Impact of chronic atrophic gastritis on Helicobacter pylori pathogenesis.

摘要

Helicobacter pylori (Hp) infection of the human stomach is ubiquitous and typically benign, although a subset of hosts develops severe pathology, including gastric adenocarcinoma. The precise mechanism as how Hp infection leads to cancer is unknown. Chronic atrophic gastritis (ChAG) is characterized by loss of acid-producing parietal cells plus pepsinogen-secreting zymogenic cells, and is viewed as a precursor to gastric cancer. The aim of my thesis was to characterize the role of ChAG in Hp pathogenesis.; Colonization of germ-free normal mice with clinical isolates of Hp from patients with ChAG (strain AG7:8) as well as acid-peptic disease (strain Hp1) results in bacterial tropism to a parietal cell-deficient niche positioned between the squamous epithelium and the proximal glandular epithelium that contains surface mucus cells expressing NeuAcalpha2,3Galbeta1,4 glycan receptors for bacterial adhesins. The result is development of lymphoid aggregates within this region. Germ-free transgenic mice with a genetically engineered, attenuated diphtheria toxin A fragment (tox 176)-mediated ablation of parietal cells exhibit many features of ChAG, including an expansion of NeuAcalpha2,3Galbeta1,4 expressing gastric epithelial progenitors (GEPs). The Hp strains exhibited an expanded zone of colonization and lymphoid aggregate formation within the normally acid-protected glandular epithelium. Follow-up scanning confocal microscopy and transmission EM revealed that a subset of these expanded GEPs harbors intracellular collections of AG7:8 (and Hp1). The notion that adult mammalian epithelial progenitors can function as a repository for Hp is unprecedented and broadens the view of host habitats available to Hp and perhaps other pathogens. GEP invasion during ChAG may represent a mechanism by which the outcome of infection is skewed towards neoplastic transformation.; To gain further insights about the adaptation of Hp to ChAG, we sequenced the 1,596,366 bp AG7:8 genome. I identified 43 genes that are not represented in the two previously sequenced Hp strains from patients with acid-peptic disease, plus 37 genes whose ORFs are split due to in-frame stop codons. The distribution and evolution of these genes is being examined in a panel of 52 clinical isolates from a Swedish case-control study of gastric cancer, and in gnotobiotic tox176 and normal mice colonized for one year with AG7:8.