Integrated multiomics of host-bacteria interactions during C. elegans gut infections.

当我们意识到我们体内的微生物细胞是人体细胞的十倍时，与肠道微生物保持良好的关系对我们的健康至关重要就不足为奇了。也许不那么明显的事实是，我们的肠道微生物不仅决定了我们肥胖和心血管健康的倾向，还决定了我们患癌症、糖尿病、神经退行性疾病和自身免疫性疾病的风险。它们还会影响我们的年龄，影响我们从疾病、手术或积极治疗中恢复的程度，甚至会影响我们的情绪！因此，了解我们如何与肠道微生物沟通已成为一项关键挑战，也是解决非常复杂疾病状态的新疗法的潜在无限来源，并帮助我们所有人更好地生活和衰老。然而，这本身就是一项非常困难的努力。我们拥有成千上万的微生物物种，它们以动态进化的群落组织起来。此外，没有两个微生物群是完全相同的，即使是双胞胎。目前，尽管生物技术和计算机科学取得了惊人的进步，但这个问题实在太昂贵，太大，无法解决。幸运的是，正如我们之前对基因组测序或大脑图谱所做的那样，我们可以首先转向一个更简单的系统：秀丽隐杆线虫，一种1毫米长的食菌蛔虫，它已经使几项诺贝尔奖得主的发现成为可能。如果我们能在小范围内解决这个问题，我们就能发现适用于大范围的基本原理，并加速新药和疗法的发现。像我们一样，秀丽隐杆线虫也有肠道微生物群，但它只在成年期在肠道内定植。在实验室里，这使我们能够精确地控制哪些细菌和多少细菌在蠕虫的肠道中定居。因为秀丽隐杆线虫是透明的，我们也可以直接观察这些细菌在蠕虫肠道内分裂和移动的过程。为了观察活蠕虫肠道中的不同细菌，我们可以进一步对它们进行颜色编码，并用荧光显微镜对它们进行拍摄。秀丽隐杆线虫实际上是我们最熟悉的动物。我们可以实时了解它的基因和细胞有多活跃，以及它有多健康。我们也可以通过RNA干扰随意关闭蠕虫的基因。我们甚至可以准确地判断蠕虫何时死亡，因为它在死亡时发出蓝色荧光。最后，我们可以通过给它们人类疾病来使它们生病。多亏了这一切，我们可以用简单的蠕虫模型来研究复杂的人类疾病。这正是我们在项目中要做的。我们将给蠕虫细菌负责人类泌尿道和肺部感染。这将模仿蠕虫的肠道生态失调：一种与我们肠道微生物的关系出错的状态，这种状态在不健康和衰老中很常见。然后，结合早期发展的所有方法（使用显微镜成像，修改和观察基因活动，评估蠕虫和细菌健康），我们将调查和阐明所有相关的蠕虫和细菌基因如何相互作用，以及它如何解释疾病状态。知道了这一点，我们将测试已知的药物是否可以在发生生态失调时用于改善蠕虫的健康。因为蠕虫与其他动物和人类共享许多生理功能、基因和疾病，了解蠕虫的生态失调是如何起作用的，以及如何预防或纠正它，将教会我们很多关于人类肠道生态失调的经验。因此，它将快速启动新疗法的开发，包括新的抗生素和治疗方法，以促进肠道健康和健康老龄化。

When one realises that we carry ten times more microbial cells than human cells, it is no surprise that maintaining a good relationship with our gut microbes is essential for our health. Perhaps less evident is the fact that our gut microbes not only determine our propension to obesity and cardiovascular health, they also determine our risk of developing cancers, diabetes, neurodegenerative, and auto-immune diseases. They also condition how we age, how well we recover from illnesses, surgeries or aggressive therapies, and they can even influence our moods!Understanding how we communicate with our gut microbes has thus become a key challenge, and a potentially unlimited source of new therapies to tackle very complex disease states, and help all of us live and age much better. Yet, it is in itself a very difficult endeavor. We host thousands of microbial species organised in dynamically evolving communities. Moreover, no two microbiotas are identical, not even in twins. At the moment, despite amazing advances in biotechnology and computer sciences, it is simply too expensive and too big to solve.Fortunately, as we did before with genome sequencing or brain mapping, we can turn to a simpler system first: C. elegans, a 1mm-long bacterium-eating roundworm that already enabled several Nobel Prize-winning discoveries. If we can solve the problem at a smaller scale, we can uncover essential principles that apply at a larger scale, and accelerate discovery of new drugs and therapies.Like us, C. elegans has a gut microbiota, but it only colonizes its intestine during adulthood. In the laboratory, this allows us to precisely control which and how many bacteria colonize the worm gut. Because C. elegans is transparent, we can also directly look at these bacteria as they divide and move in the worm gut. To watch together different bacteria in the gut of live worms, we can further color-code them and film them by fluorescence microscopy. C. elegans is actually the most intimately known animal. We can know in real-time how active its genes and cells are, and how healthy it is. We can also switch off worm genes at will using RNA interference. We can even tell precisely when a worm dies, as it emits blue fluorescence at death. Lastly, we can make worm sick by giving them human diseases. Thanks to all this, we can use simple worm models to study complex human diseases.This is exactly what we will do in our project. We will give the worms bacteria that are responsible for human urinary tract and lung infections. This will emulate gut dysbiosis in worms: a state where the relationship with our gut microbes goes awry, and which is frequent in ill-health and ageing. Then, combining all the approaches evolved earlier (using microscopy imaging, modifying and looking at gene activities, assessing worm and bacterial health), we will investigate and elucidate how all relevant worm and bacterial genes interact, and how it explains disease states. Knowing that, we will then test if known drugs can be used to improve worm health when dysbiosis happens.Because worms share a lot of physiological functions, genes and diseases with other animals and humans, knowing how dysbiosis works in worms and how to prevent or correct it, will teach us a lot about our own human experience of gut dysbiosis. Hence, it will quick-start the development of new therapies, including new antibiotics and treatments to promote gut health and healthy ageing.