eGUT: a Tool for Predictive Computer Simulation of the Gut Microbiota and Host Interactions

点击翻译按钮获取中文摘要

We want to build, apply, and disseminate eGUT, a new computer simulation platform for the animal and human gut, to reduce and replace animal experiments.The gut, in particular the large intestine, is teeming with microorganisms, collectively called the microbiota: 50% of faeces are microorganisms. Overall the indigenous microorganisms called commensals are beneficial for the host, illustrated by the fact that germ-free animals develop rather poorly. It is the behaviour of the microbiota and their metabolic and other effects on the host which we want to simulate in eGUT. The host can be represented by the gut wall (the mucosa), as all interactions are mediated through the gut wall.Due to an increasing awareness of the importance of the gut microbiota, the number of studies using animal experiments has risen sharply, so that the need to develop alternatives to animal experiments is becoming increasingly urgent.It is very difficult to estimate the number of animal experiments that eGUT will avoid, so the numbers should be treated with caution. We estimate that eGUT, once fully developed and accepted, could save up to 150,000 animals globally per year. However, it will take some thorough case studies to improve and validate eGUT and to demonstrate that eGUT can make reliable predictions of animal experiments based on in vitro laboratory data, before the use of eGUT will become widely accepted. We will therefore focus on these case studies to make a convincing case for the use of eGUT. After this, more and more scientists will adopt it, mainly to reduce the numbers of animals used, but eventually to fully replace a range of animal experiments, for example in the area of nutrition.Objectives:1. Build eGUTeGUT will be based on the long experience of JK and collaborators with developing individual-based models of the interactions of microorganisms. It will build on our state of the art individual-based Dynamics of Microbial Communities Simulator iDynoMiCS, which was published in 2011 and released for public use (open source) on www.idynomics.org. While iDynoMiCS is an excellent basis for eGUT, a number of additions to simulate the gut will be necessary (add a description of the gut wall, add superindividuals and related procedures to allow simulation of a large system, couple several simulations of individual gut compartments into a multi-compartment simulation). Moreover, we want eGUT to be more user-friendly by adding a graphical user interface and by providing more detailed documentation and hands-on tutorials. This is time consuming but very important to allow scientists without mathematical or computer science backgrounds to use eGUT, and this functionality will enable a far wider number or users and therefore far more impact on the 3Rs.2. Apply eGUTBecause we need test cases for eGUT to validate it and to convince others that it makes reliable predictions, we will apply eGUT to three test cases. More than one is necessary to show that it does not just work for one specific problem, but it is important to not attempt too many as each case will require time if it is to be done well. The test cases proposed are: one from our own laboratory; one from Prof Hauke Smidt at Wageningen University in The Netherlands; and one from Prof Tine Licht from the National Food Institute at the Technical University of Denmark.3. Disseminate eGUTDissemination is very important to build up a user base for eGUT, so we will run two one-week workshops where we will teach potential users of eGUT how they can apply it to their own research in order to reduce or replace animal experiments. Further, we will build a dedicated web site and use media channels to promote eGUT (blogs, YouTube, popular science magazines), amongst other plans for dissemination.