Immunomodulatory effects of pre- and probiotics

The number of people aged 65 years and over is expected to rise by over 60% in the next 25 years, which presents an enormous challenge for the healthcare system. Elderly people suffer from more frequent and severe infections than younger people; influenza is particularly common in older individuals and is a major cause of death in the elderly population. Ageing dramatically affects immune function; as we age, the repertoire of cells potentially available to respond to a new pathogen shrinks and there is an accumulation of poorly functioning mature cells. This phenomenon is known as immunosenescence and partly explains the increased susceptibility for infection in older individual. Vaccination is recommended to protect the older people against influenza, but immunosenescence also reduces the efficacy of vaccination. It has been estimated that 30-50% of older adults fail to mount protective antibody responses after influenza vaccination, representing a considerable waste of resource and a false sense of security for those receiving the vaccinations. Probiotics are beneficial bacteria, which can be consumed and which have a long and safe record of use in humans. They have shown promise in the prevention or treatment of several disease states ranging from lactose intolerance, constipation and diarrhoea, alleviation of allergy and even to more chronic systemic diseases, such as cardiovascular disease and cancer. Often they are taken together with prebiotics, which are normally fermentable carbohydrates that provide a food source for the beneficial bacteria when they reach the lower gut. There is particular interest in the positive influences of pre- and probiotics in older people, who are subject to alteration in gut microflora composition as well as immunosenescence. Several studies have demonstrated beneficial effects of specific pre- and probiotics on immune function in older subjects. However, none of these studies have taken into account the age-related shift in immune cell populations. Furthermore, there is little understanding of the mechanisms underlying these effects. Despite this, probiotics have recently been proposed as prime candidates for 'anti-immunosenescence' therapy. We propose to investigate the impact of a pre- and probiotic on immune function in young and older subjects, taking into account the age-related shifts in immunity due to immunosenescence. We aim to establish biomarkers and methodology which could be exploited to establish the underpinning science behind the immunomodulatory effects of commercial pre- and probiotics. The project will involve 60 young (18-35y) and 60 older (65-85y) subjects, who will take a pre- and probiotic mixture or a placebo for a total of 8 weeks. The probiotic is not currently commercially produced, but has been demonstrated to have particular ecological fitness and anti-pathogenic effects in the gastrointestinal tract in old age. A suitable prebiotic will be selected on the basis of ability to promote optimal growth and survival of this probiotic. After 4 weeks on the treatment, the subjects will receive an influenza vaccination. Blood samples will be taken before treatment, and at 4, 6 and 8 weeks after commencement. The samples taken at 6 and 8 weeks will be used to assess the immune response to the vaccination. A wide range of immune parameters will be assessed, taking into account the age-related shifts in immune cell populations. In conjunction with the human study, a series of in vitro studies will investigate the mechanistic basis for the impact of the probiotic on immune function and will determine whether there are differential effects of the probiotic in young and older subjects at the cellular and molecular level. The overall aim of both components of the project is to determine whether older subjects derive specific additional benefit from pre- and probiotics by modulation of the impact of immunological ageing.

Immunosenescence is a gradual deterioration and dysregulation of the immune system during ageing. It results in increased susceptibility of older subjects to infection and renders vaccination less effective. Probiotics have been suggested to strengthen specific and innate immune responses in healthy individuals, to reduce the duration and severity of respiratory infections in both the old and the young, and to augment the antibody response to influenza and polio vaccination. However, it is not clear whether probiotics are able to specifically improve the function of immunosenescent cell populations in older subjects. The proposed project will involve 60 young and 60 older subjects, who will take a pre- and probiotic mixture or a placebo for a total of 8 weeks. The probiotic is not currently commercially produced, but has been demonstrated to have particular ecological fitness and anti-pathogenic effects in the gastrointestinal tract in old age. A suitable prebiotic will be selected on the basis of ability to promote optimal growth and survival of this probiotic. After 4 weeks on the treatment, the subjects will receive an influenza vaccination. Blood samples will be taken before treatment, and at 4, 6 and 8 weeks after commencement. A wide range of immune parameters will be assessed, taking into account the age-related shifts in immune cell populations. In conjunction with the human study, a series of in vitro studies will investigate the mechanistic basis for the impact of the probiotic on immune function and will determine whether there are differential effects of the probiotic in young and older subjects at the cellular and molecular level. The proposed project will demonstrate for the first time whether pre- and probiotics are of particular benefit in older individuals by modulating the impact of immunological ageing.

The BBSRC identifies the issues of an ageing population as a critical national priority. Life expectancy in the UK today is almost 80, and approximately one in six adults is now over 65. This has been attributed to improved living and working conditions, better nutrition and effective strategies for dealing with infectious disease. However, greater longevity brings with it the challenges of maintaining quality of life for as long as possible and developing strategies to alleviate the problems associated with age-related diseases. The proposed project will deliver potential benefit to (a) the ageing community, (b) the UK healthcare system, (c) regulatory bodies assessing health claims, (d) companies wishing to substantiate claims relating to immune function and host defense for their products, (e) companies with an interest in developing new probiotic products and (f) other academics. This research will benefit the ageing community and the UK healthcare system because it will demonstrate the potential for dietary intervention to modulate the age-related dysregulation of immunity, which results in increased susceptibility to infection in older people, and renders vaccination ineffective in a significant proportion of those who receive it. It will directly benefit regulatory bodies assessing health claims, because it will generate a working model for the substantiation of claims relating to immune function for all age groups. Clearly, this process will also be of benefit to the companies who wish to make the claims. Finally, the probiotic which we intend to test in our human intervention is not currently used commercially, but there is potential, once the project is completed for a company to commercialise it. Our networking capacity and links with industry are substantial and will be used to maximize the impact of the project. We also hold, or have held, a number of positions on regulatory or advisory bodies and Task Forces. Our continued participation in these activities will facilitate discussion of issues and ideas generated by the project. Links with non-academics, through AGEnet and through other activities, will maximize dissemination of the work to a wider audience. The potential for the probiotic which we intend to test in our human intervention to be developed commercially could be facilitated by the Knowledge Transfer Centre at the University of Reading. Reading leads one of the most successful Knowledge Transfer Partnership Programmes in the UK and has been assisting companies, charities and academic teams to work together successfully since 1994. It is Europe's leading programme helping businesses and charities to improve their competitiveness and productivity through the better use of knowledge, technology and skills that reside within universities. We intend to engage the staff working on the project fully in implementing our impact plan. All of the staff employed on the project will be encouraged to make full use of our in-house training, particularly in communication and teambuilding. The main post-doctoral researcher on the project will also be encouraged to attend the European Nutrition Leadership Programme, which is a residential course, funded jointly by the food industry, the EU and participating organizations, and which serves to develop research, leadership, communication and professional skills in researchers at an early stage in their careers.