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.
Lofgren
Jennifer L
JL
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Whary
Mark T
MT
Ge
Zhongming
Z
Muthupalani
Sureshkumar
S
Taylor
Nancy S
NS
Mobley
Melissa
M
Potter
Amanda
A
Varro
Andrea
A
Eibach
Daniel
D
Suerbaum
Sebastian
S
Wang
Timothy C
TC
Fox
James G
JG
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