Lack of commensal flora in Helicobacter pylori-infected INS-GAS mice reduces gastritis and delays intraepithelial neoplasia.
OBJECTIVE
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.
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Jennifer L
JL
Lofgren
Mark T
MT
Whary
Zhongming
Z
Ge
Sureshkumar
S
Muthupalani
Nancy S
NS
Taylor
Melissa
M
Mobley
Amanda
A
Potter
Andrea
A
Varro
Daniel
D
Eibach
Sebastian
S
Suerbaum
Timothy C
TC
Wang
James G
JG
Fox
D000230:Adenocarcinoma / Q000382:microbiology* / Q000473:pathology; D000818:Animals; D041963:Bacteroidetes / Q000302:isolation & purification; D005260:Female; D005755:Gastrins / Q000097:blood / Q000235:genetics; D005756:Gastritis / Q000150:complications / Q000382:microbiology*; D005770:Gastrointestinal Neoplasms / Q000382:microbiology* / Q000473:pathology; D005856:Germ-Free Life; D016481:Helicobacter Infections / Q000150:complications / Q000382:microbiology*; D016480:Helicobacter pylori; D018836:Inflammation Mediators / Q000097:blood; D007328:Insulin / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011230:Precancerous Conditions / Q000382:microbiology* / Q000473:pathology; D012737:Sex Factors
D005755:Gastrins; D018836:Inflammation Mediators; D007328:Insulin