Significance Theory predicts that chronic pathogens with vertical or familial transmission should become less virulent over time because of coevolution. Although transmitted in this way, Helicobacter pylori is the major causative agent of gastric cancer. In two distinct Colombian populations with similar levels of H. pylori infection but different incidences of gastric cancer, we examined human and pathogen ancestry in matched samples to assess whether their genomic variation affects the severity of premalignant lesions. Interaction between human Amerindian ancestry and H. pylori African ancestry accounted for the geographic disparity in clinical presentation. We conclude that coevolutionary relationships are important determinants of gastric disease risk and that the historical colonization of the Americas continues to influence health in modern American populations.

BACKGROUND & AIMS Helicobacter pylori-induced gastric carcinogenesis has been linked to the microbial oncoprotein CagA. Spermine oxidase (SMO) metabolizes the polyamine spermine into spermidine and generates H2O2 that causes apoptosis and DNA damage. We determined if pathogenic effects of CagA are attributable to SMO. METHODS Levels of SMO, apoptosis, and DNA damage (8-oxoguanosine) were measured in gastric epithelial cell lines infected with cagA+ or cagA− H. pylori strains, or transfected with a CagA expression plasmid, in the absence or presence of SMO small interfering RNA, or an SMO inhibitor. The role of CagA in induction of SMO and DNA damage was assessed in H. pylori-infected gastritis tissues from humans, gerbils, and both wild-type and hypergastrinemic INS-GAS mice, using immunohistochemistry and flow cytometry. RESULTS cagA+ strains or ectopic expression of CagA, but not cagA− strains, led to increased levels of SMO, apoptosis, and DNA damage in gastric epithelial cells, and knockdown or inhibition of SMO blocked apoptosis and DNA damage. There was increased SMO expression, apoptosis, and DNA damage in gastric tissues from humans infected with cagA+, but not cagA− strains. In gerbils and mice, DNA damage was CagA-dependent and present in cells that expressed SMO. Gastric epithelial cells with DNA damage that were negative for markers of apoptosis accounted for 42–69% of cells in gerbils and INS-GAS mice with dysplasia and carcinoma. CONCLUSIONS By inducing SMO, H. pylori CagA generates cells with oxidative DNA damage, and a subpopulation of these cells are resistant to apoptosis and thus at high risk for malignant transformation.

BACKGROUND & AIMS-Helicobacter pylori-induced immune responses fail to eradicate the bacterium. Nitric oxide (NO) can kill H. pylori. However, translation of inducible NO synthase (iNOS) and NO generation by H. pylori-stimulated macrophages is inhibited by the polyamine spermine derived from ornithine decarboxylase (ODC), and is dependent on availability of the iNOS substrate L-arginine (L-Arg). We determined if spermine inhibits iNOS-mediated immunity by reducing L-Arg uptake into macrophages.