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BIOLOGICAL SCIENCES / MICROBIOLOGY
Helicobacter pylori evolution during progression from chronic atrophic gastritis to gastric cancer and its impact on gastric stem cells
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*Center for Genome Sciences, Washington University School of Medicine, St. Louis, MO 63108; Department of Anatomy, Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain 17666, United Arab Emirates; Department of Microbiology, Tumor, and Cell Biology, Karolinska Institute, 171 77 Stockholm, Sweden; and Swedish Institute for Infectious Disease Control, 171 82 Solna, Sweden
Contributed by Jeffrey I. Gordon, January 22, 2008 (received for review December 5, 2007)
We have characterized the adaptations of Helicobacter pylori to a rarely captured event in the evolution of its impact on host biology—the transition from chronic atrophic gastritis (ChAG) to gastric adenocarcinoma—and defined the impact of these adaptations on an intriguing but poorly characterized interaction between this bacterium and gastric epithelial stem cells. Bacterial isolates were obtained from a single human host colonized with a single dominant strain before and after his progression from ChAG to gastric adenocarcinoma during a 4-year interval. Draft genome assemblies were generated from two isolates, one ChAG-associated, the other cancer-associated. The cancer-associated strain was less fit in a gnotobiotic transgenic mouse model of human ChAG and better able to establish itself within a mouse gastric epithelial progenitor-derived cell line (mGEP) that supports bacterial attachment. GeneChip-based comparisons of the transcriptomes of mGEPs and a control mouse gastric epithelial cell line revealed that, upon infection, the cancer-associated strain regulates expression of GEP-associated signaling and metabolic pathways, and tumor suppressor genes associated with development of gastric cancer in humans, in a manner distinct from the ChAG-associated isolate. The effects on GEP metabolic pathways, some of which were confirmed in gnotobiotic mice, together with observed changes in the bacterial transcriptome are predicted to support aspects of an endosymbiosis between this microbe and gastric stem cells. These results provide insights about how H. pylori may adapt to and influence stem cell biology and how its intracellular residency could contribute to gastric tumorigenesis.
microbial pathogenesis | intracellular bacteria | genome sequencing | functional genomics | gnotobiotic mice
Author contributions: M.G., S.L.C., and J.I.G. designed research; M.G. and S.L.C. performed research; S.M.K., L.E., and J.I.G. contributed new reagents/analytic tools; M.G., S.L.C., and J.I.G. analyzed data; and M.G., S.L.C., and J.I.G. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The GeneChip data reported in this paper have been deposited in the Gene Expression Omnibus (GEO) database, www.ncbi.nlm.nih.gov/geo (accession nos. GSE10261 and GSE10262). Whole Genome Shotgun projects have been deposited in NNA Data Bank of Japan, European Molecular Biology Laboratory Nucleotide Sequence Database, and GenBank [accession nos. ABJO00000000 (H. pylori Kx1) and ABJP00000000 (H. pylori Kx2)]. Genome assemblies used in this paper are the first versions [accession nos. ABJO01000000 (Kx1) and ABJP01000000 (Kx2)]. The raw sequence data used in this paper have been deposited in the GenBank Short Read Archive [accession nos. SRA000264 (Kx1) and SRA000265 (Kx2)].
This article contains supporting information online at www.pnas.org/cgi/content/full/0800668105/DC1.
¶To whom correspondence should be addressed. E-mail: jgordon{at}wustl.edu
© 2008 by The National Academy of Sciences of the USA
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