Persistent colonization of the human stomach with the Gram-negative bacterium Helicobacter pylori is associated with an increased risk for the development of gastric adenocarcinoma. Gastric cancer is the second leading cause of cancer-related death worldwide, and H. pylori has been classified as a type I carcinogen by the World Health Organization. Among H. pylori-infected persons, the risk of gastric cancer is determined by multiple variables, including characteristics of H. pylori strains, host genetic characteristics, and environmental factors. The long-term goal of this work is to define the mechanisms by which H. pylori infection can lead to gastric cancer, and to develop improved approaches for identifying individuals who have an increased risk for gastric cancer. In previous studies, we have shown that persons infected with GagA? positive H. pylori strains have an increased gastric cancer risk compared to persons infected with GagA? negative strains. H. pylori-induced gastric cancer in the Mongolian gerbil model is GagA-dependent, and we have shown that both a high-salt diet and a low-iron diet increase the risk of gastric cancer in H. pylori? infected gerbils. Furthermore, we have shown that exposure of H. pylori to high-salt conditions stimulates upregulation of GagA production. In this project, we propose to investigate further the regulation of H. pylori virulence by dietary factors that impact gastric cancer.
Aim 1 proposes to define the roles of three salt? regulated H. pylori outer membrane proteins (HopQ and two VacA-Iike proteins) in gastric cancer development. We will use multiple experimental approaches, including conventional cell culture, gastric organ culture and gastric organoid culture, and the Mongolian gerbil model of H. pylori-induced gastric cancer.
Aim 2 will identify shared .features of the pathways by which a high-salt diet and a low-iron diet augment gastric cancer risk in the H. pylori-infected gerbil model.
Aim 3 will analyze regulation of salt? responsive H. pylori genes in vivo and analyze adaptation of H. pylori to a carcinogenic gastric environment.
These aims will interdigitate with work proposed in Projects 1 and 2 (which each focus on H. pylori-induced epithelial cell alterations) and will utilize both the Gastric Histopathology and Proteomics Cores. These studies should lead to important advances in our understanding of the molecular mechanisms by which H. pylori infection and relevant dietary factors promote the development of gastric cancer. Ultimately, these studies should lead to advances in the prevention and therapy of malignancies that develop in the setting of chronic inflammation.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-C (O1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Vanderbilt University Medical Center
United States
Zip Code
Noto, Jennifer M; Chopra, Abha; Loh, John T et al. (2018) Pan-genomic analyses identify key Helicobacter pylori pathogenic loci modified by carcinogenic host microenvironments. Gut 67:1793-1804
Butt, Julia; Blot, William J; Teras, Lauren R et al. (2018) Antibody Responses to Streptococcus Gallolyticus Subspecies Gallolyticus Proteins in a Large Prospective Colorectal Cancer Cohort Consortium. Cancer Epidemiol Biomarkers Prev 27:1186-1194
Shen, Xi; Liu, Liping; Peek, Richard M et al. (2018) Supplementation of p40, a Lactobacillus rhamnosus GG-derived protein, in early life promotes epidermal growth factor receptor-dependent intestinal development and long-term health outcomes. Mucosal Immunol 11:1316-1328
Mera, Robertino M; Bravo, Luis E; Camargo, M Constanza et al. (2018) Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial. Gut 67:1239-1246
Singh, Kshipra; Coburn, Lori A; Asim, Mohammad et al. (2018) Ornithine Decarboxylase in Macrophages Exacerbates Colitis and Promotes Colitis-Associated Colon Carcinogenesis by Impairing M1 Immune Responses. Cancer Res 78:4303-4315
Corley, Douglas A; Peek Jr, Richard M (2018) When Should Guidelines Change? A Clarion Call for Evidence Regarding the Benefits and Risks of Screening for Colorectal Cancer at Earlier Ages. Gastroenterology 155:947-949
Gobert, Alain P; Al-Greene, Nicole T; Singh, Kshipra et al. (2018) Distinct Immunomodulatory Effects of Spermine Oxidase in Colitis Induced by Epithelial Injury or Infection. Front Immunol 9:1242
Raghunathan, Krishnan; Foegeding, Nora J; Campbell, Anne M et al. (2018) Determinants of Raft Partitioning of the Helicobacter pylori Pore-Forming Toxin VacA. Infect Immun 86:
Scoville, Elizabeth A; Allaman, Margaret M; Brown, Caroline T et al. (2018) Alterations in Lipid, Amino Acid, and Energy Metabolism Distinguish Crohn's Disease from Ulcerative Colitis and Control Subjects by Serum Metabolomic Profiling. Metabolomics 14:
Sierra, Johanna C; Asim, Mohammad; Verriere, Thomas G et al. (2018) Epidermal growth factor receptor inhibition downregulates Helicobacter pylori-induced epithelial inflammatory responses, DNA damage and gastric carcinogenesis. Gut 67:1247-1260

Showing the most recent 10 out of 203 publications