The impact of parietal cells onHelicobacter pyloritropism and host pathology: An analysis using gnotobiotic normal and transgenic mice

Abstract

Helicobacter pylori infection of the human stomach is common and typically benign, although a subset of hosts develops severe pathology. Infection occurs in an organ with distinct microenvironments characterized by pronounced differences in the composition of acid-producing parietal cells. In this study, we examine determinants of bacterial tropism to various gastric niches by using germ-free normal and transgenic mice with an engineered parietal cell ablation. Mice were colonized for 8 weeks with a clinical isolate (Hp1) that expresses adhesins recognized by epithelial NeuAc␣2,3Gal␤1,4 glycan receptors. In normal mice, Hp1 has tropism for a parietal cell-deficient niche where sialylated glycans are expressed by a narrow band of pit cells positioned at the boundary between the squamous epithelium (forestomach) and the proximal glandular epithelium. Lymphoid aggregates that develop in this niche, but not elsewhere in the stomach, were analyzed by GeneChip and quantitative RT-PCR studies of laser capture microdissected mucosa and yielded a series of biomarkers indicative of immune cell activation and maturation. Genetic ablation of parietal cells produced a new source of NeuAc␣2,3Gal␤1,4 glycans in amplified gastric epithelial lineage progenitors, with accompanying expansion of Hp1 within the glandular epithelium. Lymphoid aggregates that develop in this formerly acid-protected epithelium have molecular features similar to those observed at the forestomach͞glandular junction. These findings demonstrate the important roles played by parietal cells and glycan receptors in determining the positioning of H. pylori within the gastric ecosystem, and emphasize the need to consider the evolution of pathology within a given host in a niche-specific context. gastric acid ͉ adhesin receptors ͉ immune response ͉ germ-free animals A t least half of all humans harbor Helicobacter pylori in their stomachs. This microaerophilic bacterium is usually acquired in childhood and remains in the stomach of its host for decades (1). In most cases, the host-microbial relationship is benign, marked only by mild mucosal inflammation. However, in a subset of individuals, this relationship evolves to produce gastric or duodenal ulcers, adenocarcinoma, or mucosal lymphoma (2).Lee and coworkers (3) have emphasized that severe pathology more often develops in regions of the gastric epithelium where there is a marked transition in the census of acid-producing parietal cells. They and others proposed that local environmental pH gradients at these transitions provide the organism with an opportunity to sample and occupy niches where growth conditions are optimal (3, 4). Once the organism becomes entrenched, pH and other niche-associated factors (e.g., redox state, nutrient availability) then presumably shape the nature of the host-microbial interaction (5).These speculations emphasize the importance of viewing the nature of the host-microbial cross-talk, the genetic microevolution of this bacterium (6, 7), and the structure of the pathogenic cascad...

Molecular Properties of Adult Mouse Gastric and Intestinal Epithelial Progenitors in Their Niches

“…tox176-mediated parietal cell ablation results in augmented GEP proliferation, with a progressive increase in their fractional representation to ϳ10% of all epithelial cells in gastric units by 16 weeks of age, as judged by transmission EM (22). Germ-free Atpb4-tox176 mice were used because loss of the acid-barrier to colonization produces bacterial overgrowth in the stomach and gastritis (20,22).…”

Intracellular Helicobacter pylori in gastric epithelial progenitors

“…One half was homogenized in 0.5 ml of PBS and plated on selective medium to assay for the presence of viable H. pylori. The other half was immediately frozen in OCT compound (Sakura, Torrance, CA) or fixed overnight at 4°C in Bouin's solution for immunohistochemical analysis (18).…”

The spatial orientation of Helicobacter pylori in the gastric mucus

“…orientation apparently involves other mechanisms in addition to pH sensing, such as adherence of the bacteria to carbohydrate epitopes that show a region-specific expression pattern (36).…”