The Knotty Problem Of Enterochromaffin Cells And Gastro-intestinal Function: Unravelling Cause And Effect
Funder
National Health and Medical Research Council
Funding Amount
$403,097.00
Summary
It is crucial to understand how the food we eat controls the secretions and movements of a healthy or a diseased gastrointestinal (GI) system. One way control is achieved involves the release of serotonin (5-HT) from the enterochromaffin cells present in the epithelial lining of the intestine. This is the subject of our proposal and our results will help us to understand the causes of GI disorders and help to formulate new treatments.
Relationships Between Diet And Gastric Motor Function In Functional Dyspepsia
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
Functional dyspepsia (FD) is a condition characterised by abdominal symptoms without a cause that is identifiable by conventional diagnostic tests. Symptoms (eg fullness, bloating) are frequently induced by eating. 20 - 40 % of the adult population in Western countries are affected by FD, and the condition, therefore, represents a considerable financial burden to the health care system. FD affects quality of life adversely. In many people with FD, stomach contractions and the 'sensitivity' of th ....Functional dyspepsia (FD) is a condition characterised by abdominal symptoms without a cause that is identifiable by conventional diagnostic tests. Symptoms (eg fullness, bloating) are frequently induced by eating. 20 - 40 % of the adult population in Western countries are affected by FD, and the condition, therefore, represents a considerable financial burden to the health care system. FD affects quality of life adversely. In many people with FD, stomach contractions and the 'sensitivity' of the stomach are abnormal. Often, people with FD avoid fatty foods in the belief that these cause or exacerbate symptoms. There is, however, little information about the potential role of dietary habits in causing symptoms, the relationship between eating and disturbances in stomach function, and the impact of dietary changes on symptoms. Our previous studies suggest an important role for nutrients, particularly fat, in FD. We will address the hypothesis that dietary factors, particularly fat intake, have substantial implications for the pathophysiology and treatment of FD. Our studies will involve physiological (stomach emptying, appetite and food intake) and epidemiological (dietary habits, dyspeptic symptoms and quality of life-related aspects) measurements. The subjects-patients with FD will receive standardised test meals of varying nutrient composition, and we will study the effects on their stomach and on symptoms. We will also test some medications in an attempt to alleviate symptoms during and after food ingestion, particularly after fatty foods. Other studies will assess the dietary habits of patients with FD in relation to symptom occurrence and investigate the possibility that dietary intervention (reduction of fat content in the diet, exclusion of offending foods) will benefit these patients. The proposed studies will provide the most comprehensive studies to date of the relationship between symptoms in patients with FD with dietary habits and stomach function.Read moreRead less
Spatio-temporal Analysis Of Rat Intestinal Motility In Physiological And Disease Models
Funder
National Health and Medical Research Council
Funding Amount
$358,750.00
Summary
This project addresses the question of how the movements of the gut are controlled in health and disease. The progress of food along the gut is due to movements of the involuntary muscle of the wall of the intestine. Three fundamental mechanisms are involved. One is the spontaneous ability of the intestinal muscle to contract rhythmically and is driven by a delicate net of pacemaker cells. Fast propulsion of food contents depends on nerve circuits in the gut wall that generate a powerful pumping ....This project addresses the question of how the movements of the gut are controlled in health and disease. The progress of food along the gut is due to movements of the involuntary muscle of the wall of the intestine. Three fundamental mechanisms are involved. One is the spontaneous ability of the intestinal muscle to contract rhythmically and is driven by a delicate net of pacemaker cells. Fast propulsion of food contents depends on nerve circuits in the gut wall that generate a powerful pumping behaviour to prevent over-filling or to eject toxic or irritating substances (eg: some laxatives activate this mechanisms). This is often called peristalsis. A third mechanism consists of activity of nerve cells in the gut, that slowly propagates along the intestine and causes the muscle to contract, sweeping along any remnants. The movements generated by these three mechanisms occur in segments of intestine isolated from rats. The major difficulty up until now has been to relate the actual movements in living animals to these fundamental mechanisms. It is now possible to bridge this gap because we have developed methods to record, display and measure graphically the actual movements. Movements are transformed into spatio-temporal maps which show all of the contractions over a period of time. Coordinated activity is visible in these maps as recognisable patterns or visual objects. Measurements can be readily made with conventional statistics. The literature in gastroenterology is full of descriptions of motility based on indirect methods of recordings. In this project we will be able to correlate the previous indirect methods with the new graphic methods and thus establish a clearer, simpler and more accurate classification of normal patterns of intestinal motility. We will then use this to establish what goes wrong in a number of experimental diseases known to affect adversely the movements of the intestine.Read moreRead less
Cooperative Motor Control Of The Pyloric Junction By Myogenic And Neuronal Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$271,527.00
Summary
The coordinated muscle movement in the junction between the stomach and small intestine is an essential mechanism for controlling the speed of gastric content moving into the intestine for further digestion. The muscle movement determines the gastric emptying at an optimal rate and prevents intestinal contents reflux to the stomach. Failure of this coordination is likely to be involved in a variety of clinical conditions including accelerated or delayed gastric emptying. Up to date, little infor ....The coordinated muscle movement in the junction between the stomach and small intestine is an essential mechanism for controlling the speed of gastric content moving into the intestine for further digestion. The muscle movement determines the gastric emptying at an optimal rate and prevents intestinal contents reflux to the stomach. Failure of this coordination is likely to be involved in a variety of clinical conditions including accelerated or delayed gastric emptying. Up to date, little information is available about the interaction between nerve, muscle and pacemaker cells during this coordinated movement. In this project, we will investigate how the nerve, muscle and pacemaker cells work together to control this coordinated movement. We will study this mechanism at both cellular and organ levels and try to establish the patterns of muscle movement and their coordination between the stomach and the small intestine. The interaction between the nerve and pacemaker cells will be characterised in these studies. Our work will provide structural evidence for this activity. It includes identification of the nerve pathways connecting between the small intestine and stomach and determination of whether the pacemaker cell network is an uniform continuous or a discontinuous or a transitional structure across the junction. These studies will reveal the correlation between pacemaker cell mediated activity and the density of these cells in each junctional region. We will also determine whether the difference in propagation activity across the junction is due to differences in the number of cells for signal conduction or electrical connections between the cells. This study will advance our knowledge for understanding how the nerve, muscle and pacemaker cells work in concert in this junction, which is an important step for further clinical investigation of related disease.Read moreRead less
Neuromodulation Of Triggering Of Transient Lower Oesophageal Sphincter Relaxation And Gastro-oesophageal Reflux
Funder
National Health and Medical Research Council
Funding Amount
$369,779.00
Summary
Reflux of stomach contents into the gullet is a very common condition. If reflux is not treated, more severe problems may manifest. In patients with reflux disease the anatomy of the junction between the gullet and the stomach is altered. This research program will undertake novel studies to explore how this alteration exacerbates the triggering reflux after a meal and potentially identify new targets for pharmacological therapy for this common problem.
Mechanisms By Which Aging Induces Constipation In The Elderly
Funder
National Health and Medical Research Council
Funding Amount
$369,717.00
Summary
Chronic constipation is one of the most common reasons why the elderly community seek medical attention. There is now strong evidence to suggest that the high prevalence of constipation in the elderly is likely due to a dramatic loss of specific nerves that lie in the wall of the colon. This project will use latest imaging technologies to identify the mechanisms by which these nerves are impaired with age that lead to constipation in the elderly.
Transcutaneous Electrical Stimulation To Relieve Chronic Constipation In Children
Funder
National Health and Medical Research Council
Funding Amount
$82,450.00
Summary
1 in 300 children suffer from chronic constipation that is not fixed by changing their diet or taking laxatives. They continue to suffer the problem into adulthood. They also have fecal incontinence or soiling that causes problems with socialising and schooling. We are testing a method of electrical stimulation through the skin on the belly to increase the movement of the bowel. Initial results are encouraging, showing that the rate of movement of the bowel is increased and soiling is decreased.
Gastroduodenal Motility And Glycaemic Control In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$393,750.00
Summary
The recent application of novel techniques to evaluate gastrointestinal motor function has established that the rate which the stomach empties food is abnormally slow in ~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent complication in diabetes; much less common than damage to the eyes, kidneys or nerves. Abnormal stomach emptying may contribute to a number of problems in diabetes, including sym ....The recent application of novel techniques to evaluate gastrointestinal motor function has established that the rate which the stomach empties food is abnormally slow in ~50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent complication in diabetes; much less common than damage to the eyes, kidneys or nerves. Abnormal stomach emptying may contribute to a number of problems in diabetes, including symptoms such as nausea and bloating, and poor control of blood glucose concentrations. It is now recognised that the blood glucose level itself has a reversible effect on both stomach contractions and symptoms. For example, when the blood glucose is abnormally high (hyperglycaemia), the rate at which the stomach empties food into the intestine is slower and symptoms, such as fullness, are greater. The rate of stomach emptying and the absorption of glucose from the intestine affect the rise in the blood glucose level after a meal; this is an important issue because it is desirable to maintain blood glucose levels within the normal range to minimise the risk of both the development and progression of the complications of diabetes. In many people with diabetes eating a meal results in a substantial fall in blood pressure, which may cause fainting and falls. By slowing gastric emptying the magnitude of the fall in blood pressure is minimised. Our group has been the recipient of ongoing support from the NH and MRC for approximately 18 years to conduct research in this area. As a result we have performed the most comprehensive studies to date and developed new methods to evaluate stomach and intestinal function in people with diabetes, resulting in international recognition. The studies proposed in the current application represent a logical development from our previous work and have important implications for the management of diabetes.Read moreRead less
Mechanics Of Normal And Disordered Gastric Emptying Studied Using Simultaneous Ultrasound And High Resolution Manometry
Funder
National Health and Medical Research Council
Funding Amount
$145,626.00
Summary
Optimal digestion and absorption relies on the stomach breaking down food and delivering it to the small intestine at an optimal rate. Abnormalities in the processes controlling the stomach's processing of food may lead to malnutrition, gastrointestinal symptoms or unpredictable drug absorption, and are commonly seen in patients with diabetes mellitus, gastrointestinal reflux disease and nonulcer dyspepsia, or following stomach surgery. Currently our understanding of the way the stomach empties ....Optimal digestion and absorption relies on the stomach breaking down food and delivering it to the small intestine at an optimal rate. Abnormalities in the processes controlling the stomach's processing of food may lead to malnutrition, gastrointestinal symptoms or unpredictable drug absorption, and are commonly seen in patients with diabetes mellitus, gastrointestinal reflux disease and nonulcer dyspepsia, or following stomach surgery. Currently our understanding of the way the stomach empties food is incomplete, and there is little information as to the mechanisms by which diseases cause abnormal stomach emptying. Recent developments in recording methods mean that we can now simultaneously measure stomach contractions, the pressures these generate and flow from the stomach. This information is synchronised and displayed for analysis using computer techniques. In this project these novel methods will be used initially to examine the normal processes by which meals with a variety of compositions and consistencies empty from the stomach. This will provide information as to which aspects of the way the stomach functions are important for breaking down food into particles, and which aspects control the flow of food from the stomach into the intestine. The mechanisms by which the rate of emptying of the stomach is controlled by feedback signals caused by the presence of foodstuffs in the small intestine will be investigated by examining the effects of infusing nutrients into the intestine on the motions of the stomach wall, pressures within the stomach and the passage of stomach contents into the small intestine. The mechanism of action of drugs and diseases which slow stomach emptying will then be examined by measuring the movements, pressures and emptying of the stomach in subjects receiving the drug, or in patients with dibetes, and comparing this information with the processes observed during normal stomach emptying.Read moreRead less
Gastric Motility And Blood Glucose Control In Diabetes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$354,947.00
Summary
The recent application of novel techniques to evaluate gastrointestinal motor function has established that the rate of which the stomach empties food is slow in up to 50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent complication in diabetes; much less common than damage to the eyes, kidneys or nerves. It is now recognised that disordered stomach emptying may contribute to a number of problems i ....The recent application of novel techniques to evaluate gastrointestinal motor function has established that the rate of which the stomach empties food is slow in up to 50% of people who have insulin-dependent (type 1) or non-insulin dependent (type 2) diabetes. Delayed stomach emptying was thought to be an infrequent complication in diabetes; much less common than damage to the eyes, kidneys or nerves. It is now recognised that disordered stomach emptying may contribute to a number of problems in diabetes, e.g. symptoms such as nausea and bloating and poor control of blood glucose concentrations. In some people symptoms are disabling and affect quality of life adversely. The effects of stomach emptying on blood glucose control is likely to be important, as it is desirable to maintain blood glucose levels within the normal range to minimise the risk of both the development and progression of complications of diabetes. In many people with diabetes, particularly older people with type 2 diabetes, there is a fall in blood pressure after a meal which may result in fainting and falls. The magnitude of the fall in blood pressure is determined by the rate at which the stomach empties; faster emptying results in a greater fall in blood pressure. In the past both slow stomach emptying and symptoms were assumed to result from irreversible nerve damage, however it is now recognised that the blood glucose level itself has a reversible effect on both stomach contractions and symptoms. Our group has been the recipient of ongoing support from the NH and MRC for approximately 15 years to conduct research in this area. As a result we have performed the most comprehensive studies to date and developed new methods to evaluate stomach function in people with diabetes, resulting in international recognition. The studies proposed in this current application represent a logical development from our previous work and have important implications for the management of diabetes.Read moreRead less