Dendritic cell subsets in the maintenance of gut health and response to bioactives

In order to maintain human health, it is vital that harmful pathogens that enter the body (such as bacteria and viruses) are quickly eliminated by the immune system. However, immune responses must be carefully controlled so that they are only activated at an appropriate time. If this tight regulation is disrupted, the immune system can potentially attack and damage the organs and tissue of the body, resulting in so-called 'autoimmune disease'. Similarly, allergies can result if the immune system is activated in response to normally harmless substances, such as metal in jewellery or food substances. A particularly critical area of the body for immune regulation is the intestine. The intestine is lined with trillions of bacteria which are important in maintaining normal health, but could potentially trigger an immune response causing inflammatory bowel disease. Similarly, as food substances pass through the intestine, they could also potentially trigger immune activation in the absence of tight control, resulting in food allergy. Therefore, understanding the cells and molecules that control activation of the immune system is paramount if we are going to understand how our immune system functions to maintain normal health. In the food industry, there is great interest in the design of foodstuffs that can actively promote human health (so called 'bioactives'), especially in the gut. For example, many dairy products and drinks contain so-called 'probiotics', which are live bacteria intended to enhance gut health. However, the mechanisms by which bioactives enhance gut health are ill defined, and often there is mistrust from the public in manufacturer's claims that their products will improve health. Therefore, it is essential to understand how bioactives affect the biology of the gut to promote health, to provide important read-outs that can be used to scientifically assess existing and novel bioactives. The only way that enhancement of gut health will be achieved is by increasing our basic understanding of the cells and molecules that maintain and promote normal gut health. As immune regulation is critical in maintaining a healthy gut, understanding how immune responses in the intestine are regulated will be critical in identifying potentially beneficial effects of bioactives. An important cell type involved in regulating all immune responses is the dendritic cell (DC). Our laboratories have recently shown, using mouse models, that important subsets of DC present in the intestine are critical in maintenance of gut health. These DC subsets are characterised by the expression of different proteins on their surface, called CD103 and integrin alphav beta8, and by their ability to produce important molecules called TGF-beta and retinoic acid. The DC promote immune regulation by inducing an immune cell type called 'regulatory T-cells', which are important cells in preventing harmful immune reactions. To build on our mouse studies, it is now critical to identify the role of these specialised DCs in human gut health. Our proposal will characterise these specialised DCs, in terms of the protein markers and molecules they express and how they function in healthy humans. We will go on to identify how known bioactives affect the biology of these DC subsets. This work will therefore identify important cells and pathways that are central to the maintenance of gut health, provide novel data on the how known bioactives work, and identify read-outs by which novel bioactive food substances can be scientifically evaluated for potential beneficial effects on the gut.

The immune system must be capable of quickly eliminating harmful pathogens that enter the body. However, at the same time the immune system must be tightly regulated to prevent harmful responses against innocuous or self-antigens. If this regulation is abrogated, allergy or autoimmune disease can result. The regulatory balance is especially vital in the intestine, where commensal bacteria and food antigens can potentially trigger immune responses in the gastrointestinal tract. A critical area of research aims to determine the cells and molecules in the intestine that are important in maintaining immune homeostasis at times of health, and what factors contribute to immune diseases of the gut. Recent work in our laboratories has identified intestinal dendritic cell (DC) subsets that are critical in prevention of harmful immune reactions and maintenance of intestinal health in mice. Specifically, these DC express the biomarkers integrin alphav beta8 and CD103, can activate the cytokine TGFbeta, and metabolise vitamin A into its active form retinoic acid. Our work has shown that these DCs are important in the induction of regulatory T-cells in the intestine, a cell type that is essential in maintaining gut health by suppressing autoimmunity and immune pathology. To build upon our studies in mice, it is now critical to translate our findings into human subjects. Our proposal aims to determine how these specialised gut DCs function to maintain intestinal health in humans. Additionally, we will determine how potential dietary bioactives affect these cells and their specific biomarkers. This work will identify important molecules and cells involved in the maintenance of intestinal health, and highlight potential biomarkers of use to the food industry when designing dietary bioactives to enhance human health.

The research in this proposal aims to identify cells and molecules involved in maintaining the intestine in a healthy state, and determine how bioactive food stuffs can act upon cells of the intestine to promote health. This research will therefore potentially benefit a wide range of people. As well as being of great interest to scientists and clinicians working in a similar scientific area (who can use our research findings to better understand their systems of interest), research in this proposal will benefit those working in the food industry, specifically those with an interest in producing bioactive food stuffs aimed at enhancing health and wellbeing. Our research will be of interest to the food industry via highlighting potential mechanisms by which bioactive foods function to promote health, and also provide important biological readouts for testing novel bioactive food components. In addition to industry, our research will also benefit organisations that set guidelines on the usefulness and safety of bioactives (e.g. European Food Safety Authority, Committee on Medical Aspects of Food and Nutrition Policy, World Health Organisation), by providing data on potentially important biological readout for bioactive foodstuffs that may be of use when assessing effects of potential novel bioactives. As a result of the benefits to the food industry and regulatory agencies, in the long term our research may benefit the wider public, by indirectly increasing the numbers of useful bioactive foods on the market that benefit health (via better identification of substances that modulate the intestinal immune system) and improving information provided to the public about the benefits of such bioactives. To ensure that the people mentioned above will benefit from the research, we will attend national and international meetings (based around mucosal immunology) to present our findings, to inform as many people in the field as possible. In addition, we will show our progress at the DRINC dissemination events, attended by both academic and industry researchers interested in intestinal immunology and health. Where appropriate, we will publish our findings in high-profile scientific journals to ensure our data is accessible to a wider scientific audience. Disseminating our findings to the wider scientific community will allow further research in academia and in the bioactive food industry based on our studies, which in the long term may lead to better bioactives to improve health in the wider public.