Exploring host-gut microbial genetic and immune interactions using twins

微生物对维持健康的免疫系统至关重要，是我们饮食和健康之间的纽带。我们有大约100万亿个肠道微生物，它们的数量是人类细胞的10倍，是人类基因的100倍。这些微生物会产生各种各样的酶、化学物质、激素和维生素，它们可能会与我们的身体相互作用。我们肠道微生物的改变与许多人类疾病有关，包括肥胖、结肠炎、过敏和自闭症。直到最近，多亏了基因测序，我们才能够正确地研究它们，并意识到绝大多数对我们无害，而且许多是有益的。对肠道微生物的研究尤其令人兴奋，因为我们知道我们可以通过手术、药物、益生菌和饮食来改变它们的组成。这样，我们就有可能通过微生物操纵来改变许多疾病。目前在西方世界，我们正在经历一场过敏的流行，许多自身免疫性疾病也在增加，这可能与我们肠道微生物的异常和最近的变化有关。我们的微生物和我们的身体之间沟通的主要方式是通过肠道里的免疫细胞。这项研究旨在提供关于我们肠道内的人类免疫细胞与肠道内数万亿微生物之间相互作用的重要信息。最近我们发现，在我们的粪便中发现的微生物在个体之间差异很大，其中一些差异是由于我们人类基因的差异。然而，粪便中的微生物并不一定代表肠壁中微生物的丰度或功能，肠壁中微生物可能对宿主健康有更大的影响。我们缺乏关于肠壁微生物和宿主细胞反应之间关系的重要信息，如果我们要在这个令人兴奋的领域取得进展，我们就需要这些信息。该项目将为100对同卵双胞胎的肠壁微生物和宿主细胞反应提供有价值的资源数据库。使用双胞胎的好处是，这使我们能够确定与年龄、早期家庭环境和重要的人类基因无关的影响。我们最近表明，我们自己的基因决定了哪些种类的细菌在我们的肠道中繁殖，这在人与人之间差别很大。双胞胎志愿者年龄在40岁以上，没有任何重大疾病，将接受正常的结肠镜检查。我们已经试点了我们的志愿者，发现超过60%的人热衷于参与。在手术过程中，我们将在肠的三个不同部位进行活检和刷牙，一直到小肠的末端。这将使我们能够在每个位点测试不同的微生物种类，以及最重要的微生物如何与人类免疫基因（通过基因表达水平测量）和免疫系统的其他标记相互作用。由于微生物很少单独工作以及探索相关物种，我们将研究具有相似功能的微生物网络并将其构建到我们的资源中。该资源将使该领域的其他科学家能够查找潜在的有趣基因和微生物，并探索它们各自的功能。它还将使科学家能够比较粪便中的微生物结果，并预测肠道和人体免疫系统内的影响。最后，我们将做一些试点研究，测试将人类免疫相关微生物移植到无菌小鼠体内的效果，以测试微生物是否直接影响免疫系统。最终的目标将是找到帮助我们免疫系统的关键微生物，并通过饮食或其他方法找到增加其数量或功能的方法。这项研究有可能对许多疾病和涉及衰老、饮食和免疫系统的医学领域产生巨大影响。我们收到了来自世界各地的学者的支持信，他们将从这项工作中受益。

Microbes are crucial in maintaining a healthy immune system and are the link between our diet and health. We have around 100 trillion gut microbes that outnumber our human cells ten to one and our genes 100 to one. The microbes produce a wide range of enzymes, chemicals, hormones and vitamins that can potentially interact with our bodies. Alterations to our gut microbes have been implicated in many human diseases ranging from obesity, colitis, allergy and autism. Only recently thanks to genetic sequencing have we been able to study them properly and realise that the vast majority are not harmful to us and many are beneficial. Study of the gut microbes is particularly exciting because we know that we can alter their composition through surgery, drugs, probiotics and diet. In this way we could potentially alter many diseases via microbial manipulation. We are currently experiencing an epidemic of allergies in the western world as well as increases in many autoimmune diseases and this could be related to abnormalities and recent changes in our gut microbes. The main method of communication between our microbes and our body is via the immune cells in the gut lining.This is a study designed to provide vital information about the interactions between our human immune cells in our gut lining and the trillions of microbes that inhabit our gut. Recently we have discovered that the microbes found in our stools vary enormously between individuals and that some of this variation is due to differences in our human genes. However microbes in the stool do not necessarily represent the abundance or functions of the microbes in the gut wall, which may have even greater effect on host health. We lack vital information on the relationship between microbes in the gut wall and our host cellular responses which we need if we are to progress this exciting field. This project will provide a valuable resource database of microbes in the gut wall and the cellular responses of the host in 100 pairs of identical twins. The benefit of using twins is that this allows us to determine effects which are independent of age, early family environment and importantly human genetics. We have recently shown that our own genes determine which species of bacteria proliferate in our guts which vary markedly between people. Twin volunteers will be aged over 40 without any major diseases and will undergo a normal screening colonoscopy. We have already piloted our volunteers and found over 60% keen to participate. During the procedure we will obtain biopsies and brushings at 3 different sites in the bowel, going up to the end of the small intestine. This will allow us to test the different microbe species at each site and how the most important ones interact with the human immune genes (measured by levels of gene expression) and other markers of the immune system. As microbes rarely work alone as well as exploring the associated species we will look at the networks of microbes that have similar functions and build this into our resource. The resource will enable other scientists in the field to look up potentially interesting genes and microbes and explore their respective functions. It will also allow scientists to compare microbe results from stools and predict the effects seen within the gut and the human immune system. Finally, we will do some pilot studies to test the effects of transplanting immune related microbes from humans into sterile mice which will test if the microbes are directly affecting the immune system. The ultimate aim will be to find the key microbes that help our immune system and develop ways to increase their numbers or their function through diet or other methods. The study has the potential to have enormous impact across many diseases and fields of medicine involving ageing, diet and the immune system. We have support letters from a wide range of academics across the world who would benefit from this work.