Immunomodulatory effects of pre- and probiotics

预计未来25年，65岁及以上人口的数量将增加60%以上，这对医疗保健系统构成了巨大的挑战。与年轻人相比，老年人感染更频繁、更严重；流感在老年人中尤其常见，是老年人死亡的主要原因。衰老极大地影响免疫功能；随着我们年龄的增长，潜在可用于对新病原体做出反应的细胞库减少，功能不佳的成熟细胞积累。这种现象被称为免疫衰老，这在一定程度上解释了老年人感染的敏感性增加。建议接种疫苗以保护老年人免受流感侵袭，但免疫衰老也会降低接种疫苗的效果。据估计，30-50%的老年人在接种流感疫苗后未能产生保护性抗体反应，这对接种疫苗的人来说是相当大的资源浪费和错误的安全感。益生菌是有益的细菌，可以食用，在人类身上有长期安全的使用记录。它们在预防或治疗几种疾病方面表现出了希望，从乳糖不耐受、便秘和腹泻，减轻过敏，甚至到更慢性的系统性疾病，如心血管疾病和癌症。它们通常与益生元一起服用，益生元通常是可发酵的碳水化合物，当有益细菌到达较低的肠道时，它们为有益细菌提供食物来源。人们特别感兴趣的是益生菌前和益生菌对老年人的积极影响，他们容易受到肠道微生物区系组成和免疫衰老的影响。一些研究已经证明，特定的前和益生菌对老年人的免疫功能有有益的影响。然而，这些研究都没有考虑到与年龄相关的免疫细胞种群的变化。此外，人们对这些影响背后的机制知之甚少。尽管如此，益生菌最近被建议作为“抗免疫衰老”治疗的主要候选药物。我们建议调查前和益生菌对年轻和老年受试者免疫功能的影响，考虑到免疫衰老引起的与年龄相关的免疫变化。我们的目标是建立生物标志物和方法学，可以用来建立商业前和益生菌免疫调节作用背后的基础科学。该项目将包括60名年轻的(18-35岁)和60名年长(65-85岁)的受试者，他们将服用益生菌和益生菌的混合物或安慰剂，总共为期8周。这种益生菌目前还没有商业化生产，但已经被证明在老年人的胃肠道中具有特殊的生态适应性和抗致病作用。将根据促进该益生菌最佳生长和存活的能力来选择合适的益生菌。治疗4周后，受试者将接受流感疫苗接种。在治疗前、治疗后4、6和8周采集血样。6周和8周时采集的样本将用于评估接种疫苗后的免疫反应。考虑到免疫细胞种群的年龄变化，将评估一系列广泛的免疫参数。与人类研究相结合，一系列体外研究将探索益生菌影响免疫功能的机制基础，并将在细胞和分子水平上确定益生菌在年轻和老年受试者中是否存在差异效应。该项目两个组成部分的总体目标是确定老年受试者是否通过调节免疫老化的影响而从益生菌前和益生菌中获得具体的额外好处。

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.