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The Translation of Helicobacter pylori Basic Research to Patient Care

2006; Elsevier BV; Volume: 130; Issue: 1 Linguagem: Inglês

10.1053/j.gastro.2005.06.032

1528-0012

Peter B. Ernst, David A. Peura, Sheila E. Crowe,

Gastric Cancer Management and Outcomes

In 1984, Barry Marshall and Robin Warren proposed a role for bacterial infections in the pathogenesis of gastroduodenal disease, which triggered an avalanche of research intended to prove or disprove their theory. The result has been a series of advances that have enhanced our understanding of these diseases and completely modernized the clinical approach to their management. In just over 20 years, many aspects of the immunopathogenesis of these diseases have been dissected at the molecular level, with key pathogenic mechanisms being validated by the identification of genes that are associated with the development of gastric cancer. There has been particular emphasis on understanding the molecular structures associated with Helicobacter pylori and their role in modifying the host responses. Gastric immune and inflammatory responses have emerged as key elements in the pathogenesis of gastritis and epithelial cell damage. This review summarizes important findings emanating from basic research primarily related to the immunopathogenesis of H pylori that have advanced the practice of medicine or our understanding of gastroduodenal disease. In 1984, Barry Marshall and Robin Warren proposed a role for bacterial infections in the pathogenesis of gastroduodenal disease, which triggered an avalanche of research intended to prove or disprove their theory. The result has been a series of advances that have enhanced our understanding of these diseases and completely modernized the clinical approach to their management. In just over 20 years, many aspects of the immunopathogenesis of these diseases have been dissected at the molecular level, with key pathogenic mechanisms being validated by the identification of genes that are associated with the development of gastric cancer. There has been particular emphasis on understanding the molecular structures associated with Helicobacter pylori and their role in modifying the host responses. Gastric immune and inflammatory responses have emerged as key elements in the pathogenesis of gastritis and epithelial cell damage. This review summarizes important findings emanating from basic research primarily related to the immunopathogenesis of H pylori that have advanced the practice of medicine or our understanding of gastroduodenal disease. Gastric secretions have evolved to facilitate the acid and peptic degradation of luminal contents. This environment precludes successful colonization by most microorganisms, but Helicobacter pylori has adapted to survive in this niche. Epidemiologic studies have provided convincing evidence that H pylori is associated with, and indeed responsible for, several gastroduodenal diseases, including a generally benign, subclinical gastritis, peptic ulcers, and gastric cancer.1Ernst P.B. Gold B. The disease spectrum of H. pylorithe immunopathogenesis of gastroduodenal ulcer and gastric cancer. 54th ed. Annual Reviews, Palo Alto, CA2000: 615-640Google Scholar, 2Uemura N. Okamoto S. Yamamoto S. Matsumura N. Yamaguchi S. Yamakido M. Taniyama K. Sasaki N. Schlemper R.J. Helicobacter pylori infection and the development of gastric cancer.N Engl J Med. 2001; 345: 784-789Crossref PubMed Scopus (2208) Google Scholar, 3Correa P. Bacterial infections as a cause of cancer.J Natl Cancer Inst. 2003; 95: E3Crossref PubMed Google Scholar, 4Blaser M.J. Atherton J.C. Helicobacter pylori persistence biology and disease.J Clin Invest. 2004; 113: 321-333Crossref PubMed Google Scholar, 5Parsonnet J. Forman D. Helicobacter pylori infection and gastric cancer—for want of more outcomes.JAMA. 2004; 291: 244-245Crossref PubMed Scopus (29) Google ScholarOur understanding of this organism began in earnest in 1984, when Marshall and Warren suggested that gastric “curved bacilli” were associated with gastritis and peptic ulceration.6Marshall B.J. Warren J.R. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration.Lancet. 1984; 8390: 1311-1315Abstract Google Scholar It was subsequently learned that clearance of infection offered a permanent cure for most ulcerogenic diseases. From 1984 to 1989, the number of publications on this subject was relatively limited; however, the subsequent rate of productivity has averaged more than 1700 reports per year for the past 10 years (Figure 1). The efforts of Marshall and Warren changed the practice of medicine and, in 2005, their leadership in this area was recognized with them being awarded the Nobel Prize in Physiology or Medicine. This review samples the vast volume of literature to highlight some of the important scientific advances relating the impact of the initial observation by Marshall and Warren to the management of diseases triggered by chronic infection with H pylori. In addition, we discuss some of the areas in which ongoing scientific investigations related to Helicobacter spp may enhance our ability to prevent or treat diseases of the digestive tract.The Benefits of Simply Being Able to Grow the BacteriumThe initial advance that facilitated the explosion of research related to H pylori was the development of methods to culture the organism. Soon after, it was shown that intentional infection of a volunteer (Dr Marshall) led to gastritis that resolved after antibiotic therapy.7Marshall B.J. Armstrong J.A. McGechie D.B. Glancy R.J. Attempt to fulfill Koch’s postulates for pyloric Campylobacter.Med J Aust. 1985; 142: 436-439Crossref PubMed Google Scholar The classic approach to bacteriology demonstrated that H pylori is a gram-negative, flagellated organism that produces a number of enzymes, including catalase and urease, that help neutralize host responses and favor colonization.8Kavermann H. Burns B.P. Angermuller K. Odenbreit S. Fischer W. Melchers K. Haas R. Identification and characterization of Helicobacter pylori genes essential for gastric colonization.J Exp Med. 2003; 197: 813-822Crossref PubMed Scopus (150) Google Scholar, 9Guo B.P. Mekalanos J.J. Rapid genetic analysis of Helicobacter pylori gastric mucosal colonization in suckling mice.Proc Natl Acad Sci U S A. 2002; 99: 8354-8359Crossref PubMed Scopus (28) Google Scholar One of the early benefits gained from this basic research was the demonstration that urease is produced by virtually all strains of H pylori. This led to the development of more effective and reliable diagnostic tests, including the rapid urease CLO test and the13C-urea breath test. A stool antigen test has also emerged as an informative, noninvasive means with which to diagnose infection.10Suerbaum S. Michetti P. Helicobacter pylori infection.N Engl J Med. 2002; 347: 1175-1186Crossref PubMed Scopus (1347) Google Scholar In addition, the ability to culture H pylori provided a diagnostic test that allowed assessment of antibiotic sensitivity.In the more detailed basic research investigations into the genome of H pylori that followed, the bacterium was shown to have tremendous genetic diversity.11Suerbaum S. Smith J.M. Bapumia K. Morelli G. Smith N.H. Kunstmann E. Dyrek I. Achtman M. Free recombination within Helicobacter pylori.Proc Natl Acad Sci U S A. 1998; 95: 12619-12624Crossref PubMed Scopus (387) Google Scholar, 12Salama N. Guillemin K. McDaniel T.K. Sherlock G. Tompkins L. Falkow S. A whole-genome microarray reveals genetic diversity among Helicobacter pylori strains.Proc Natl Acad Sci U S A. 2000; 97: 14668-14673Crossref PubMed Scopus (442) Google Scholar, 13Israel D.A. Salama N. Krishna U. Rieger U.M. Atherton J.C. Falkow S. Peek Jr, R.M. Helicobacter pylori genetic diversity within the gastric niche of a single human host.Proc Natl Acad Sci U S A. 2001; 98: 14625-14630Crossref PubMed Scopus (227) Google Scholar, 14Falush D. Kraft C. Taylor N.S. Correa P. Fox J.G. Achtman M. Suerbaum S. Recombination and mutation during long-term gastric colonization by Helicobacter pyloriestimates of clock rates, recombination size, and minimal age.Proc Natl Acad Sci U S A. 2001; 98: 15056-15061Crossref PubMed Scopus (241) Google Scholar, 15Webb G.F. Blaser M.J. Dynamics of bacterial phenotype selection in a colonized host.Proc Natl Acad Sci U S A. 2002; 99: 3135-3140Crossref PubMed Scopus (36) Google Scholar Understanding the genetic heterogeneity of the species makes it possible to survey antibiotic-resistant genes using assays of DNA obtained from infected biopsy specimens; in the future, this may be possible from stool. Evaluating antibiotic resistance is particularly useful for the management of refractory infections, the incidence of which may increase because 10%–30% or more of the strains of H pylori tested are now recognized as being resistant to some of the more common treatment regimens.10Suerbaum S. Michetti P. Helicobacter pylori infection.N Engl J Med. 2002; 347: 1175-1186Crossref PubMed Scopus (1347) Google Scholar, 16Graham D.Y. Antibiotic resistance in Helicobacter pyloriimplications for therapy.Gastroenterology. 1998; 115: 1272-1277Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar, 17Megraud F. Resistance of Helicobacter pylori to antibiotics.Aliment Pharmacol Ther. 1997; 11: 43-53Crossref PubMed Google Scholar, 18Duck W.M. Sobel J. Pruckler J.M. Song Q. Swerdlow D. Friedman C. Sulka A. Swaminathan B. Taylor T. Hoekstra M. Griffin P. Smoot D. Peek R. Metz D.C. Bloom P.B. Goldschmidt S. Parsonnet J. Triadafilopoulos G. Perez-Perez G.I. Vakil N. Ernst P. Czinn S. Dunne D. Gold B.D. Antimicrobial resistance incidence and risk factors among Helicobacter pylori-infected persons, United States.Emerg Infect Dis. 2004; 10: 1088-1094Crossref PubMed Google Scholar These advances in diagnostics and therapy have changed the practice of gastroenterology and the impact this infection has on gastroduodenal disease, particularly in populations that can afford the costs of diagnosis and treatment.EpidemiologyMost new H pylori infections occur in children; however, in the absence of specific clinical signs associated with infection, the mode of transmission is difficult to define.1Ernst P.B. Gold B. The disease spectrum of H. pylorithe immunopathogenesis of gastroduodenal ulcer and gastric cancer. 54th ed. Annual Reviews, Palo Alto, CA2000: 615-640Google Scholar Vomitus, saliva, and feces are the presumed sources of direct transmission, particularly in crowded housing conditions. Generally, infection correlates inversely to socioeconomic conditions,19Graham D.Y. Malaty H.M. Evans D.G. Evans Jr, D.J. Klein P.D. Adam E. Epidemiology of Helicobacter pylori in an asymptomatic population in the United States. Effect of age, race, and socioeconomic status.Gastroenterology. 1991; 100: 1495-1501Abstract PubMed Google Scholar with lifetime infection rates in countries with a strong economy dropping toward 10%, while rates in countries with emerging economies approach 80%–90%.10Suerbaum S. Michetti P. Helicobacter pylori infection.N Engl J Med. 2002; 347: 1175-1186Crossref PubMed Scopus (1347) Google Scholar, 20Parsonnet J. The incidence of Helicobacter pylori infection.Aliment Pharmacol Ther. 1995; 9: 45-51PubMed Google Scholar, 21Frenck Jr, R.W. Clemens J. Helicobacter in the developing world.Microbes Infect. 2003; 5: 705-713Crossref PubMed Scopus (164) Google Scholar Once established, the infection almost invariably persists for life unless antibiotic therapy is administered.Most infected individuals experience asymptomatic gastritis, although recurrent gastroduodenal ulceration may occur in 10%–15% of the infected population. The incidence of gastric cancer is lower, with approximately 1% of infected individuals developing adenocarcinoma and even fewer experiencing gastric mucosa-associated lymphoid tissue lymphoma.1Ernst P.B. Gold B. The disease spectrum of H. pylorithe immunopathogenesis of gastroduodenal ulcer and gastric cancer. 54th ed. Annual Reviews, Palo Alto, CA2000: 615-640Google Scholar, 2Uemura N. Okamoto S. Yamamoto S. Matsumura N. Yamaguchi S. Yamakido M. Taniyama K. Sasaki N. Schlemper R.J. Helicobacter pylori infection and the development of gastric cancer.N Engl J Med. 2001; 345: 784-789Crossref PubMed Scopus (2208) Google Scholar, 3Correa P. Bacterial infections as a cause of cancer.J Natl Cancer Inst. 2003; 95: E3Crossref PubMed Google Scholar, 22Hansson L.E. Nyren O. Hsing A.W. Bergstrom R. Josefsson S. Chow W.H. Fraumeni Jr, J.F. Adami H.O. The risk of stomach cancer in patients with gastric or duodenal ulcer disease.N Engl J Med. 1996; 335: 242-249Crossref PubMed Scopus (398) Google Scholar, 23Zucca E. Bertoni F. Roggero E. Bosshard G. Cazzaniga G. Pedrinis E. Biondi A. Cavalli F. Molecular analysis of the progression from Helicobacter pylori-associated chronic gastritis to mucosa-associated lymphoid-tissue lymphoma of the stomach.N Engl J Med. 1998; 338: 804-810Crossref PubMed Scopus (174) Google Scholar, 24Fischbach W. Dragosics B. Kolve-Goebeler M.E. Ohmann C. Greiner A. Yang Q. Bohm S. Verreet P. Horstmann O. Busch M. Duhmke E. Muller-Hermelink H.K. Wilms K. Allinger S. Bauer P. Bauer S. Bender A. Brandstatter G. Chott A. Dittrich C. Erhart K. Eysselt D. Ellersdorfer H. Ferlitsch A. Fridrik M.A. Gartner A. Hausmaninger M. Hinterberger W. Hugel K. Ilsinger P. Jonaus K. Judmaier G. Karner J. Kerstan E. Knoflach P. Lenz K. Kandutsch A. Lobmeyer M. Michlmeier H. Mach H. Marosi C. Ohlinger W. Oprean H. Pointer H. Pont J. Salabon H. Samec H.J. Ulsperger A. Wimmer A. Wewalka F. The German-Austrian Gastrointestinal Lymphoma Study GroupPrimary gastric B-cell lymphoma results of a prospective multicenter study.Gastroenterology. 2000; 119: 1191-1202Abstract Full Text Full Text PDF PubMed Scopus (166) Google Scholar, 25Ekstrom A.M. Held M. Hansson L.E. Engstrand L. Nyren O. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection.Gastroenterology. 2001; 121: 784-791Abstract Full Text Full Text PDF PubMed Google Scholar H pylori is now recognized as the major trigger for a sequence of phenotypic changes in the gastric mucosa, progressing from inflammation to superficial gastritis, chronic atrophic gastritis, intestinal metaplasia, dysplasia, and finally carcinoma26Correa P. Human gastric carcinogenesis a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention.Cancer Res. 1992; 52: 6735-6740PubMed Google Scholar (Figure 2). A recent study has even suggested that the presence of H pylori is necessary for the development of noncardia gastric cancer.27Brenner H. Arndt V. Stegmaier C. Ziegler H. Rothenbacher D. Is Helicobacter pylori infection a necessary condition for noncardia gastric cancer?.Am J Epidemiol. 2004; 159: 252-258Crossref PubMed Scopus (122) Google Scholar Another very provocative study suggests that gastric cancer in animal models infected with Helicobacter spp is unique in that the malignant stem cells emerge from a pool of bone marrow–derived precursors that are recruited during the infection.28Houghton J. Stoicov C. Nomura S. Rogers A.B. Carlson J. Li H. Cai X. Fox J.G. Goldenring J.R. Wang T.C. Gastric cancer originating from bone marrow-derived cells.Science. 2004; 306: 1568-1571Crossref PubMed Scopus (754) Google ScholarFigure 2Proposed 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.26Correa P. Human gastric carcinogenesis a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention.Cancer Res. 1992; 52: 6735-6740PubMed Google Scholar, 29Dixon M.F. Genta R.M. Yardley J.H. Correa P. Classification and grading of gastritis. The updated Sydney System.Am J Surg Pathol. 1996; 20: 1161-1181Crossref PubMed Scopus (2940) Google Scholar 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.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Studies that examined the impact of strain variation on inflammation and disease have yielded several interesting associations (discussed in more detail in the following text). Nonetheless, the predictive value of specific bacterial factors for disease outcome remains limited, with most “virulent” strains being found in asymptomatic subjects. The variation in the host response also affects outcome of infection, as evidenced by genetic studies in humans suggesting that mutations leading to an increase in gastric immune/inflammatory responses are associated with gastric cancer.30El-Omar E.M. Rabkin C.S. Gammon M.D. Vaughan T.L. Risch H.A. Schoenberg J.B. Stanford J.L. Mayne S.T. Goedert J. Blot W.J. Fraumeni Jr, J.F. Chow W.H. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms.Gastroenterology. 2003; 124: 1193-1201Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar, 31Macarthur M. Hold G.L. El-Omar E.M. Inflammation and cancer II. Role of chronic inflammation and cytokine gene polymorphisms in the pathogenesis of gastrointestinal malignancy.Am J Physiol Gastrointest Liver Physiol. 2004; 286: G515-G520Crossref PubMed Google Scholar The evidence accumulated thus far therefore indicates that the pathogenesis of disease associated with this infection is multifactorial.Generally, epidemiologic studies have focused on the deleterious effects of infection with H pylori. Nonetheless, some reports suggest that the historical persistence in humans has led to a degree of protection from diarrheal infections32Perry S. Sanchez L. Yang S. Haggerty T.D. Hurst P. Parsonnet J. Helicobacter pylori and risk of gastroenteritis.J Infect Dis. 2004; 190: 303-310Crossref PubMed Scopus (22) Google Scholar and possibly adenocarcinomas of the esophagus; however, these latter associations are provocative and not universally reproducible.33Bhan M.K. Bahl R. Sazawal S. Sinha A. Kumar R. Mahalanabis D. Clemens J.D. Association between Helicobacter pylori infection and increased risk of typhoid fever.J Infect Dis. 2002; 186: 1857-1860Crossref PubMed Scopus (31) Google Scholar, 34Clemens J. Albert M.J. Rao M. Qadri F. Huda S. Kay B. van Loon F.P. Sack D. Pradhan B.A. Sack R.B. Impact of infection by Helicobacter pylori on the risk and severity of endemic cholera.J Infect Dis. 1995; 171: 1653-1656Crossref PubMed Google Scholar, 35Fox J.G. Wang T.C. Helicobacter pylori—not a good bug after all!.N Engl J Med. 2001; 345: 829-832Crossref PubMed Scopus (72) Google Scholar While interesting and potentially important, the epidemiologic associations need the support of some mechanistic studies to definitively prove or disprove the theory that H pylori infection may have once had or indeed still has a benefit to an infected population that outweighs its known detrimental effects.The Ecology and Pathogenesis of Gastroduodenal Disease Associated With H pylori InfectionColonizationThe conundrum that quickly emerged in H pylori research was how an infection that resides predominantly in the lumen could mediate the gastritis and epithelial cell diseases associated with the infection. The description of the genome of 2 distinct strains of H pylori represents a major advance in our understanding of the ecology of the organism that can impact the pathogenesis and treatment of disease associated with this infection.4Blaser M.J. Atherton J.C. Helicobacter pylori persistence biology and disease.J Clin Invest. 2004; 113: 321-333Crossref PubMed Google Scholar, 36Lee A. The Helicobacter pylori genome—new insights into pathogenesis and therapeutics.N Engl J Med. 1998; 338: 832-833Crossref PubMed Scopus (14) Google Scholar Using this technology, investigators have generated microarrays that display the entire H pylori genome, thereby enabling the examination of the genes expressed by the bacteria in the context of varying physiologic or pathologic conditions. For example, this type of approach has shown that the bacterial genes that are turned on in the human gastric mucosa differ from the pattern observed in vitro.37Graham J.E. Peek Jr, R.M. Krishna U. Cover T.L. Global analysis of Helicobacter pylori gene expression in human gastric mucosa.Gastroenterology. 2002; 123: 1637-1648Abstract Full Text Full Text PDF PubMed Google Scholar This aspect of the bacterial ecology and phenotypic flexibility reinforces the importance of validating observations made in model systems against the events that transpire in the human gastric mucosa.The gene expression approach has also been used by Merrell et al to examine changes in H pylori gene expression following exposure to low pH.38Merrell D.S. Goodrich M.L. Otto G. Tompkins L.S. Falkow S. pH-regulated gene expression of the gastric pathogen Helicobacter pylori.Infect Immun. 2003; 71: 3529-3539Crossref PubMed Scopus (146) Google Scholar Pursuing the “cat on the hot tin roof” hypothesis, these investigators observed a response to this ecologic niche that was manifest by an increase in the expression of genes encoding proteins involved in the motility apparatus. The changes in the motility of H pylori were complemented by an increase in the expression of genes encoding urease and proteins associated with the optimal function of this enzyme.The urease produced by H pylori reflects the adaptation of the organism to the gastric milieu in that this enzyme functions optimally at 2 different pH values: one being the predictable pH 7.2 and the other pH 3.39Mobley H.L.T. Hu L.-T. Foxall P.A. Helicobacter pylori urease properties and role in pathogenesis.Scand J Gastroenterol. 1991; 26: 39-46Crossref Google Scholar Because this enzyme functions well at a low pH, it was originally proposed that urease reached the extracellular environment, where it could metabolize urea to NH3, which in turn would buffer protons in the gastric lumen.40Phadnis S.H. Parlow M.H. Levy M. Ilver D. Caulkins C.M. Connors J.B. Dunn B.E. Surface localization of a Helicobacter pylori urease and heat shock protein homolog requires bacterial lysis.Infect Immun. 1995; 64: 905-912Google Scholar However, Scott et al suggested that the main function of the enzyme occurs within the bacteria to generate ammonia ions, which buffer H+ ions as they reach the cytoplasm of the organism.41Scott D.R. Weeks D. Hong C. Postius S. Melchers K. Sachs G. The role of internal urease in acid resistance of Helicobacter pylori.Gastroenterology. 1998; 114: 58-70Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar, 42Scott D.R. Marcus E.A. Weeks D.L. Sachs G. Mechanisms of acid resistance due to the urease system of Helicobacter pylori.Gastroenterology. 2002; 123: 187-195Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Thus, upon infection, H pylori adapts to the gastric pH, both by producing the molecular machinery required to neutralize the acid and by rapidly migrating to the relatively safe confines beneath the mucus blanket. In this niche, H pylori enjoys the same cytoprotective mechanisms that are essential for the maintenance of structural integrity and function of the host epithelium. Moreover, the organism is well equipped to continue to adapt to changes in this niche, as is thoroughly discussed by Blaser and Atherton.4Blaser M.J. Atherton J.C. Helicobacter pylori persistence biology and disease.J Clin Invest. 2004; 113: 321-333Crossref PubMed Google Scholar Several other reviews that focus on the bacterial factors and their role in colonization and disease are available.4Blaser M.J. Atherton J.C. Helicobacter pylori persistence biology and disease.J Clin Invest. 2004; 113: 321-333Crossref PubMed Google Scholar, 39Mobley H.L.T. Hu L.-T. Foxall P.A. Helicobacter pylori urease properties and role in pathogenesis.Scand J Gastroenterol. 1991; 26: 39-46Crossref Google Scholar, 43Mobley H.L. Island M.D. Hausinger R.P. Molecular biology of microbial ureases.Microbiol Rev. 1995; 59: 451-480Crossref PubMed Google Scholar, 44Sachs G. Weeks D.L. Melchers K. Scott D.R. The gastric biology of Helicobacter pylori.Annu Rev Physiol. 2003; 65: 349-369Crossref PubMed Scopus (86) Google Scholar The importance of studying these fundamental issues in bacteriology arises from the potential therapeutic opportunities associated with targeting molecules such as urease, which are essential for effective colonization and survival.H pylori shows a strict tropism for the gastric mucosa or sites in which there is gastric metaplasia. This ecologic niche may reflect positive selection by gastric epithelial cells, for example, the tissue-specific expression of receptors. The corollary is also true, because H pylori does not colonize epithelium in the stomach that has undergone intestinal metaplasia (Figure 3). Two possible mechanisms that could cause this are the loss of tropic factors or the production by intestinal epithelial cells of antimicrobial factors that select against colonization. The latter possibility is supported by the fact that H pylori rarely colonizes the deeper portions of the gastric glandular mucosa, where O-glycans that impair H pylori growth are found.45Kawakubo M. Ito Y. Okimura Y. Kobayashi M. Sakura K. Kasama S. Fukuda M.N. Fukuda M. Katsuyama T. Nakayama J. Natural antibiotic function of a human gastric mucin against Helicobacter pylori infection.Science. 2004; 305: 1003-1006Crossref PubMed Scopus (168) Google ScholarFigure 3H 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.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Some reports suggest that β-defensin type 246O’Neil D.A. Cole S.P. Martin-Porter E. Housley M.P. Liu L. Ganz T. Kagnoff M.F. Regulation of human beta-defensins by gastric epithelial cells in response to infection with Helicobacter pylori or stimulation with interleukin-1.Infect Immun. 2000; 68: 5412-5415Crossref PubMed Scopus (86) Google Scholar, 47Hamanaka Y. Nakashima M. Wada A. Ito M. Kurazono H. Hojo H. Nakahara Y. Kohno S. Hirayama T. Sekine I. Expression of human beta-defensin 2 (hBD-2) in Helicobacter pylori induced gastritis antibacterial effect of hBD-2 against Helicobacter pylori.Gut. 2001; 49: 481-487Crossref PubMed Scopus (65) Google Scholar and LL-3748Hase K. Murakami M. Iimura M. Cole S.P. Horibe Y. Ohtake T. Obonyo M. Gallo R.L. Eckmann L. Kagnoff M.F. Expression of LL-37 by human gastric epithelial cells as a potential host defense mechanism against Helicobacter pylori.Gastroenterology. 2003; 125: 1613-1625Abstract Full Text Full Text PDF PubMed Scopus (110) Google Scholar are expressed at higher levels in gastric epithelial cells in response to infection or inflammatory cytokines. These observations suggest that H pylori infection manipulates the expression of antimicrobial factors to protect its own gastric niche by either limiting its own proliferation or inhibiting the growth of other species of bacteria that may compete for the same niche. This ability to control the antibacterial factors in its own ecologic niche is supported by another study showing that H pylori decreases the expression of the antibacterial molecule secretory leukocyte protease inhibitor.49Wex T. Treiber G. Nilius M. Vieth M. Roessner A. Malfertheiner P. Helicobacter pylori-mediated gastritis induces local downregulation of secretory leukocyte protease inhibitor in the antrum.Infect Immun. 2004; 72: 2383-2385Crossref PubMed Scopus (13) Google Scholar This response may remove an element of the host response that would be detrimental to the persistent infection of H pylori. The controlled expression of any putative antimicrobial factor by epithelial cells could provide a novel therapeutic approach for vaccine-based therapies.The cag Pathogenicity IslandOnce H pylori has migrated to the gastric epithelium, one can postulate that the organism attaches to host cells and damages them to obtain nutrients from the subsequent inflammatory exudate or transudate (Figure 4). The most studied interaction between the bacteria and gastric epithelium involves a segment of bacterial DNA referred to as the cag pathogenicity island (PAI). Genes within the cag PAI encode proteins that provide a type IV secretion apparatus (ie, cagE), which allows bacterial macromolecules to translocate into the host cell (ie, cagA).4Blaser M.J. Atherton J.C. Helicobacter pylori persistence biology and disease.J Clin Invest. 2004; 113: 321-333Crossref PubMed Google Scholar, 50Naumann M.