Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia

Gastroenterology. 2011 Jan;140(1):210-20. doi: 10.1053/j.gastro.2010.09.048. Epub 2010 Oct 13.


Background & aims: Transgenic FVB/N insulin-gastrin (INS-GAS) mice have high circulating gastrin levels, and develop spontaneous atrophic gastritis and gastrointestinal intraepithelial neoplasia (GIN) with 80% prevalence 6 months after Helicobacter pylori infection. GIN is associated with gastric atrophy and achlorhydria, predisposing mice to nonhelicobacter microbiota overgrowth. We determined if germfree INS-GAS mice spontaneously develop GIN and if H pylori accelerates GIN in gnotobiotic INS-GAS mice.

Methods: We compared gastric lesions, levels of messenger RNA, serum inflammatory mediators, antibodies, and gastrin among germfree and H pylori-monoinfected INS-GAS mice. Microbiota composition of specific pathogen-free (SPF) INS-GAS mice was quantified by pyrosequencing.

Results: Germfree INS-GAS mice had mild hypergastrinemia but did not develop significant gastric lesions until 9 months old and did not develop GIN through 13 months. H pylori monoassociation caused progressive gastritis, epithelial defects, oxyntic atrophy, marked foveolar hyperplasia, dysplasia, and robust serum and tissue proinflammatory immune responses (particularly males) between 5 and 11 months postinfection (P<0.05, compared with germfree controls). Only 2 of 26 female, whereas 8 of 18 male, H pylori-infected INS-GAS mice developed low to high-grade GIN by 11 months postinfection. Stomachs of H pylori-infected SPF male mice had significant reductions in Bacteroidetes and significant increases in Firmicutes.

Conclusions: Gastric lesions take 13 months longer to develop in germfree INS-GAS mice than male SPF INS-GAS mice. H pylori monoassociation accelerated gastritis and GIN but caused less severe gastric lesions and delayed onset of GIN compared with H pylori-infected INS-GAS mice with complex gastric microbiota. Changes in gastric microbiota composition might promote GIN in achlorhydric stomachs of SPF mice.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / microbiology*
  • Adenocarcinoma / pathology
  • Animals
  • Bacteroidetes / isolation & purification
  • Female
  • Gastrins / blood
  • Gastrins / genetics
  • Gastritis / complications
  • Gastritis / microbiology*
  • Gastrointestinal Neoplasms / microbiology*
  • Gastrointestinal Neoplasms / pathology
  • Germ-Free Life
  • Helicobacter Infections / complications
  • Helicobacter Infections / microbiology*
  • Helicobacter pylori*
  • Inflammation Mediators / blood
  • Insulin / genetics
  • Male
  • Mice
  • Mice, Transgenic
  • Precancerous Conditions / microbiology*
  • Precancerous Conditions / pathology
  • Sex Factors


  • Gastrins
  • Inflammation Mediators
  • Insulin