Evaluation of Lineage Changes in the Gastric Mucosa Following Infection With Helicobacter pylori and Specified Intestinal Flora in INS-GAS Mice

J Histochem Cytochem. 2019 Jan;67(1):53-63. doi: 10.1369/0022155418785621. Epub 2018 Jul 3.


Gastric adenocarcinoma develops in metaplastic mucosa associated with Helicobacter pylori infection in the stomach. We have sought to evaluate the precise lineage changes in the stomachs of insulin-gastrin (INS-GAS) mice infected with H. pylori and/or intestinal flora (Altered Schaedler's Flora; ASF). Stomachs from groups infected with H. pylori contained progressive spasmolytic polypeptide-expressing metaplasia (SPEM) compared with germ-free and mice infected with ASF alone. The overall phenotype of the H. pylori-infected mice was dominated by Ulex europaeus lectin (UEAI)-positive foveolar hyperplasia that was distinct from GSII/CD44v9-positive SPEM. However, in the mice with H. pylori co-infected with ASF, we identified a subpopulation of UEAI-positive foveolar cells that co-expressed intestinal mucin 4 (MUC4). These regions of foveolar cells were variably positive for CD44v9 as well as TFF3. Interestingly, an intravascular lesion identified in a dual H. pylori/ASF-infected mouse expressed both UEAI and Muc4. Finally, we identified an increase in the number of tuft cells within the mucosa of H. pylori-infected groups. Our findings suggest that H. pylori infection promotes foveolar hyperplasia as well as metaplasia, while co-infection may promote progressive foveolar and metaplastic lesions as well as dysplasia. Grading of gastric lesions in mice as preneoplastic requires multiple immunostaining markers to assign lineage derivation and behavior.

Keywords: CD44; MUC4; SPEM; carcinogenesis; foveolar hyperplasia; gastric; invasion; metaplasia.

Publication types

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

MeSH terms

  • Adenocarcinoma / microbiology
  • Adenocarcinoma / pathology
  • Animals
  • Doublecortin-Like Kinases
  • Gastric Mucosa / microbiology
  • Gastric Mucosa / pathology*
  • Gastrointestinal Microbiome
  • Helicobacter Infections / microbiology
  • Helicobacter Infections / pathology*
  • Helicobacter pylori / isolation & purification*
  • Helicobacter pylori / physiology
  • Hyaluronan Receptors / analysis
  • Immunohistochemistry
  • Intercellular Signaling Peptides and Proteins / analysis
  • Male
  • Mice
  • Mucin-4 / analysis
  • Protein Serine-Threonine Kinases / analysis
  • Stomach Neoplasms / microbiology
  • Stomach Neoplasms / pathology


  • Hyaluronan Receptors
  • Intercellular Signaling Peptides and Proteins
  • Muc4 protein, mouse
  • Mucin-4
  • spasmolytic polypeptide
  • Doublecortin-Like Kinases
  • Dclk1 protein, mouse
  • Protein Serine-Threonine Kinases