Expression of Secretory Mucins in the Human Upper Gastrointestinal Tract; The Role of MUC5AC in the Adhesion of Helicobacter Pylori

The "natural habitat" of H. pylori within the human body seems to be the gastric mucus and the mucus-producing epithelium. The question is; what is so special about the gastric mucus that H. pylori can establish itself there? This mucus-layer, like all the mucus-layers in the body, is composed of mucins; large glycoproteins that are able form watery gels to protect the underlying epithelium. Several questions immediately arise, each of which we will try to answer in this thesis: 1. What is the nature of the gastric mucin? 2. What is the nature of the interaction between the bacterium and the mucin? 3. Can the expression of this gastric mucin sufficiently explain the gastric tropism towards the stomach? 4. Which mucins, or other secretory proteins, are produced in the metaplastic epithelia within the upper GI tract, and can this knowledge help us understand the underlying pathology and the role of H. pylori herein? BACKGROUND AND OBJECTIVES: Helicobacter pylori shows a characteristic tropism for the mucus-producing gastric epithelium. In infected patients, H. pylori colocalizes in situ with the gastric secretory mucin MUC5AC. The carbohydrate blood-group antigen Lewis B (LeB) was deemed responsible for the adherence of H. pylori to the gastric surface epithelium. We sought to determine if MUC5AC is the carrier of LeB, and thus if MUC5AC is the underlying gene product functioning as the main receptor for H. pylori in the stomach. METHODS: We studied three types of human tissue producing MUC5AC: Barrett's esophagus (BE), normal gastric tissue, and gastric metaplasia of the duodenum (GMD). Tissue sections were immuno-fluorescently stained for MUC5AC or LeB, and subsequently incubated with one of three strains of Texas red-labeled H. pylori, one of which was unable to bind to LeB. We determined the colocalization of MUC5AC or LeB with adherent H. pylori. RESULTS: The binding patterns for the two LeB-binding strains to all tissues were similar, whereas the strain unable to bind to LeB did not bind to any of the tissues. In normal gastric tissue, the LeB-binding strains always bound to MUC5AC- and LeB-positive epithelial cells. In four nonsecretor patients, colocalization of the LeB-binding strains was found to MUC5AC-positive gastric epithelial cells. In BE, the LeB-binding H. pylori strains colocalized very specifically to MUC5AC-positive cells. MUC5AC-producing cells in GMD contained LeB. Yet, LeB-binding H. pylori not only colocalized to MUC5AC or LeB present in GMD, but also bound to the LeB-positive brush border of normal duodenal epithelium. CONCLUSIONS: Mucin MUC5AC is the most important carrier of the LeB carbohydrate structure in normal gastric tissue and forms the major receptor for H. pylori.

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