Defining a gut-brain-liver axis

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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.