Abstract
Helicobacter pylori colonizes the mucus niche of the gastric mucosa and is a risk factor for gastritis, ulcers and cancer. The main components of the mucus layer are heavily glycosylated mucins, to which H. pylori can adhere. Mucin glycosylation differs between individuals and changes during disease. Here we have examined the H. pylori response to purified mucins from a range of tumor and normal human gastric tissue samples. Our results demonstrate that mucins from different individuals differ in how they modulate both proliferation and gene expression of H. pylori. The mucin effect on proliferation varied significantly between samples, and ranged from stimulatory to inhibitory, depending on the type of mucins and the ability of the mucins to bind to H. pylori. Tumor-derived mucins and mucins from the surface mucosa had potential to stimulate proliferation, while gland-derived mucins tended to inhibit proliferation and mucins from healthy uninfected individuals showed little effect. Artificial glycoconjugates containing H. pylori ligands also modulated H. pylori proliferation, albeit to a lesser degree than human mucins. Expression of genes important for the pathogenicity of H. pylori (babA, sabA, cagA, flaA and ureA) appeared co-regulated in response to mucins. The addition of mucins to co-cultures of H. pylori and gastric epithelial cells protected the viability of the cells and modulated the cytokine production in a manner that differed between individuals, was partially dependent of adhesion of H. pylori to the gastric cells, but also revealed that other mucin factors in addition to adhesion are important for H. pylori-induced host signaling. The combined data reveal host-specific effects on proliferation, gene expression and virulence of H. pylori due to the gastric mucin environment, demonstrating a dynamic interplay between the bacterium and its host.
Highlights
Half of the world’s population is infected with the bacterium Helicobacter pylori. 1–3% of infected individuals develop gastric adenocarcinoma or MALT lymphoma and another 10–15% develop gastritis or gastric and duodenal ulcers, whereas the majority show no symptoms [1]
Many studies have focused on the host response to H. pylori, but fewer studies have investigated how H. pylori is affected by the host and in particular by the host mucins
We investigated how interindividual differences and infection associated changes in mucins, the building blocks of the mucus niche that H. pylori resides in and the host’s first line of defense, affect H. pylori. We show that these differences can change the interactions with H. pylori, causing modulations in proliferation and gene expression as well as alterations in how the bacteria affects the viability of host cells and host cell signaling
Summary
Half of the world’s population is infected with the bacterium Helicobacter pylori. 1–3% of infected individuals develop gastric adenocarcinoma or MALT lymphoma and another 10–15% develop gastritis or gastric and duodenal ulcers, whereas the majority show no symptoms [1]. Adherence of H. pylori to the gastric mucosa is highly relevant for the development of gastric disease [2,3,4]. Most of them live in the mucus layer of the superficial gastric mucosa where they can bind to the highly glycosylated mucins [6,7]. The mucus layer protects the gastric mucosa by acting as a physical barrier preventing H. pylori from binding to the epithelia [7,11]. Terminal 1,4-linked N-acetylglucosamine (a1,4GlcNAc), which is a carbohydrate structure on mucins present in the gastric glands, has been demonstrated to have antimicrobial activity [12], which may contribute to protection against H. pylori colonization of the gastric glands
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