Title: Inflammatie en oxidatieve stress in de pathogenesis van gastro-intestinale dysfunctie
Other Titles: Role of inflammation and oxidative stress in the pathogenesis of gastrointestinal dysfunction
Authors: Vanormelingen, Christophe
Issue Date: 16-Jan-2015
Abstract: Gastric motility is regulated via central and local neuronal networks of which the latter functions as an autonomic nervous system mediating motility and reflexes without input from the central nervous system. The neuronal plexus mediating autonomic muscle function is called the myenteric plexus. One of the key inhibitory neurotransmitters in this plexus is nitric oxide. Nitric oxide, which is a gaseous neurotransmitter, is released by nitrergic neurons and induces muscle relaxation. There is extensive evidence that loss of nitrergic motor control is a potential consequence of acute gastrointestinal inflammation or diabetes-induced oxidative stress in patients suffering from functional GI disorders and diabetes respectively. In addition, increased small intestinal permeability has been proposed to be the initial trigger of inflammatory alterations or auto-immune diabetes in these patient groups. The eventual loss of nitrergic neurons can be a major factor underlying gastric dysmotility, which may contribute to symptom generation in patients with motor disorders. However, the exact relationship between, increased permeability, persisting (low-grade) inflammation, altered motor control and symptom generation in the stomach remains to be elucidated. The aim of my PhD project was to establish a spontaneous animal model of impaired nitrergic gastric motor control (the BB-rat), to study the mechanisms involved in loss of nitrergic motor function and to evaluate the relevance of our findings into human pathology.The BB-rat consists of a diabetes-resistant (control) and a diabetes-prone (BB-DP) strain, with spontaneous development of diabetes (BB-DPH) after the age of 160 days in about half of the population. Previous data from BB-rats showed ganglionic inflammation, loss of nNOS expression and nitrergic motor control in the small intestine, independently of hyperglycaemia. We now studied neuromuscular function, gastric accommodation and the presence of inflammation in the gastric fundus of BB rats that were 30, 70 and 220 days old. No changes were observed at the age of 30 days when comparing BB-DP with control rats. At the age of 70 days, BB-DP rats displayed a significant loss of muscle relaxation that was attributed to the loss of nitrergic function. Additionally these animals also displayed an increased inflammatory infiltrate at the level of the neuromuscular layer. Similar changes were found in BB-DP and BB-DPH rats of 220 days with an additional loss of nitrergic neurons at this time found. We found gastric accommodation to be impaired in BB-DP animals and this was at least partially attributable to a loss of nitrergic control. In summary, BB-DP rats of 220 days display altered fundic muscle function and impaired accommodation, which is driven by loss of myenteric nitrergic function, and may be driven by a low grade inflammatory insult. These changes in gastric neuromuscular control develop independently from the presence or development of diabetes and without overt muscular lesions. Hence, the non-diabetic BBDP rat provides aspontaneous model for inflammation-induced impaired gastric accommodation.Previous data in the BB-rat showed that there was an additional loss of nitrergic neurons at the level of the small intestine in the hyperglycaemic animals when compared to their normoglycaemic counterparts. Since oxidative stress levels are reported to be increased in diabetic animals and patients, we studied the level of oxidative stress in our model and if this could explain the additional loss of nitrergic neurons in hyperglycaemic animals. We found that oxidative stress levels were increased in hyperglycaemic animals and that an additional loss of nitrergic neurons was present in these animals when compared to their normoglycaemic counterparts. Both normo- and hyperglycaemic animals had an increased inflammation when compared to control animals, suggesting that the hyperglycaemic state causes this additional loss. This was confirmed by the fact that anti-oxidative treatment reduced the additional loss of the nitrergic neurons in these hyperglycaemic animals. These findings suggest that at the level of the small intestine an additional loss of nitrergic neurons could be caused by the increased levels of oxidative stress found in diabetic animals.Increased intestinal permeability has been found prior to the development of diabetes in both animal models and diabetes patients. To date, alterations in permeability have been studied by carbohydrate absorption testing (e.g. lactulose/mannitol), but this does not allow to establish the site of involvement and the underlying molecular changes. Increased duodenal permeability and local immune activation have been demonstrated in functional dyspepsia and can be associated with delayed gastric emptying and dyspeptic symptoms. The aim of this study was to establish whether duodenal permeability is altered in Type-1 and -2 diabetes patients compared to controls and whether this is associated with their symptom burden. We found that duodenal permeability was increased in all diabetes patients and were able to find underlying molecular changes that could explain this. The total amount of mast cells and eosinophils, suggested to contribute to permeability changes in functional GI-patients, was not found to be increased in these patients. Dyspeptic symptoms were increased, but did not significantly correlate with alterations in local permeability. The average gastric emptying rate was not different from healthy controls and although this correlated with the alterations in emptying rate no significance was found. With this study, we are the first to report on local alterations in duodenal permeability in diabetes patients; however these alterations have no or little effect on gastric motility and symptoms.To conclude, we were able to study both inflammation and diabetes induced loss of nitrergic neurons at the level of the myenteric plexus in the GI-tract. This loss induced an impaired gastric function, making this an interesting model to help us understand the pathophysiology that might be present in patients sufferingfrom impaired gastric function. Increased permeability is often suggested to be the initial trigger of immune alterations that eventually lead to an impaired neurogastro function, but most of the data is coming from animal studies and little is known about alterations in patients. We found an increased duodenal permeability in diabetes patients, but this was not associated with presence of inflammatory cells, gastric symptoms or a delay in emptying. This could suggest that there is no direct relationship but more studies with higher n-numbers and specified patient groups should be performed to completely rule out the possible effect of duodenal permeability on emptying rate and symptoms.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Translational Research in GastroIntestinal Disorders

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