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Project
The role of mucosal integrity and low-grade inflammation in functional dyspepsia.
FD is a common functional gastrointestinal disorder encountered in clinical practice and is characterized by a diversity of symptoms localized in the epigastric region. When the gastrointestinal tract of a patient with FD is observed during routine endoscopic examination, no organic abnormalities are found, hence the term functional. The available treatment options for this disorder remain unsatisfactory, which is mostly related to the poorly understood pathophysiology. FD is associated with a high human and healthcare burden, underlining the need to elucidate the cause of dyspeptic symptom generation. There is growing evidence that FD is a heterogeneous disorder; the wide variety of symptoms seen in patients with FD argues for diverse pathophysiological pathways. Studies have demonstrated the presence of several alterations of the stomach and more recently of the duodenum in patients with FD. Whether these abnormalities play a crucial role in the manifestation of dyspeptic symptoms needs to be further elucidated. The general aim of this thesis was therefore to advance the role of duodenal implications in the pathophysiology ofFD.</>
It is well established that food ingestion plays a significant role in dyspeptic symptom generation in the majority of patients with FD. However, whether these postprandial symptoms are generated in the stomach or in the small intestine is unknown. We therefore evaluated the time course of dyspeptic symptoms after a meal and compared the intensityof these symptoms when food is predominantly in the stomach to the symptom severity when food is mainly in the small intestine. We observed that the stomach seems to play a relevant role in the induction of fullness, bloating and belching, while epigastric pain and epigastric burning are suggested to be generated in the small intestine. As these results suggest at least a partial contribution of the small intestine in dyspepticsymptom generation, we aimed to further elucidate the involvement of the duodenum in FD. Several studies have reported the presence of low-grade inflammation in the duodenal mucosa of patients with FD. The origin ofthis low-grade inflammation remains to be identified, but we hypothesized that patients with FD display impaired duodenal barrier function. This will enable luminal antigens to pass through the epithelium, in that way eliciting immune responses in the lamina propria and resulting in low-grade inflammation. Duodenal integrity of routine endoscopic biopsy specimens was therefore assessed and we found functional and structural evidence of increased permeability in patients with FD. We also detected increased numbers of eosinophils and mast cells in the lamina propria of duodenal biopsy samples, and demonstrated an association with the changesin duodenal integrity. We next investigated activation of eosinophils and mast cells in patients with FD and found ultrastructural changes in degranulation of these cells. The cause of increased duodenal permeability and immune activation in FD is unclear, but a likely candidate is an increased duodenal acid exposure</> since this has been shown to be present in patients with FD. For this reason, we perfused the duodenum of healthy volunteers with acid during 30 min and demonstrated that duodenal acid perfusion disrupts epithelial integrity and activates mast cells.</>
To conclude, we identified a specific set of small intestinal symptoms, thereby underlining the possible pathophysiological role of the duodenum in FD. Our study is of particular interest, as we are the first to demonstrate increased duodenal permeability in patients with FD. We alsoconfirmed the involvement of an inflammatory mechanism in the pathophysiology of FD and reported that this could be associated with altered duodenal barrier function. Moreover, increased duodenal acid exposure was identified as a potential mechanism involved in the generation of decreased duodenal integrity and immune activation. These data challenge the classical paradigm that the structure of the gastrointestinal tract is unaltered in patients with FD and provide evidence that FD is an organic rather than a functional disorder. Our findings suggest that inhibitors of mast cell activation, stabilizers of cell-to-cell adhesion proteins and acid suppressive therapy could be of therapeutic potential for the treatment of FD.</>
It is well established that food ingestion plays a significant role in dyspeptic symptom generation in the majority of patients with FD. However, whether these postprandial symptoms are generated in the stomach or in the small intestine is unknown. We therefore evaluated the time course of dyspeptic symptoms after a meal and compared the intensityof these symptoms when food is predominantly in the stomach to the symptom severity when food is mainly in the small intestine. We observed that the stomach seems to play a relevant role in the induction of fullness, bloating and belching, while epigastric pain and epigastric burning are suggested to be generated in the small intestine. As these results suggest at least a partial contribution of the small intestine in dyspepticsymptom generation, we aimed to further elucidate the involvement of the duodenum in FD. Several studies have reported the presence of low-grade inflammation in the duodenal mucosa of patients with FD. The origin ofthis low-grade inflammation remains to be identified, but we hypothesized that patients with FD display impaired duodenal barrier function. This will enable luminal antigens to pass through the epithelium, in that way eliciting immune responses in the lamina propria and resulting in low-grade inflammation. Duodenal integrity of routine endoscopic biopsy specimens was therefore assessed and we found functional and structural evidence of increased permeability in patients with FD. We also detected increased numbers of eosinophils and mast cells in the lamina propria of duodenal biopsy samples, and demonstrated an association with the changesin duodenal integrity. We next investigated activation of eosinophils and mast cells in patients with FD and found ultrastructural changes in degranulation of these cells. The cause of increased duodenal permeability and immune activation in FD is unclear, but a likely candidate is an increased duodenal acid exposure</> since this has been shown to be present in patients with FD. For this reason, we perfused the duodenum of healthy volunteers with acid during 30 min and demonstrated that duodenal acid perfusion disrupts epithelial integrity and activates mast cells.</>
To conclude, we identified a specific set of small intestinal symptoms, thereby underlining the possible pathophysiological role of the duodenum in FD. Our study is of particular interest, as we are the first to demonstrate increased duodenal permeability in patients with FD. We alsoconfirmed the involvement of an inflammatory mechanism in the pathophysiology of FD and reported that this could be associated with altered duodenal barrier function. Moreover, increased duodenal acid exposure was identified as a potential mechanism involved in the generation of decreased duodenal integrity and immune activation. These data challenge the classical paradigm that the structure of the gastrointestinal tract is unaltered in patients with FD and provide evidence that FD is an organic rather than a functional disorder. Our findings suggest that inhibitors of mast cell activation, stabilizers of cell-to-cell adhesion proteins and acid suppressive therapy could be of therapeutic potential for the treatment of FD.</>
Date:1 Oct 2009 → 30 Sep 2014
Keywords:Functional dyspepsia, Duodenum, Mucosal integrity, Visceral hypersensitivity, Low-grade inflammation, Motor control
Disciplines:Biomarker discovery and evaluation, Drug discovery and development, Medicinal products, Pharmaceutics, Pharmacognosy and phytochemistry, Pharmacology, Pharmacotherapy, Toxicology and toxinology, Other pharmaceutical sciences, Gastro-enterology and hepatology, Endocrinology and metabolic diseases
Project type:PhD project