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

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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.