Researcher: Dr John McLaughlin, University of Manchester   

Fellowship: Three Year Research Fellowship – completed August 2003

Grant Total:

Many patients are referred to Gastroenterologists with 'dyspepsia', problems related to eating (such as pain, nausea or poor appetite), but for which no satisfactory explanation can often be found. Consequently current treatments are generally disappointing.

The gut sends information to the brain by a series of nerves starting in the wall of the stomach and intestine. Their combined actions act to control normal digestive function and appetite. An interesting discovery has been that the gut hormones released when eating can also influence the activity of the intestinal nerves, and vice versa. Hence the information sent from the gut to the brain and back may be critically dependent on the interactions between nerves and cells found in the digestive tract. These will in turn be influenced by the content of the gut (e.g. nutrients). Importantly, this model is open to the idea that changes in the brain, such as stress, can reciprocally have a direct effect on the function of gut nerve and hormone cells.

The purpose of this research was to discover if dyspepsia can result from abnormal nerve/endocrine interactions and examined the effects of food molecules and neurotransmitters on gut cells.

Here is Dr McLaughlin’s final report:

Aims of Research

A special population of cells in the lining of the gut, called enteroendocrine cells (EEC), have been found to play a central role in detecting food. It has been my role to study the properties of these cells in detail, and then see if there are situations in which they don’t work properly.

They respond to food by releasing various substances which act on nearby nerve fibres. These then send messages up to the brain. EEC also seem to adapt their function in response to information being transmitted the other way, from brain to gut. Hence they occupy a key ‘crossroads’ position in communication between brain and gut: but how they really work is not known in any detail.
The specific aims of the Project are to understand the effects of food substances, the nervous system, and other gut factors (eg inflammation of its lining) on the function of EEC.
Results of Research
I have made significant progress in two key areas.

1.    Fatty acid effects on EEC: Most of the studies in progress use a ‘cell line’, STC-1, which originates from mouse intestine, and releases the hormone ‘CCK’, an important part of the controls present within the digestive system. I have previously shown that fatty food substances are potent at releasing CCK in humans and from these cells. My work has gone a long way to dissecting the cellular machinery by which fatty acids are detected and stimulate CCK cells. We have identified a receptor for fatty acids (GPR40) on these cells. The fatty acid molecule also enters the cell and acts directly on a calcium store inside the cell to trigger its effects.

2.    Inflammatory effects on EEC: Initial studies on STC-1 cells showed that mediators of inflammation (‘cytokines’) alter the functionality of STC-1 cells, including their response to fatty acids. I have established a collaboration with Prof. R Grencis, a leading Immunologist in the School of Biological Sciences in Manchester University. We have discovered that inflammation of the gut wall causes a marked increase in EEC numbers, and increased blood CCK levels. This strongly affects gut function eg feeding. Blocking CCK improves feeding. The specific immune system mechanism is found in white blood cells and is now being pursued.

Implications

Symptoms originating from the upper gut present a common and difficult clinical problem. Examples include unexplained dyspepsia, nausea, bloating or loss of appetite. These also occur when the gut is inflamed. Currently, the underlying biological reasons and processes by which these symptoms arise are not understood. Consequently, treatment is largely unsatisfactory and frustrating for both patient and doctor. Since eating generally precipitates such symptoms, it is possible that the processes by which the presence of food is recognised by the digestive system and then communicates this information to the central nervous system may be at fault.

From the aims noted above, it is clear that EEC may be key players in all this. My programme of work has unravelled part of the normal functioning of EEC, and subsequently begun to identify situations where things have gone wrong. Then, as the explanations behind these difficult disorders become understood, we hope to lead the future research field in the development of new diagnostic tests, for instance on biopsy samples, and to the development of new and effective treatments.