes (e.g. academic achievement, knowledge).


Research activity codes: 6.6 PSYCHOLOGICAL AND BEHAVIOURAL
Health categories: ORAL AND GASTROINTESTINAL;MENTAL HEALTH
Title: Dealing with feelings: the neural bases of empotional processing and regulation in Bulimia Nervosa
Funder: The British Academy

Abstract: This project aims to explore emotional processing and regulation in individuals with Bulimia Nervosa (BN) with a view to better understand its underlying causes. Previous research suggests that binge eating and purging behaviours may be linked to difficulties with emotions and impulses. However, most of the research has been conducted using self-report methods, despite the fact that these individuals have difficulties identifying and describing their emotions (known as alexithymia), making the use of self-report questionable. This project is the first to use electroencephalography (EEG) as an objective method to disentangle emotional processing and regulation in these individuals. A combination of three tasks and questionnaires will be used to measure various aspects of an emotional response and its link to impulsive behaviours in individuals with BN (N=35) and healthy controls (N=35). This study has the potential to inform future treatment for these individuals.


Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: ORAL AND GASTROINTESTINAL;MENTAL HEALTH
Title: Alcohol consumption and brain health
Funder: Wellcome Trust

Abstract: Exposure to alcohol is widespread but potentially modifiable. Whilst heavy drinking is recognized as detrimental to the brain, the impact of more moderate intake remains unclear. This project seeks to better understand the relationship between alcohol intake and brain health. Specific aims: 1. Examine the causal relationship between alcohol intake and dementia. 2. Investigate the causal association between drinking and brain imaging markers. 3. Identify mediating pathways between alcohol and brain health. The proposed studies will triangulate large-scale electronic health records with neuroimaging and genetic data in UK Biobank (n=500,000) and Million Veterans Program in the US (n=760,000). The project will include complementary observational and pseudo-experimental (Mendelian randomization) approaches, and examine for consistency of findings across methods. Outcomes: This work will comprise the largest and most in depth study of alcohol’s association with brain health. It has extensive application for the study of other exposures relating to psychiatric phenotypes. The findings are likely to be of widespread interest and relevance to scientific and clinical fields, as well as policy-makers and the public.

Lay abstract: Alcohol consumption is endemic in our society, with almost 40% of the world’s population drinking. While we know that very heavy drinking is detrimental to the brain, and can lead to dementia, more moderate intakes have been claimed to be protective. However, there were limitations in the way this research was carried out and the results may be spurious. Using huge databases, which contain information on drinking habits of millions of people in the UK and US, and the largest brain imaging and genetic samples worldwide, I will clarify how alcohol consumption affects the brain. Specifically, I will examine whether drinking affects a person’s risk of developing dementia, if and where brain structure is impacted, and through what pathways damage or protection occurs. Better understanding of these issues will hopefully identify ways to intervene, with a potentially huge public health impact.

Research activity codes: 2.3 PSYCHOLOGICAL, SOCIAL AND ECONOMIC FACTORS
Health categories: ORAL AND GASTROINTESTINAL;MENTAL HEALTH;CARDIOVASCULAR;NEUROLOGICAL
Title: Understanding and disrupting the link between obesity and metabolic disease
Funder: Wellcome Trust

Abstract: Obesity is strongly associated with common metabolic diseases (T2DM, fatty liver and cardiovascular disease) which collectively account for a huge global health burden. Insulin resistance underpins this association and our goal is to understand, and reverse, its molecular pathogenesis. Having worked on rare monogenic lipodystrophies, almost all of which are associated with the metabolic diseases typically seen in obesity, for ~20 years, we have recently convincingly shown that subtle forms of lipodystrophy are a major factor in common insulin resistance/metabolic disease. Specifically we showed that SNPs associated primarily with reduced hip (femorogluteal) fat, are as strongly associated with T2DM and cardiovascular disease risk as variants associated with central adiposity. We will build on this step-change in understanding by: 1. Deepening understanding of the molecular mechanisms by which adipocytes form and then store surplus energy in unilocular lipid droplets 2. Performing an experimental medicine intervention study designed to demonstrate the clinical and molecular impact of alleviating energetic overload using a very low energy diet in patients with partial lipodystrophy. 3. Investigating the source and action of two hormones (GDF15 and FGF21) which we hypothesize to be stress signals released in response to sustained overnutrition. Both of these molecules represent exciting therapeutic opportunities.

Lay abstract: Lipodystrophies are rare diseases characterised by a lack of body fat. Despite the widespread perception that ‘fat is bad’, it is an essential body organ for storing excess dietary energy. Interestingly, people with lipodystrophy are prone to an almost identical set of metabolic diseases (diabetes/fatty liver/heart disease) as obese people. We have long wondered why this is and recently showed that many obese people prone to metabolic disease have a subtle form of lipodystrophy so what we have learnt about rare lipodystrophies can teach us a lot about obesity-associated disease and vice versa. In the next 5 years, we will: 1. conduct cell-based studies to advance understanding of exactly how fat cells store excess energy 2. conduct a study designed to relieve energy overload in people with lipodystrophy using a new very low energy diet 3. study two very recently discovered hormones (called GDF15 and FGF21) of interest as potential weight-loss agents

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: ORAL AND GASTROINTESTINAL;METABOLIC AND ENDOCRINE;CARDIOVASCULAR
Title: Understanding the experience of the dietetic consultation and design of a more effective model of nutritional care for older adults to enhance levels of patient satisfaction
Funder: Dunhill Medical Trust

Abstract: The aim of this series of studies is to develop an understanding of the experience of the dietetic consultation from both the perspective of the patient and dietitian and to use the information gained to inform the design of a model for the provision of nutritional care in a South London borough that is effective and associated with enhanced levels of patient satisfaction. There are four broad research questions: 1. To review the existing literature on the patient experience of consultations with a dietitian and its impact on the effectiveness of the consultation, patient satisfaction and the nutritional, clinical and healthcare outcomes of care. 2. To investigate how the process of the dietetic consultation and its effectiveness, is experienced by nutritionally vulnerable patients. 3. To investigate the feelings and attitudes of dietitians about consultations with nutritionally vulnerable patients and their views on its effectiveness. 4. To develop and pilot an evidence-based model of nutritional care for nutritionally vulnerable patients, informed by studies of patient experience, that is associated with enhanced effectiveness and greater levels of patient satisfaction. This series of studies will support the aims of the Dunhill Medical Trust in addressing questions about the effectiveness and satisfaction of patients with nutritional care given by dietitians for the management of illness-related malnutrition. The importance of effective management of nutritionally vulnerable patients is a key priority for organisations with a stake in the care and management of nutritionally vulnerable adults. The National Institute for Health and Clinical Excellence recently highlighted the potential for effective management of malnourished individuals as seventh of thirty two guidelines that could generate the most cost savings to the NHS (NHS Institute for Innovation and Improvement, 2009). However, the focus of guidelines and policies in this area has tended to be on the provision of services and roles of healthcare staff rather than on understanding the patient perspective. A recent report from Age Concern poignantly drew attention to the patient perspective, suggesting that the first action in effective provision of nutritional care should be to ‘listen to us (patients)’ (Age Concern, 2010). The Francis report repeatedly highlighted the failure to recognise the patient perspective in healthcare delivery and this series of studies aims to address this deficiency in terms of the dietetic management of nutritionally vulnerable patients.


Research activity codes: 7.3 MANAGEMENT AND DECISION MAKING;7.1 INDIVIDUAL CARE NEEDS
Health categories: ORAL AND GASTROINTESTINAL;METABOLIC AND ENDOCRINE;GENERIC HEALTH RELEVANCE
Title: Identifying oral health markers of amlnutrition and sarcopenia in older people in the community
Funder: Dunhill Medical Trust

Abstract: Sarcopenia (loss of muscle mass), a major cause of disability, is closely related to malnutrition (under-nutrition). Oral health, through its influence on malnutrition, has been implicated in sarcopenia. However, the influence of poor oral health, including tooth loss, periodontal (gum) disease and dry mouth (xerostomia) on sarcopenia has not been studied comprehensively and prospectively. In a study of older British people, we will collect prospective data on sarcopenia, malnutrition and oral health. With these data we will quantify the contribution of oral health to developing sarcopenia, and investigate the role of malnutrition in linking oral health to sarcopenia. We will also ascertain which simple (self-reported) validated oral health markers, could improve early identification of those at high-risk of sarcopenia. Our goal is to provide evidence for the potentially key role of oral health in the prevention and management of malnutrition and sarcopenia.

Lay abstract: Sarcopenia (low muscle strength) is very common in older people. Sarcopenia is closely related to malnutrition (particularly undernourishment), and leads to disability. Problems of oral health (such as tooth loss, gum disease, denture problems, dryness of mouth) are also very common in older age, and can affect how well people eat. However, the potentially key role of oral health in reducing malnutrition and sarcopenia are not well-recognised. In a British study, we will collect data on sarcopenia, malnutrition and oral health at age 77-98. Using these data we will investigate the contribution of oral health to malnutrition and in turn to developing sarcopenia in older age. In this research we will ascertain which simple indicators of oral health can help identify older people who are at higher risk of malnutrition and sarcopenia. This will help achieve greater reduction of sarcopenia in older people.

Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: ORAL AND GASTROINTESTINAL;MUSCULOSKELETAL