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Celiac disease and cholecystokinin cell dysfunction : a model of interaction between the digestive, endocrine and immune systems in the gut

by Deprez, Pierre

Abstract (Summary)
The aim of our work was to study the defective CCK release that is found in adult patients with celiac disease. The CCK decreased secretion was first thought to be caused by a reduction in the number of intestinal CCK cells in the presence of mucosal atrophy, but could also be related to other mechanisms: a lack of stimulation of the mucosal CCK cells due to impaired intra-duodenal hydrolysis of nutrients, a functional abnormality of the CCK-cell, an impaired interaction of the CCK-cell with other intestinal cells (endocrine, epithelial or nervous cells), the absence of a stimulating factor (luminal cholecystokinin releasing factor) or the presence of inhibitory factors associated with the inflammatory process taking place in the mucosa. We have shown that CCK release is not only impaired in untreated celiac patients with a destructive/hypoplastic type duodenal mucosa but also in patients whose mucosa only shows a significant intraepithelial lymphocytic (IEL) infiltrate. Treated celiac patients without hypoplastic or destructive mucosa and without any increase in IEL infiltrate exhibit a basal and postprandial CCK release similar to the control group. Using immunocytochemistry and semi-quantitative PCR we have demonstrated that the defective release of CCK observed in patients with coeliac disease is not related to a decrease in the number of CCK cells present in the proximal part of the small intestine but rather to a decrease in CCK synthesis related to a decrease in mRNA content, even in patients with an infiltrative type of celiac disease. These data suggest that the inflammatory infiltrate in the mucosa of celiac patients affects the expression of the CCK gene. The next part of our work included the investigation of the role of the intraluminal nutrient hydrolysis in adult celiac patients. Our data indicates that ingestion of a pre-digested meal does not correct the defective CCK release in patients with a destructive or an infiltrative type of celiac mucosal lesion. Moreover, intraduodenal food digestion should be considered normal in celiac patients with mucosal lesions limited to an intraepithelial lymphocytic infiltrate. The decreased level of plasma CCK in this group of patients, given a pre-digested meal, strongly supports that the defective CCK release could be related to suppressive factors released by the inflammatory infiltrate. We therefore studied the effects of supernatants obtained from IEL and lamina propria lymphocyte cultures and various cytokines produced by mucosal lymphocytes on short-term organ cultures of duodenal biopsy specimens obtained from normal controls and on the CCK secreting murine neuroendocrine tumour cell line STC-1. We demonstrated a significant inhibitory effect of supernatants obtained from phytohaemagglutinin A-stimulated cultured lamina propria lymphocytes and from phytohaemagglutinin A-stimulated co-cultured lamina propria and intraepithelial lymphocytes, and of interleukin-1 and tumour necrosing factor-? on CCK release. All together these data show that the defective CCK release is already present at the initial infiltrative type of mucosal lesion seen in celiac disease and that this defective release may be related to inflammation and suppressive factors associated with the inflammatory cells. Modulation of CCK release in the gut should be considered as a complex process implying co-regulation of nutrients, releasing peptides, neurotransmitters and soluble factors including cytokines. These results may be of help in finding new directions to improve the treatment of patients with celiac disease who continue to present with abdominal complaints in spite of a strict gluten-free diet.
This document abstract is also available in French.
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The full text for this document is available in French.
Bibliographical Information:

Advisor:

School:Université catholique de Louvain

School Location:Belgium

Source Type:Master's Thesis

Keywords:cholecystokinin immunology coeliac disease

ISBN:

Date of Publication:05/28/2003

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