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.

当我们吃一顿饭时，我们的肠道会释放消化的糖，必须迅速将其吸收到组织中，以避免糖尿病的发展。这种摄取由胰腺释放的激素胰岛素控制。同时，胰岛素阻止肝脏从其商店中产生更多，不需要的糖。在糖尿病的动物中，重要的新研究，因为它们没有胰岛素，它表明它们的血糖水平可以通过激活大脑中的途径而同样有效地控制。肠道直接向大脑发送信号，该信号通过未表征的途径处理信息，然后再将消息发送回肝脏以阻止糖产生。如果正常的动物或人类吃脂肪和碳水化合物高的饮食，则大脑途径停止对肠道信号的反应并变得功能失调。这可以导致比正常血糖水平高于正常水平和糖尿病的发展。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可以看到血糖水平的急剧改善，在他们实际上减轻体重之前很久。这种效果归因于肠道中的有益变化对大脑信号传导。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某些机制，以及肠道手术如何帮助。此外，这可能使我们能够识别肠道肝轴中的点，而药物可以在不需要恢复手术的情况下采取行动改善血液糖水平。使用肠脑信号，新的小鼠模型和最新的科学工具的专业知识，我们将定义肠gut-脑轴轴的不同部分。首先，我们将衡量特定神经细胞的激活如何（被确定为对餐的反应）影响肝脏的糖产生。这只能通过使用仅在我们感兴趣的神经细胞中表达特定基因的小鼠来实现。这使我们一次只打开一种神经细胞，并测量这种对正常行为小鼠血糖水平的影响。除了选择性地激活神经细胞外，我们还可以使用新开发的方法遵循神经在大脑中建立的连接，还可以找出神经本身对胰岛素和糖（例如糖）等激素的反应。我们假设大脑中将有多个单独的途径，但是这些途径将收敛于调节肝脏的单个输出。我们将了解肠道脑叶轴的不同成分，并查看其通常与胰岛素共同作用以控制血糖。然后，我们可以研究是否可以选择性地刺激大脑途径，以改善糖尿病小鼠的血糖水平。如果是这样，这可以为替代靶标以开发治疗糖尿病的药物的替代靶标提供重要的原理证明。

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

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

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

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