The Translation of Helicobacter pylori Basic Research to Patient Care Peter B. Ernst, David A. Peura, Sheila E. Crowe  Gastroenterology  Volume 130, Issue 1, Pages 188-206 (January 2006) DOI: 10.1053/j.gastro.2005.06.032 Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 1 Impact of H pylori discovery on the number of publications found in PubMed. This figure shows the number of publications found in the National Library of Medicine literature search engine PubMed for each year since the original report by Marshall and Warren in 1984. The database was searched using the terms “pylori” or “pyloridis” for each year, while a search on “Marshall” and “Warren” was used for 1984. The 1677 reports in 2004 are compared with the following searches for the same year: rotavirus, 282; inflammatory bowel disease or IBD, 1998; HCV or hepatitis C, 3124; HIV, 10,406. The data for 2005 represent a partial year. Gastroenterology 2006 130, 188-206DOI: (10.1053/j.gastro.2005.06.032) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 2 Proposed pathogenesis for gastric cancer associated with H pylori infection. Dr P. Correa is credited with proposing the progression of gastritis to gastric cancer, which became even more relevant when H pylori was identified as a major cause of gastritis. The model has been modified from what has been described elsewhere.26,29 Because not everyone infected with H pylori develops gastric cancer, several modifiers have been identified. Currently, the perception is that gastric cancer arises from multiple “hits” that include oxidative stress and environmental toxins, which increase mutation rates. Diet, bacterial factors, and genes regulating the host response likely affect the degree of oxidative stress and DNA damage. Once key genes are mutated, the enhanced epithelial growth associated with infection drives the tumor proliferation. The percentages represent estimates from various studies, while the modifiers reflect many reports, including several cited in the text. Gastroenterology 2006 130, 188-206DOI: (10.1053/j.gastro.2005.06.032) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 3 H pylori infection displays a preferential tropism for gastric epithelium. This figure shows photomicrographs of human gastric antral biopsy specimens stained with the modified Genta stain. The left panel shows a lower-power magnification of the tissue with the metaplastic mucus-producing cells indicated in blue. At higher power (right panel), H pylori can be seen adjacent to the gastric epithelium (arrows). The numbers of bacteria are significantly greater in the areas devoid of metaplastic cells. Stained slides provided courtesy of Drs D. Graham and H. El-Zimaity. Gastroenterology 2006 130, 188-206DOI: (10.1053/j.gastro.2005.06.032) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 4 Potential interactions between H pylori and gastric epithelial cells. This figure summarizes the best-known interactions between bacterial products and host cell receptors that have been described in the text. Any of these potential interactions could enhance bacterial binding, although secreted bacterial products may also engage the receptors. These interactions allow the epithelial cell to transduce a signal to the host, indicating that a luminal infection is present that may represent some danger. One aspect that is evident is that few bacterial/epithelial cell interactions have been validated in vivo or linked to specific signaling pathways that result in a known epithelial cell response. It is also evident that no single pathway is responsible for all changes in epithelial cell responses. Furthermore, it is clear that the bacterial effects on epithelial cell signaling are insufficient to explain the magnitude of gastritis and the local or systemic consequences that are attributed to H pylori. Hence, these interactions complement the effects of cytokines, neuroendocrine influences, and other signals emanating from the lamina propria. ROS, reactive oxygen species; PG, peptidoglycan; cagA-P, the phosphorylated form of cagA; PMN, polymorphonuclear cell; mϕ, macrophage. Gastroenterology 2006 130, 188-206DOI: (10.1053/j.gastro.2005.06.032) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 5 Signaling responses of gastric epithelial cells during H pylori infection. Several signaling pathways have been studied using intact organisms or specific bacterial products. Substantial crosstalk exists between the respective pathways triggered by bacteria or host response molecules. Some of the major events that have been characterized include the pathways involving the translocated CagA in the development of the hummingbird phenotype; the translocation of peptidoglycan (PG) into the cell where it interacts with NOD1; the differential role of the cag PAI in signal transduction; the effects of intact H pylori on ERK, p38, and c-Jun-N-terminal kinase MAPKs; and the role of oxidative stress (ROS, reactive oxygen species; RNS, reactive nitrogen species) in modifying transcription factors by reduction via redox factor-1 (ref-1), which reduces C-Jun to C-Jun-R. Together, these pathways provide specific targets for novel therapies that interfere with the control of phosphorylation, the transactivation by transcription factors, or the control of oxidative stress. cagA-P, the phosphorylated form of cagA; PMN, polymorphonuclear cell; SHP-2, Csk, MAPK, MAPPK, P38, and Erk are all signaling molecules. (See text for more details and references.) Gastroenterology 2006 130, 188-206DOI: (10.1053/j.gastro.2005.06.032) Copyright © 2006 American Gastroenterological Association Terms and Conditions

Figure 6 The immunopathogenesis of gastritis and epithelial cell damage. This figure shows the various means by which the gastric immune and inflammatory responses mediate epithelial cell damage. First, Th1 cells can directly induce epithelial cell death via Fas/FasL interactions. T-cell–derived cytokines not only enhance the induction of apoptosis but also up-regulate the expression of receptors such as class II HLA molecules, increase bacterial binding, and favor the induction of apoptosis by H pylori. In addition, Th1 cells complement the effects of H pylori by stimulating epithelial cells to produce cytokines that recruit and activate neutrophils (PMN) and/or macrophages (mϕ) or dendritic cells (DC). In turn, activated phagocytes impart an oxidative stress that damages epithelial cells and cellular DNA. Finally, gastric T cells can modulate B-cell responses, possibly leading to the production of autoantibodies. This includes those of the IgG class that can activate complement (C′) and contribute to immune complex–mediated inflammation. From this model, it is clear that genetic polymorphisms can increase the expression of cytokines that drive inflammation (ie, IL-1β, TNF-α, IL-8) or decrease the expression of those that prevent inflammation (ie, IL-10) and contribute to an increase in gastritis. Because gastritis is believed to favor the development of adenocarcinoma, it makes sense that polymorphisms in genes encoding these cytokines are associated with increased rates of gastric cancer. Genetic screening of the host for these and other polymorphisms may aid in our evaluation of the importance of residual H pylori infection rates in a population. Gastroenterology 2006 130, 188-206DOI: (10.1053/j.gastro.2005.06.032) Copyright © 2006 American Gastroenterological Association Terms and Conditions