Lack of Commensal Flora in Helicobacter pylori –Infected INS-GAS Mice Reduces Gastritis and Delays Intraepithelial Neoplasia

• Published in: Gastroenterology (New York, N.Y. 1943) Vol. 140; no. 1; pp. 210 - 220.e4
• Main Authors: Lofgren, Jennifer L, Whary, Mark T, Ge, Zhongming, Muthupalani, Sureshkumar, Taylor, Nancy S, Mobley, Melissa, Potter, Amanda, Varro, Andrea, Eibach, Daniel, Suerbaum, Sebastian, Wang, Timothy C, Fox, James G
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 2011
• Subjects: Adenocarcinoma - microbiology; Adenocarcinoma - pathology; Animals; Bacteroidetes - isolation & purification; Enteric Microbiota; Female; Gastric Adenocarcinoma; Gastrins - blood; Gastrins - genetics; Gastritis - complications; Gastritis - microbiology; Gastroenterology and Hepatology; Gastrointestinal Neoplasms - microbiology; Gastrointestinal Neoplasms - pathology; Germ-Free Life; Helicobacter Infections - complications; Helicobacter Infections - microbiology; Helicobacter pylori; Hypergastrinemic Mice; Inflammation Mediators - blood; Insulin - genetics; Male; Mice; Mice, Transgenic; Microbiome; Precancerous Conditions - microbiology; Precancerous Conditions - pathology; Sex Factors; INS-GAS; Gastric Adenocarcinoma; germfree; gastrointestinal intraepithelial neoplasia; Enteric Microbiota; SPF; GIN; Hypergastrinemic Mice; Microbiome; GF; transgenic insulin-gastrin; specific pathogen-free
• DOI: 10.1053/j.gastro.2010.09.048
• ISSN: 0016-5085

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.