Developing and validating a computational model of the gut microbiota-mucosa interactions to replace and reduce animal experiments

许多最近的发现揭示了生活在我们肠道中的细菌对我们健康的迷人而重要的影响。例如，它们训练我们的免疫系统，影响体重增加，甚至影响我们的情绪和行为。因此，对肠道细菌的研究数量急剧增加。由于许多这些研究使用动物实验，越来越多的动物被使用。我们的长期目标是用计算机模拟取代许多这样的动物实验，我们一直在开发软件，让没有编程经验的科学家也能运行这样的计算机模拟。我们称这个软件为eGUT，即电子肠道。我们估计eGUT最终可以在全球每年取代75000个动物实验。这个学生项目的具体目的是填补我们eGUT软件的一个重要空白。间隙是肠粘膜的计算模型。粘膜是人体组织细胞和细菌相遇的肠壁。我们将开发这个计算粘膜模型，并使用工程（非动物）模型和昆虫模型的实验来检验我们的eGUT模型是否可以做出正确的预测。我们将与开发这些模型的专家Wilmes教授（卢森堡）和Moya教授（西班牙）合作，在他们的实验室进行实验。在学习结束时，英国益生菌国际公司的研究人员和Hardt教授和Stecher教授的两个世界领先的实验室将测试我们的eGUT软件并帮助我们改进它。这样，越来越多的研究人员会想要使用它，因为它会使他们的研究更好。重要的是，我们的软件将帮助其他研究人员更好地理解他们所研究的系统，因为这将激励他们用计算机模拟取代动物实验。我们有两个很好的理由来解释为什么计算机模拟会促进科学的发展。一是肠道，有成千上万种不同类型的细菌，我们吃的几十种不同食物的数千种化学成分，以及我们身体器官和细胞与这些细菌和化学物质相互作用的多种方式，是一个非常复杂的系统。如果不在计算机中模拟这些系统的数学模型（即简化），就很难理解这些复杂的系统。如果计算机模拟结果与实验结果相似，可以认为简化模型是合适的。如果结果不同，人们可以找出简化的错误并修复它。系统的复杂性也意味着可能影响结果的因素非常多。因此，人们应该改变所有这些因素来研究它们的影响，这就有必要使用大量的动物。使用计算机模拟的另一个很好的理由是，动物模型通常不能很好地模拟人类。例如，老鼠的内脏与我们的内脏有很大的不同。它们不仅小得多，食物在肠道中消化的时间短得多，而且它们还有很大的盲肠，盲肠是细菌发酵纤维和其他难以消化的饮食元素的盲肠。人类没有这些盲肠。老鼠和人类的肠道还有许多不同之处，这就是为什么老鼠体内的细菌与我们不同。因此，我们不能确定在人类身上的干预结果与在老鼠身上的结果是一样的。该项目还将培养学生开发和使用计算模型、工程模型和昆虫模型来替代动物模型。这将是在科学前沿的职业生涯的一个很好的准备，我们希望学生在未来继续发展和使用eGUT，从而成为使用计算模型而不是动物实验的世界领导者。

Many recent discoveries revealed the fascinating and important effects that the bacteria living in our gut have on our health. For example, they train our immune system, affect weight gain and even our mood and behaviour. As a consequence, the number of studies of gut bacteria has risen sharply. As many of these studies use animal experiments, more and more animals are being used.Our long-term goal is to replace many of these animal experiments with computer simulations, and we have been developing software that allows scientists who have no programming experience to run such computer simulations. We call this software eGUT for electronic gut. We estimate that eGUT could ultimately replace 75,000 animal experiments worldwide each year.The specific aim of this studentship is to fill an important gap in our eGUT software. The gap is a computational model of the gut mucosa. The mucosa is the gut wall where human tissue cells and bacteria meet. We will develop this computational mucosa model and use experiments with an engineered (non-animal) model and an insect model to check whether our eGUT model can make correct predictions. We will collaborate with Profs Wilmes (Luxembourg) and Moya (Spain), the experts who developed these models, to do the experiments in their labs. At the end of the studentship, researchers in the UK company Probiotics International and the two world-leading labs of Profs Hardt and Stecher will test our eGUT software and help us improve it. This way, more and more researchers will want to use it because it will make their research better. It is important that our software will help other researchers to better understand the systems they investigate because that will motivate them to replace animal experiments with computer simulations.We have two very good reasons why computer simulations will improve the science. One is that the gut, with its thousands of different types of bacteria, the thousands of chemical components of the dozens of different types of food we eat, and the many ways in which our body organs and cells interact with these bacteria and chemicals, is a very complex system. Such complex systems are very difficult to understand without simulating mathematical models (that is simplifications) of these systems, in a computer. If the computer simulation results are similar to the results obtained in experiments, one can regard the simplified model as appropriate. If the results are different, one can find out what was wrong with the simplification and fix it. The complexity of the system also means that there is a tremendous number of factors that could affect results. One should therefore change all these factors to investigate their effect, which would make it necessary to use a huge number of animals. The other good reason to use computer simulations is that animal models are often not very good models of the human. Mice guts for example are quite different from our guts. Not only are they much smaller so that food does not spend as much time in the gut to be digested, they also have large caeca, blind sacs where bacteria ferment fibres and other elements of the diet that are difficult to digest. Humans do not have these caeca. There are many other differences between mouse and human guts, which is why mice harbour different bacteria than we do. As a consequence, one cannot be sure that results of interventions in humans will be the same as in mice.The studentship will also train the student in developing and using computational and engineered and insect models as alternatives to animal models. This will be an excellent preparation for a career at the forefront of science and we expect the student to keep developing and using eGUT in the future and thus become the world leader in using computational models instead of animal experiments.