Defining a gut-brain-liver axis

定义肠-脑-肝轴

• 批准号: BB/M001067/1
• 负责人: Simon Luckman
• 金额: $ 49.41万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FM001067%2F1
• 关键词: Defining; gut; brain; liver; axis

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.

当我们吃饭时，我们的肠道会释放消化的糖，这些糖必须迅速被组织吸收，以避免糖尿病的发展。这种摄取是由胰腺释放的胰岛素激素控制的。同时，胰岛素阻止肝脏从其储存中产生更多不需要的糖。在患有糖尿病的动物身上进行的一项重要的新研究表明，它们的血糖水平可以通过激活大脑中的通路来同样有效地控制。肠道直接向大脑发送信号，大脑通过未表征的途径处理信息，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碳水化合物的饮食，大脑通路就会停止对来自肠道的信号做出反应，并变得功能失调。这可能导致高于正常血糖水平和糖尿病的发展。有趣的是，非常肥胖的糖尿病患者通过肠道手术来控制体重，在他们真正减肥之前很久就可以看到血糖水平的大幅改善。这种效应归因于肠道到大脑信号传导的有益变化。更好地了解从肠道到大脑再到肝脏的通路将有助于我们了解导致糖尿病发展的一些机制，以及肠道手术如何提供帮助。此外，这可能使我们能够确定肠-脑-肝轴上的点，在这些点上药物可以起作用来改善血糖水平，而不需要恢复手术。利用我们在肠-脑信号传导方面的专业知识，新的小鼠模型和最新的科学工具，我们将定义肠-脑-肝轴的不同部分。首先，我们将测量特定神经细胞的激活，识别为对膳食的反应，如何影响肝脏的糖产生。这只能通过使用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。这使我们能够一次只打开一种类型的神经细胞，并测量这对正常行为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的连接，并找出神经本身对激素（如胰岛素）和营养素（如糖）的反应。我们假设大脑中有不止一个独立的通路，但这些通路将集中在一个调节肝脏的输出上，我们将了解肠-脑-肝轴的不同组成部分，并了解它通常如何与胰岛素一起控制血糖。然后，我们可以研究是否可以选择性地刺激大脑通路来改善糖尿病小鼠的血糖水平。如果是这样的话，这可以为开发治疗糖尿病的药物的替代目标提供重要的原则证据。

项目成果

Central administration of ghrelin induces conditioned avoidance in rodents.

• DOI: 10.1016/j.euroneuro.2017.05.001
• 发表时间: 2017-08
• 期刊: European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
• 作者: Schéle E;Cook C;Le May M;Bake T;Luckman SM;Dickson SL
• 通讯作者: Dickson SL

Experimental Models of Impaired Hypoglycaemia-Associated Counter-Regulation.

低血糖相关反调节受损的实验模型。

• DOI: 10.1016/j.tem.2020.05.008
• 发表时间: 2020
• 期刊: TEM
• 作者: Sankar A

Anorectic and aversive effects of GLP-1 receptor agonism are mediated by brainstem cholecystokinin neurons, and modulated by GIP receptor activation.

• DOI: 10.1016/j.molmet.2021.101407
• 发表时间: 2022-01
• 期刊: Molecular metabolism
• 影响因子: 8.1
• 作者: Costa A;Ai M;Nunn N;Culotta I;Hunter J;Boudjadja MB;Valencia-Torres L;Aviello G;Hodson DJ;Snider BM;Coskun T;Emmerson PJ;Luckman SM;D'Agostino G
• 通讯作者: D'Agostino G

A rare human variant that disrupts GPR10 signalling causes weight gain in mice.

• DOI: 10.1038/s41467-023-36966-3
• 发表时间: 2023-03-15
• 期刊: NATURE COMMUNICATIONS
• 影响因子: 16.6
• 作者: Talbot, Fleur;Feetham, Claire H.;Mokrosinski, Jacek;Lawler, Katherine;Keogh, Julia M.;Henning, Elana;de Oliveira, Edson Mendes;Ayinampudi, Vikram;Saeed, Sadia;Bonnefond, Amelie;Arslan, Mohammed;Yeo, Giles S. H.;Froguel, Philippe;Bechtold, David A.;Adamson, Antony;Humphreys, Neil;Barroso, Ines;Luckman, Simon M.;Farooqi, I. Sadaf
• 通讯作者: Farooqi, I. Sadaf

Sequential Exposure to Obesogenic Factors in Females Rats: From Physiological Changes to Lipid Metabolism in Liver and Mesenteric Adipose Tissue.

• DOI: 10.1038/srep46194
• 发表时间: 2017-04-07
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Novelle MG;Vázquez MJ;Peinado JR;Martinello KD;López M;Luckman SM;Tena-Sempere M;Malagón MM;Nogueiras R;Diéguez C
• 通讯作者: Diéguez C