Defining a gut-brain-liver axis

当我们吃饭时，我们的肠道会释放出消化的糖，这些糖必须迅速被吸收到组织中，以避免患上糖尿病。这种摄取是由胰腺释放的胰岛素激素控制的。与此同时，胰岛素阻止肝脏从其存储中产生更多不需要的糖。在没有胰岛素的糖尿病动物身上进行的重要新研究表明，通过激活大脑中的通路，可以同样有效地控制它们的血糖水平。肠道将信号直接发送给大脑，大脑通过不同的途径处理信息，然后将信息发送回肝脏，以阻止糖的产生。如果正常的动物或人类食用高脂肪和高碳水化合物的饮食，大脑通路就会停止对肠道信号的反应，变得功能失调。这可能会导致血糖水平高于正常水平，并导致糖尿病的发生。有趣的是，非常肥胖并接受肠道手术以控制体重的糖尿病患者，在他们真正减肥之前很久就可以看到他们的血糖水平大幅改善。这种效应被归因于肠道到大脑信号的有益变化。更好地了解从肠道到大脑再到肝脏的途径将有助于我们了解导致糖尿病发展的一些机制，以及肠道手术如何帮助我们。此外，这可能使我们能够确定肠道-大脑-肝脏轴上的点，药物可以在不需要恢复手术的情况下提高血糖水平。利用我们在肠道-大脑信号、新的小鼠模型和最新科学工具方面的专业知识，我们将定义肠道-大脑-肝脏轴的不同部分。首先，我们将测量特定神经细胞的激活是如何影响肝脏糖的产生的。这只能通过使用被培育成只在我们感兴趣的神经细胞中表达特定基因的小鼠来实现。这使得我们一次只能打开一种类型的神经细胞，并测量这对行为正常的小鼠的血糖水平有什么影响。除了选择性地激活神经细胞，我们还可以使用新开发的方法来跟踪神经在大脑中建立的连接，还可以了解神经本身对激素(如胰岛素)和营养物质(如糖)的反应。我们假设大脑中将有不止一条独立的途径，但这些途径将汇聚在调节肝脏的单一输出上。我们将了解肠道-大脑-肝脏轴的不同组成部分，并了解它通常如何与胰岛素协同作用来控制血糖。然后，我们可以研究是否可以有选择地刺激大脑通路，以改善糖尿病小鼠的血糖水平。如果是这样的话，这可能为开发治疗糖尿病药物的替代靶点提供重要的原则证据。

When we eat a meal, our gut releases the digested sugars, which must be quickly taken up into tissues to avoid the development of diabetes. This uptake is controlled by the hormone insulin which is released by the pancreas. At the same time, insulin stops the liver from producing more, unneeded sugar from its stores. Important new research in animals which are diabetic, because they have no insulin, has shown that their blood-sugar levels can be controlled equally as efficiently by activating pathways in the brain. The gut sends signals directly to the brain, which processes the information through uncharacterised pathways before sending messages back out to the liver to block sugar production. If normal animals or humans eat diets which are high in fat and carbohydrates, the brain pathways stop responding to signals from the gut and become dysfunctional. This can contribute to higher than normal blood-sugar levels and the development of diabetes. Interestingly, diabetic patients who are very obese and undergo gut surgery to control their weight, can see drastic improvement in their blood-sugar levels long before they actually lose any weight. This effect has been attributed to beneficial changes in gut to brain signalling. A better understanding of the pathways from gut to brain to liver will help us to understand some of the mechanisms which lead to the development of diabetes, and how gut surgery can help. Furthermore, this may allow us to identify points in the gut-brain-liver axis where drugs could act to improve blood-sugar levels without the need for reverting to surgery.Using our expertise in gut-brain signalling, new mouse models and the latest scientific tools, we will define the different parts of the gut-brain-liver axis. Firstly, we will measure how activation of specific nerve cells, identified as responding to meals, affects sugar production by the liver. This can only be achieved by using mice which have been bred to express specific genes only in the nerve cells in which we are interested. This allows us to turn on just one type of nerve cell at a time and to measure what effect this has on blood-sugar levels in normally-behaving mice. As well as activating the nerve cells selectively, we can use newly-developed methods to follow connections the nerves make in the brain and, also, to find out how the nerves themselves react to hormones, like insulin, and nutrients, such as sugar. We assume that there will be more than one separate pathway in the brain, but that these will converge on a single output which regulates the liver.We will learn about the different components of the gut-brain-liver axis and see how it normally acts in concert with insulin to control blood sugar. We can then investigate if we can stimulate the brain pathways selectively to improve blood-sugar levels in mice with diabetes. If so, this could provide important proof of principle for alternative targets to develop drugs to treat diabetes.