Disease susceptibility and gut health in the wild: Determining interactions between diet, gut microbiome and immunity.

寄生虫是人类、牲畜和野生动物非常常见的传染病。它们会导致健康不佳、体重增加的能力降低、生产力下降和经济损失。治疗寄生虫感染的药物是存在的，但随着寄生虫产生抗药性，这些控制方法就会失效。因此，发现限制感染的新方法是重要的。人体的免疫系统是保护身体免受感染和疾病的自然防御系统。然而，它必须与个人接触到的许多环境变量进行斗争和适应，例如不断变化的饮食。这些变量在任何时间点上都会因个体而异，在同一个体中也会随着时间的推移而有所不同。了解使寄生虫等感染能够有效地从体内清除的因素是重要的。预防感染需要能量，因此人们可能会预测，拥有优质饮食的人可能能够将更多能量部署到免疫系统中，从而更有效地应对感染威胁。实验室研究表明，在其他非常受控制的系统中改变实验室小鼠的饮食可以改变人体抵御寄生虫的方式。此外，在野生木鼠中，它们在自然环境中面临许多挑战(例如避免捕食、寻找食物)，更高质量的饮食提高了它们控制寄生虫的能力。然而，良好的饮食有助于寄生虫清除的机制尚不清楚，特别是在自然环境中。事实上，众所周知，饮食的变化不仅会改变人体的免疫系统，还会改变生活在肠道内的细菌集合，即微生物群。肠道微生物群本身在支持个人健康方面发挥着重要作用。因此，重要的是要了解饮食如何同时影响几个因素，包括微生物群和免疫反应，以支持对抗寄生虫感染。在野生木鼠身上的观察是强有力的，但这一研究系统在了解饮食如何提高对感染的抵抗力方面的工具有限。然而，野生家鼠种群--与实验室老鼠相同的物种--既提供了研究人体免疫系统所需的实验室试剂，也提供了现实世界的背景。因此，我们建议研究五月岛上的野生家鼠种群。我们将为一组小鼠提供改进的饮食，并将它们的抗寄生虫免疫反应和肠道内的细菌收集情况与没有接受改进饮食的小鼠进行比较。此外，为了了解微生物群对免疫系统的重要性，我们还将用一种抗体来治疗一组小鼠，这种抗体将阻止基于免疫的抗寄生虫防御。通过这种方式，我们可以梳理出饮食驱动的寄生虫清除变化是否通过免疫系统起作用。为了评估饮食驱动微生物群变化的相关性，我们将收集改善饮食和正常饮食的野生小鼠的粪便，并将粪便转移到肠道中没有任何细菌的实验室小鼠。随后感染寄生虫将测试我们是否转移了改善的清除蠕虫的能力，另外通过实验移除抗寄生虫的免疫反应将证实饮食增强的微生物群是否通过免疫系统运行。总体而言，这个项目将理清改善饮食支持健康和防止寄生虫感染的方式。它将通过使用一种新颖的跨学科研究设计来做到这一点，该研究设计在受控的实验室老鼠研究和对野生老鼠种群的调查之间架起了桥梁。这使得既可以进行详细的调查，也可以进行机械的调查，并考虑到个人免疫系统运行的真实环境。

Parasitic worms are extraordinarily common infections of humans, livestock and wildlife. They cause ill heath, a reduced ability to put on weight, reduced productivity and economic loss. Drugs exist to tackle parasite infections but as parasites develop drug resistance, these sorts of control methods lose effectiveness. Thus, discovering new ways to limit infections is important. The body's immune system is a natural defence system that protects the body from infections and disease. However, it has to contend and adapt to the many environmental variables that an individual is exposed to, such as a changing diet for example. These variables will differ between individuals at any one point in time, and over time in the same individual. Understanding the factors which enable infections, such as parasites, to be cleared efficiently from the body is important. Defending against infections takes energy and therefore one might predict that individuals with good quality diets might be able to deploy more energy in to the immune system and so respond more effectively to infectious threats. Laboratory studies have shown that changing the diet of laboratory mice in otherwise very controlled systems can change the way the body defends itself against parasites. Further, in wild wood mice, which face many challenges in their natural environment (for example avoiding predation, finding food), a better quality diet improves their ability to control parasites. However, the mechanism by which a good diet helps parasite clearance is unknown, particularly in natural settings. Indeed changes in diet are known to not only alter the body's immune system but also the collection of bacteria living within the intestine, the microbiome. The gut microbiome itself plays an important role in supporting an individual's health. It is therefore important to understand how diet affects several factors at once, including the microbiome and the immune response, to support fighting of parasitic infections.The observations in wild wood mice are powerful but this study system is limited in the tools available to understand how diet promotes resistance to infection. However, a wild house mouse population - the same species as laboratory mice - offers both the laboratory reagents required to study the body's immune system and a real world context.We therefore propose to study a wild house mouse population on the Isle of May. We will provide an improved diet to one group of mice and compare their anti-parasite immune response and the collection of bacteria living in their guts to those of mice which do not receive an improved diet. Further, to understand the importance of the microbiome versus the immune system we will also treat groups of mice with an antibody, which will block the immune-based anti-parasite defence. In this way we can tease apart whether the diet-driven changes in parasite clearance are acting via the immune system.To assess the relevance of diet-driven microbiome changes, we will collect faeces from wild mice on an improved diet versus a normal diet and transfer the faeces to laboratory mice that do not have any bacteria in their intestines. Subsequent infection with a parasite will test if we have transferred an improved ability to clear the worm and additional experimental removal of the anti-parasite immune response will confirm whether the diet-enhanced microbiome operates via the immune system.Overall, this project will disentangle the ways in which an improved diet supports health and protects against parasitic infection. It will do so by using a novel, interdisciplinary study design bridging between controlled laboratory mouse studies and investigations in wild mouse populations. This allows both detailed and mechanistic investigation as well as taking into account the real-world environment in which an individual's immune system operates.