Immunomodulatory effects of pre- and probiotics

预计未来25年，65岁及以上的人口数量将增长60%以上，这对医疗保健系统构成了巨大挑战。老年人感染的频率和严重程度高于年轻人；流感在老年人中特别常见，是老年人死亡的一个主要原因。衰老会显著影响免疫功能；随着我们年龄的增长，可能对新病原体作出反应的细胞数量会减少，并且会有功能不良的成熟细胞的积累。这种现象被称为免疫衰老，部分解释了老年人对感染的易感性增加。建议接种疫苗以保护老年人免受流感侵害，但免疫衰老也会降低疫苗接种的效力。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，这是一种相当大的资源浪费，并给接种疫苗的人带来了错误的安全感。益生菌是有益的细菌，可以被消耗，并且在人类中有长期和安全的使用记录。它们在预防或治疗几种疾病状态方面显示出希望，包括乳糖不耐症、便秘和腹泻、缓解过敏，甚至是更慢性的全身性疾病，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，当它们到达下肠道时，为有益细菌提供食物来源。人们对益生菌和益生菌对老年人的积极影响特别感兴趣，老年人受到肠道菌群组成改变和免疫衰老的影响。一些研究已经证明了特定益生菌和益生菌对老年人免疫功能的有益作用。然而，这些研究都没有考虑到免疫细胞群中与年龄相关的变化。此外，人们对这些效应背后的机制了解甚少。尽管如此，益生菌最近被提出作为“抗免疫衰老”治疗的主要候选者。我们建议研究预益生菌和益生菌对年轻人和老年人免疫功能的影响，同时考虑到由于免疫衰老导致的年龄相关的免疫变化。我们的目标是建立生物标记物和方法，可以用来建立商业益生菌和益生菌免疫调节作用背后的基础科学。该项目将涉及60名年轻人（18-35岁）和60名老年人（65-85岁），他们将服用益生菌前和益生菌混合物或安慰剂，共8周。益生菌目前尚未商业化生产，但已被证明在老年胃肠道中具有特殊的生态适应性和抗致病性作用。根据促进益生菌最佳生长和存活的能力选择合适的益生元。治疗4周后，受试者将接种流感疫苗。在治疗前和开始治疗后4、6和8周采集血样。在第6周和第8周采集的样本将用于评估对疫苗接种的免疫反应。考虑到免疫细胞群中与年龄相关的变化，将评估广泛的免疫参数。在人体研究的同时，一系列的体外研究将调查益生菌对免疫功能影响的机制基础，并将确定益生菌在细胞和分子水平上对年轻人和老年人的影响是否存在差异。该项目的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衰老的影响从益生菌和益生菌中获得特定的额外益处。

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.