Gastric colonisation with a restricted commensal microbiota replicates the promotion of neoplastic lesions by diverse intestinal microbiota in the Helicobacter pylori INS-GAS mouse model of gastric carcinogenesis
- Kvin Lertpiriyapong1,
- Mark T Whary1,
- Sureshkumar Muthupalani1,
- Jennifer L Lofgren1,
- Eric R Gamazon2,
- Yan Feng1,
- Zhongming Ge1,
- Timothy C Wang3,
- James G Fox1
- 1Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
- 2Section of Genetic Medicine, Department of Medicine, The University of Chicago, Chicago, Illinois, USA
- 3Division of Digestive and Liver Diseases, College of Physicians and Surgeons, Columbia University, New York, New York, USA
- Correspondence to Dr James G Fox, Division of Comparative Medicine, Massachusetts Institute of Technology, Building 16-825c, 77 Massachusetts Avenue, Cambridge, MA 02139, USA;
- Received 30 April 2013
- Revised 3 June 2013
- Accepted 4 June 2013
- Published Online First 28 June 2013
Objectives Gastric colonisation with intestinal flora (IF) has been shown to promote Helicobacter pylori (Hp)-associated gastric cancer. However, it is unknown if the mechanism involves colonisation with specific or diverse microbiota secondary to gastric atrophy.
Design Gastric colonisation with Altered Schaedler's flora (ASF) and Hp were correlated with pathology, immune responses and mRNA expression for proinflammatory and cancer-related genes in germ-free (GF), Hp monoassociated (mHp), restricted ASF (rASF; 3 species), and specific pathogen-free (complex IF), hypergastrinemic INS-GAS mice 7 months postinfection.
Results Male mice cocolonised with rASFHp or IFHp developed the most severe pathology. IFHp males had the highest inflammatory responses, and 40% developed invasive gastrointestinal intraepithelial neoplasia (GIN). Notably, rASFHp colonisation was highest in males and 23% developed invasive GIN with elevated expression of inflammatory biomarkers. Lesions were less severe in females and none developed GIN. Gastritis in male rASFHp mice was accompanied by decreased Clostridum species ASF356 and Bacteroides species ASF519 colonisation and an overgrowth of Lactobacillus murinus ASF361, supporting that inflammation-driven atrophy alters the gastric niche for GI commensals. Hp colonisation also elevated expression of IL-11 and cancer-related genes, Ptger4 and Tgf-β, further supporting that Hp infection accelerates gastric cancer development in INS-GAS mice.
Conclusions rASFHp colonisation was sufficient for GIN development in males, and lower GIN incidence in females was associated with lower inflammatory responses and gastric commensal and Hp colonisation. Colonisation efficiency of commensals appears more important than microbial diversity and lessens the probability that specific gastrointestinal pathogens are contributing to cancer risk.