Helicobacter pylori and Esophageal Disease: Wake-up Call?
2010; Elsevier BV; Volume: 139; Issue: 6 Linguagem: Inglês
10.1053/j.gastro.2010.10.037
ISSN1528-0012
Autores Tópico(s)Gastroesophageal reflux and treatments
ResumoSee “A national study of Helicobacter pylori infection in gastric biopsy specimens,” by Sonnenberg A, Lash RH, Genta RM, on page 1894.The history of science is marked by the nature of discovery.1Kuhn T.S. The structure of scientific revolutions.in: The University of Chicago Press, Chicago1962: 1-172Google Scholar Sometimes, discoveries bias a field and it takes a long time for the true directions to emerge. This concept is particularly relevant to microbiology, because most of the bacteria of which physicians are aware are pathogens and were discovered owing to their link with disease: Mycobacterium tuberculosis, Vibrio cholerae, and Neisseria meningitis serve as examples. Yet most bacteria in the human body are commensals.2Turnbaugh P.J. Ley R.E. Hamady M. et al.The human microbiome project.Nature. 2007; 449: 804-810Crossref PubMed Scopus (3479) Google ScholarThe discovery of Helicobacter pylori in 1979–1982 by Marshall and Warren3Marshall BJ, Warren JR. The bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease. 2005 Nobel Prize in Physiology or Medicine.Google Scholar was a major event in the field of gastroenterology, recognized in many ways including the awarding of the 2005 Nobel Prize in Medicine. The initial discoveries of H pylori were as pathogen: an organism in the stomach that provoked an inflammatory response, called by pathologists “chronic gastritis,” and leading, as suspected by Marshall and Warren, to peptic ulceration,4Warren J.R. Marshall B.J. Unidentified curved bacilli on gastric epithelium in active chronic gastritis.Lancet. 1983; 1: 1273-1275PubMed Google Scholar, 5Marshall B.J. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration.Lancet. 1984; 1: 1311-1315Abstract PubMed Scopus (4173) Google Scholar and as later determined, to increased risk for intestinal metaplasia, atrophic gastritis, and gastric adenocarcinoma (reviewed in Peek and Blaser6Peek R.M. Blaser M.J. Helicobacter pylori and gastrointestinal tract adenocarcinomas.Nature Rev Cancer. 2002; 2: 28-37Crossref PubMed Scopus (1457) Google Scholar). After a strong body of work over the following decade, H pylori became established firmly as a human pathogen.7NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease.JAMA. 1994; 272: 65-69Crossref PubMed Scopus (1063) Google Scholar As a consequence, major pharmaceutical companies developed methods to ensure its eradication, and governmental agencies and foundations have sought ways to promote such strategies. Why not rid the world of a pathogen that clearly may lead to a serious and sometimes lethal disease, peptic ulceration, and to a very serious and common form of malignancy—gastric cancer? Indeed, why not?However, all mammals, even marine mammals, seem to have helicobacters residing in their stomachs,8Harper C.M.G. Feng Y. Xu S. Helicobacter cetorum sp. nov., a urease-positive Helicobacter species isolated from dolphins and whales.J Clin Microbiol. 2002; 40: 4536-4543Crossref PubMed Scopus (67) Google Scholar, 9Solnick J.V. Schauer D.B. Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases.Clin Microbiol Rev. 2001; 14: 59-97Crossref PubMed Scopus (325) Google Scholar and there is no evidence that any mammalian acid-producing stomach has evolved without their presence. In particular, H pylori has been colonizing the human stomach for ≥58,000 years, dating from the last out of Africa,10Linz B. Balloux F. Moodley Y. et al.An African origin for the intimate associate between humans and Helicobacter pylori.Nature. 2007; 445: 915-918Crossref PubMed Scopus (687) Google Scholar and probably much, much longer. Helicobacter pylori traveled with us as we have migrated to all corners of the world during prehistory.11Moodley Y. Linz B. Yamaoka Y. et al.The peopling of the Pacific from a bacterial perspective.Science. 2009; 323: 527-530Crossref PubMed Scopus (235) Google Scholar What are the implications of an ancestral gastric microbial colonization conserved over 100 million years of mammalian evolution? Might there not be some costs associated with changing such a longstanding relationship?In this issue of Gastroenterology, Sonnenberg et al12Sonnenberg A. Lash R.H. Genta R.M. A national study of Helicobacter pylori infection in gastric biopsy specimens.Gastroenterology. 2010; 139: 1894-1901Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar report on a large study based on >78,000 US patients who had had upper gastrointestinal endoscopy performed, and from whom histopathologic analysis of gastric biopsies was done. The investigators sought to ascertain the relationships between the presence of H pylori, chronic gastritis, and intestinal metaplasia with each other and with Barrett's esophagus. The results, reflecting the straightforward design and large scale of these studies, are clear cut. All 3 findings by the pathologists—the presence of H pylori, chronic gastritis, and intestinal metaplasia—were strongly correlated with each other, confirming many prior studies.13Kuipers E.J. Pena A.S. Meuwissen S.G.M. et al.Long-term sequelae of Helicobacter pylori gastritis.Lancet. 1995; 345: 1525-1528PubMed Scopus (720) Google Scholar, 14Ohkusa T. Fujiki K. Takashimizu I. et al.Improvement in atrophic gastritis and intestinal metaplasia in patients in whom Helicobacter pylori was eradicated.Ann Intern Med. 2001; 134: 380-386Crossref PubMed Scopus (198) Google Scholar However, Sonnenberg et al showed that all 3 findings were also inversely associated with Barrett's esophagus. The study was robust and internally consistent, so there is no doubt that the findings are correct. The important issue is how physicians, scientists, and patients should interpret these results.Barrett's esophagus is an intermediate lesion along the pathway between reflux esophagitis (also known as gastroesophageal reflux disease [GERD]) and esophageal adenocarcinoma (EAC).15Shaheen N. Ransahoff D.F. Gastroesophageal reflux, Barrett esophagus, and esophageal cancer: scientific review.JAMA. 2002; 287: 1972-1981Crossref PubMed Scopus (378) Google Scholar As with other pathogenetic sequences, relatively many individuals have GERD, fewer have Barrett's, and fewest develop EAC.15Shaheen N. Ransahoff D.F. Gastroesophageal reflux, Barrett esophagus, and esophageal cancer: scientific review.JAMA. 2002; 287: 1972-1981Crossref PubMed Scopus (378) Google Scholar Most important, GERD, Barrett's, EAC (and the closely related adenocarcinomas affecting the adjacent gastric cardia) each are increasing in epidemic proportions all over the developed world,16Lagergren J. Bergstrom R. Lindgren A. et al.Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma.N Eng J Med. 1999; 340: 825-831Crossref PubMed Scopus (2576) Google Scholar, 17Devesa S.S. Blot W.J. Fraumeni Jr, J.F. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States.Cancer. 1998; 83: 2049-2053Crossref PubMed Scopus (1951) Google Scholar, 18Pohl H. Welch H.G. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence.J Natl Cancer Inst. 2005; 97: 142-146Crossref PubMed Scopus (1082) Google Scholar, 19Bollschweiler E. Wolfgarten E. Gutschow C. et al.Demographic variations in the rising incidence of esophageal adenocarcinoma in white males.Cancer. 2001; 92: 549-555Crossref PubMed Scopus (404) Google Scholar, 20Bresalier R.S. Barrett's esophagus and esophageal adenocarcinoma.Ann Rev Med. 2009; 60: 221-231Crossref PubMed Scopus (17) Google Scholar and EAC is a terrible and difficult-to-treat form of cancer. These conditions, 1 nested within the other, arose in the mid-to-late 20th century and are continuing to climb in incidence.How do the findings of Sonnenberg et al12Sonnenberg A. Lash R.H. Genta R.M. A national study of Helicobacter pylori infection in gastric biopsy specimens.Gastroenterology. 2010; 139: 1894-1901Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar relate to these events? Is there a causal relationship between the inverse association of H pylori (and its related conditions), and Barrett's (and its related conditions), and if so, in which direction (A→B, or B→A)? Alternatively, do the findings reflect an underlying process affecting the risk of both (thus, C→A and C→B), or are they just spurious? The large scale and internal consistency of the Sonnenberg et al study argue that the findings are not artifactual. In fact, their findings confirm and extend many other studies over the last decade showing parallel relationships in different populations, and using different techniques of ascertainment.21Chow W.-H. Blaser M.J. Blot W.J. et al.An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma.Cancer Research. 1998; 58: 588-590PubMed Google Scholar, 22Ye W. Held M. Lagergren J. et al.Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia.J Natl Cancer Inst. 2004; 96: 388Crossref PubMed Scopus (305) Google Scholar, 23de Martel C. Llosa A.E. Farr S.M. et al.Helicobacter pylori infection and the risk of development of esophageal adenocarcinoma.J Infect Dis. 2005; 191: 761-767Crossref PubMed Scopus (97) Google Scholar, 24Islami F. Kamangar F. Helicobacter pylori and esophageal cancer risk: a meta-analysis.Cancer Prev Res. 2008; 1: 329-338Crossref PubMed Scopus (256) Google Scholar, 25Whiteman D.C. Parmer P. Fahey P. Association of Helicobacter pylori infection with reduced risk for esophageal cancer is independent of environmental and genetic modifiers.Gastroenterology. 2010; 139: 73-83Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar Although the Sonnenberg et al study was not designed to address the vectors and direction of causality, it should now be clear to all impartial observers that there truly is a reciprocal relationship between H pylori and Barrett's esophagus.How can the relationship be explained? Could GERD and related conditions be causing the loss of H pylori? This is highly unlikely, because GERD usually develops in adults but H pylori is acquired in early childhood. Could the absence of H pylori be predisposing to GERD? As most gastroenterologists know, once acquired, H pylori colonization generally persists for life.26Atherton J.C. Blaser M.J. Co-adaptation of Helicobacter pylori and humans: ancient history, modern implications.J Clin Invest. 2009; 119: 2475-2487Crossref PubMed Scopus (403) Google Scholar unless interrupted by antibiotic treatment or by the development of chronic atrophic gastritis very late in life. Thus, since time immemorial, H pylori has persistently colonized most of the world's population, essentially for their full lifetime26Atherton J.C. Blaser M.J. Co-adaptation of Helicobacter pylori and humans: ancient history, modern implications.J Clin Invest. 2009; 119: 2475-2487Crossref PubMed Scopus (403) Google Scholar; in most cases, however, its presence leads to no symptoms. Indeed, when what we now know as H pylori was recognized in the 19th century by German pathologists, it was essentially universal, and they concluded that it was not worth studying because it was a commensal.During the 20th century and now into the 21st century, the prevalence of this ancestral common human bacterium has been undergoing a precipitous decline in developed countries. Now, fewer than 6% of US children are carrying the organism,27Chen Y. Blaser M.J. Helicobacter pylori colonization is inversely associated with childhood asthma.J Infect Dis. 2008; 198: 553-560Crossref PubMed Scopus (283) Google Scholar and parallel phenomena are being observed across the developed world.28Segal I. Otley A. Issenman R. et al.Low prevalence of Helicobacter pylori in Canadian children: a cross-sectional analysis.Can J Gastroenterol. 2008; 22: 485-489PubMed Google Scholar, 29Rothenbacher D. Bode G. Berg G. et al.Prevalence and determinants of Helicobacter pylori infection in preschool children: a population-based study from Germany.Int J Epidemiol. 1998; 27: 135-141Crossref PubMed Scopus (96) Google Scholar Thus, over the course of a century, the ancient, persistent, nearly universal and dominant inhabitant30Bik E.M. Eckburg P.B. Gill S.R. et al.Molecular analysis of the bacterial microbiota in the human stomach.Proc Natl Acad Sci U S A. 2006; 103: 732-737Crossref PubMed Scopus (734) Google Scholar, 31Andersson A.F. Lindberg M. Jakobsson H. et al.Comparative analysis of human gut microbiota by barcoded pyrosequencing.PLoS ONE. 2008; 3: e2836Crossref PubMed Scopus (750) Google Scholar of the human stomach has been essentially disappearing. The reasons for its disappearance are manifold32Blaser M.J. Falkow S. What are the consequences of the disappearing human microbiota?.Nature Rev Microbiol. 2009; 7: 887-894Crossref PubMed Scopus (580) Google Scholar; regardless, its decline is continuing, and with effects throughout the world, while GERD and its sequelae are increasing.20Bresalier R.S. Barrett's esophagus and esophageal adenocarcinoma.Ann Rev Med. 2009; 60: 221-231Crossref PubMed Scopus (17) Google Scholar GERD was essentially first reported in the medical literature in the 1930s,33Winkelstein A. Peptic esophagitis: a new clinical entity.JAMA. 1935; 104: 906-909Crossref Scopus (125) Google Scholar Dr Norman Barrett first described metaplasia in the esophagus in the 1950s,34Barrett N.R. Chronic peptic ulcer of the oesophagus and “oesophagitis.”.Br J Surg. 1950; 38: 175-182Crossref PubMed Scopus (674) Google Scholar and the rise in EAC began to occur in the 1970s.17Devesa S.S. Blot W.J. Fraumeni Jr, J.F. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States.Cancer. 1998; 83: 2049-2053Crossref PubMed Scopus (1951) Google Scholar All of these trends have occurred as H pylori has been disappearing, and Sonnenberg et al12Sonnenberg A. Lash R.H. Genta R.M. A national study of Helicobacter pylori infection in gastric biopsy specimens.Gastroenterology. 2010; 139: 1894-1901Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar provide yet more evidence that this is a linked association.Interestingly, paralleling the inverse associations of H pylori and esophageal disease have come multiple reports of inverse associations with childhood-onset asthma,27Chen Y. Blaser M.J. Helicobacter pylori colonization is inversely associated with childhood asthma.J Infect Dis. 2008; 198: 553-560Crossref PubMed Scopus (283) Google Scholar, 35Chen Y. Blaser M.J. Inverse associations of Helicobacter pylori with asthma and allergies.Arch Intern Med. 2007; 167: 821-827Crossref PubMed Scopus (300) Google Scholar, 36Janson C. The effect of infection burden.J Allergy Clin Immunol. 2007; 120: 673-679Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar and protection from other infections,37Rothenbacher D. Blaser M.J. Bode G. et al.An inverse relationship between gastric colonization by Helicobacter pylori and diarrheal illnesses in children: results of a population-based cross-sectional study.J Infect Dis. 2000; 182: 1446-1449Crossref PubMed Scopus (72) Google Scholar, 38Chang A.H. Haggerty T.D. de Martel C. et al.Effect of Helicobacter pylori infection on symptoms of gastroenteritis due to enterohepatic Escherichia coli in adults.Dig Dis Sci. 2010 Jul 16; ([Epub ahead of print])Google Scholar or their reactivation.39Perry S. de Jon B.C. Solnick J.V. et al.Infection with Helicobacter pylori is associated with protection against tuberculosis.PLoS One. 2010; 51: e8804Crossref Scopus (118) Google Scholar Because the stomach produces 2 hormones, leptin and ghrelin, centrally involved in human energy homeostasis,40Mix H. Widjaja A. Jandl O. et al.Expression of leptin and leptin receptor isoforms in the human stomach.Gut. 2000; 47: 481-486Crossref PubMed Scopus (166) Google Scholar, 41Inui A. Asakawa A. Bowers C.Y. et al.Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ.FASEB Journal. 2004; 18: 439-456Crossref PubMed Scopus (344) Google Scholar and H pylori status affects their regulation,26Atherton J.C. Blaser M.J. Co-adaptation of Helicobacter pylori and humans: ancient history, modern implications.J Clin Invest. 2009; 119: 2475-2487Crossref PubMed Scopus (403) Google Scholar, 42Nwokolo C.U. Freshwater D.A. O'Hare P. et al.Plasma ghrelin following cure of Helicobacter pylori.Gut. 2003; 52: 637-640Crossref PubMed Scopus (229) Google Scholar could lack of H pylori in childhood be contributing to the worldwide epidemic of childhood onset obesity and diabetes?Isn't it time for gastroenterologists to think more broadly about the effect of an ecological extinction of major proportions occurring in our bodies? Because familial, and specifically maternal, carriage is important in the transmission of H pylori to the next generation,43Rothenbacher D. Winkler M. Gonser T. et al.Role of infected parents in transmission of Helicobacter pylori to their children.Pediatr Infect Dis. 2002; 21: 674-679Crossref Scopus (98) Google Scholar, 44Nahar S. Kibria K.M. Hossain M.E. et al.Evidence of intra-familial transmission of Helicobacter pylori by PCR-based RAPD fingerprinting in Bangladesh.Eur J Clin Microbiol Infect Dis. 2009; 28: 767-773Crossref PubMed Scopus (26) Google Scholar it follows that this extinction affects not only us but our children and grandchildren.Our relationships with our microbiota are not static, especially as we age; organisms that are pathogenic in old age might have been commensals or even symbionts earlier in life. Hosts respond to their commensals with both adaptive and innate effectors in the mucosa and lamina propria45Pamer E. Immune responses to commensal and environmental microbes.Nat Immunol. 2007; 8: 1173-1178Crossref PubMed Scopus (135) Google Scholar, 46Varol C. Zigmond E. Jung S. Securing the immune tightrope: mononuclear phagocytes in the intestinal lamina propria.Nat Rev Immunol. 2010; 10: 415-426Crossref PubMed Scopus (162) Google Scholar, 47Hooper L.V. Macpherson A.J. Immune adaptations that maintain homeostasis with the intestinal microbiota.Nat Rev Immunol. 2010; 10: 159-169Crossref PubMed Scopus (952) Google Scholar; why are we using the term “chronic gastritis” to describe the gastric version of the ancient conserved responses to our endogenous microbiota, which in the stomach is predominantly H pylori? Many organisms that we already consider commensals are opportunistic pathogens (eg, viridens streptococci, Candida albicans, and Klebsiella); we are not attempting to eradicate these organisms from everyone. The clear report of Sonnenberg et al suggests that it is time to rethink the “why” and “how” about H pylori and its relationship to humans.Gastroenterologists must study the growing field of human microbial ecology to address the epidemics of today and to not be further propagating them. Ecology is complex, and H pylori has a complex, deeply evolved biological relationship with humans. Simple approaches,48Graham D. The only good Helicobacter pylori is a dead Helicobacter pylori.Lancet. 1997; 350: 71Abstract Full Text Full Text PDF Scopus (3) Google Scholar like “test and treat” fail to appreciate this complexity. We clearly need to remove H pylori from persons with peptic ulcer disease and from those who are at substantial risk for gastric cancer, but the latter is an important research frontier; we must understand from whom to eradicate H pylori and when,6Peek R.M. Blaser M.J. Helicobacter pylori and gastrointestinal tract adenocarcinomas.Nature Rev Cancer. 2002; 2: 28-37Crossref PubMed Scopus (1457) Google Scholar before disease is inevitable. However, this is a relatively small segment of the overall population in most localities and is most relevant relatively late in life.But if H pylori protects our esophagus, our airways, and maybe our waistline, should we now begin thinking about giving it back in some form, especially to children, just as pediatricians give live vaccines of persistent microbes today? More than a decade ago, I speculated that doctors will be giving H pylori to the children of the future.49Blaser M.J. Not all Helicobacter pylori strains are created equal: should all be eliminated?.Lancet. 1997; 349: 1020-1022Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 50Blaser M.J. Science, medicine, and the future: Helicobacter pylori and gastric diseases.Br Med J. 1998; 316: 1507-1510Crossref PubMed Scopus (243) Google Scholar If we will someday do so, first we must have much deeper knowledge of H pylori, so as to safely restore our ancient companion, maximizing benefit and minimizing risk, and to then be able to eradicate it from the right persons at the right time. Perhaps in such a way, we can curtail these growing epidemics, and before Mother Nature's introduced H pylori-replacements become our new dominant gastric bacteria, without the benefit of millennia of co-evolution and likely to be much less benign. See “A national study of Helicobacter pylori infection in gastric biopsy specimens,” by Sonnenberg A, Lash RH, Genta RM, on page 1894. See “A national study of Helicobacter pylori infection in gastric biopsy specimens,” by Sonnenberg A, Lash RH, Genta RM, on page 1894. See “A national study of Helicobacter pylori infection in gastric biopsy specimens,” by Sonnenberg A, Lash RH, Genta RM, on page 1894. The history of science is marked by the nature of discovery.1Kuhn T.S. The structure of scientific revolutions.in: The University of Chicago Press, Chicago1962: 1-172Google Scholar Sometimes, discoveries bias a field and it takes a long time for the true directions to emerge. This concept is particularly relevant to microbiology, because most of the bacteria of which physicians are aware are pathogens and were discovered owing to their link with disease: Mycobacterium tuberculosis, Vibrio cholerae, and Neisseria meningitis serve as examples. Yet most bacteria in the human body are commensals.2Turnbaugh P.J. Ley R.E. Hamady M. et al.The human microbiome project.Nature. 2007; 449: 804-810Crossref PubMed Scopus (3479) Google Scholar The discovery of Helicobacter pylori in 1979–1982 by Marshall and Warren3Marshall BJ, Warren JR. The bacterium Helicobacter pylori and its role in gastritis and peptic ulcer disease. 2005 Nobel Prize in Physiology or Medicine.Google Scholar was a major event in the field of gastroenterology, recognized in many ways including the awarding of the 2005 Nobel Prize in Medicine. The initial discoveries of H pylori were as pathogen: an organism in the stomach that provoked an inflammatory response, called by pathologists “chronic gastritis,” and leading, as suspected by Marshall and Warren, to peptic ulceration,4Warren J.R. Marshall B.J. Unidentified curved bacilli on gastric epithelium in active chronic gastritis.Lancet. 1983; 1: 1273-1275PubMed Google Scholar, 5Marshall B.J. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration.Lancet. 1984; 1: 1311-1315Abstract PubMed Scopus (4173) Google Scholar and as later determined, to increased risk for intestinal metaplasia, atrophic gastritis, and gastric adenocarcinoma (reviewed in Peek and Blaser6Peek R.M. Blaser M.J. Helicobacter pylori and gastrointestinal tract adenocarcinomas.Nature Rev Cancer. 2002; 2: 28-37Crossref PubMed Scopus (1457) Google Scholar). After a strong body of work over the following decade, H pylori became established firmly as a human pathogen.7NIH Consensus Development Panel on Helicobacter pylori in Peptic Ulcer Disease.JAMA. 1994; 272: 65-69Crossref PubMed Scopus (1063) Google Scholar As a consequence, major pharmaceutical companies developed methods to ensure its eradication, and governmental agencies and foundations have sought ways to promote such strategies. Why not rid the world of a pathogen that clearly may lead to a serious and sometimes lethal disease, peptic ulceration, and to a very serious and common form of malignancy—gastric cancer? Indeed, why not? However, all mammals, even marine mammals, seem to have helicobacters residing in their stomachs,8Harper C.M.G. Feng Y. Xu S. Helicobacter cetorum sp. nov., a urease-positive Helicobacter species isolated from dolphins and whales.J Clin Microbiol. 2002; 40: 4536-4543Crossref PubMed Scopus (67) Google Scholar, 9Solnick J.V. Schauer D.B. Emergence of diverse Helicobacter species in the pathogenesis of gastric and enterohepatic diseases.Clin Microbiol Rev. 2001; 14: 59-97Crossref PubMed Scopus (325) Google Scholar and there is no evidence that any mammalian acid-producing stomach has evolved without their presence. In particular, H pylori has been colonizing the human stomach for ≥58,000 years, dating from the last out of Africa,10Linz B. Balloux F. Moodley Y. et al.An African origin for the intimate associate between humans and Helicobacter pylori.Nature. 2007; 445: 915-918Crossref PubMed Scopus (687) Google Scholar and probably much, much longer. Helicobacter pylori traveled with us as we have migrated to all corners of the world during prehistory.11Moodley Y. Linz B. Yamaoka Y. et al.The peopling of the Pacific from a bacterial perspective.Science. 2009; 323: 527-530Crossref PubMed Scopus (235) Google Scholar What are the implications of an ancestral gastric microbial colonization conserved over 100 million years of mammalian evolution? Might there not be some costs associated with changing such a longstanding relationship? In this issue of Gastroenterology, Sonnenberg et al12Sonnenberg A. Lash R.H. Genta R.M. A national study of Helicobacter pylori infection in gastric biopsy specimens.Gastroenterology. 2010; 139: 1894-1901Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar report on a large study based on >78,000 US patients who had had upper gastrointestinal endoscopy performed, and from whom histopathologic analysis of gastric biopsies was done. The investigators sought to ascertain the relationships between the presence of H pylori, chronic gastritis, and intestinal metaplasia with each other and with Barrett's esophagus. The results, reflecting the straightforward design and large scale of these studies, are clear cut. All 3 findings by the pathologists—the presence of H pylori, chronic gastritis, and intestinal metaplasia—were strongly correlated with each other, confirming many prior studies.13Kuipers E.J. Pena A.S. Meuwissen S.G.M. et al.Long-term sequelae of Helicobacter pylori gastritis.Lancet. 1995; 345: 1525-1528PubMed Scopus (720) Google Scholar, 14Ohkusa T. Fujiki K. Takashimizu I. et al.Improvement in atrophic gastritis and intestinal metaplasia in patients in whom Helicobacter pylori was eradicated.Ann Intern Med. 2001; 134: 380-386Crossref PubMed Scopus (198) Google Scholar However, Sonnenberg et al showed that all 3 findings were also inversely associated with Barrett's esophagus. The study was robust and internally consistent, so there is no doubt that the findings are correct. The important issue is how physicians, scientists, and patients should interpret these results. Barrett's esophagus is an intermediate lesion along the pathway between reflux esophagitis (also known as gastroesophageal reflux disease [GERD]) and esophageal adenocarcinoma (EAC).15Shaheen N. Ransahoff D.F. Gastroesophageal reflux, Barrett esophagus, and esophageal cancer: scientific review.JAMA. 2002; 287: 1972-1981Crossref PubMed Scopus (378) Google Scholar As with other pathogenetic sequences, relatively many individuals have GERD, fewer have Barrett's, and fewest develop EAC.15Shaheen N. Ransahoff D.F. Gastroesophageal reflux, Barrett esophagus, and esophageal cancer: scientific review.JAMA. 2002; 287: 1972-1981Crossref PubMed Scopus (378) Google Scholar Most important, GERD, Barrett's, EAC (and the closely related adenocarcinomas affecting the adjacent gastric cardia) each are increasing in epidemic proportions all over the developed world,16Lagergren J. Bergstrom R. Lindgren A. et al.Symptomatic gastroesophageal reflux as a risk factor for esophageal adenocarcinoma.N Eng J Med. 1999; 340: 825-831Crossref PubMed Scopus (2576) Google Scholar, 17Devesa S.S. Blot W.J. Fraumeni Jr, J.F. Changing patterns in the incidence of esophageal and gastric carcinoma in the United States.Cancer. 1998; 83: 2049-2053Crossref PubMed Scopus (1951) Google Scholar, 18Pohl H. Welch H.G. The role of overdiagnosis and reclassification in the marked increase of esophageal adenocarcinoma incidence.J Natl Cancer Inst. 2005; 97: 142-146Crossref PubMed Scopus (1082) Google Scholar, 19Bollschweiler E. Wolfgarten E. Gutschow C. et al.Demographic variations in the rising incidence of esophageal adenocarcinoma in white males.Cancer. 2001; 92: 549-555Crossref PubMed Scopus (404) Google Scholar, 20Bresalier R.S. Barrett's esophagus and esophageal adenocarcinoma.Ann Rev Med. 2009; 60: 221-231Crossref PubMed Scopus (17) Google Scholar and EAC is a terrible and difficult-to-treat form of cancer. These conditions, 1 nested within the other, arose in the mid-to-late 20th century and are continuing to climb in incidence. How do the findings of Sonnenberg et al12Sonnenberg A. Lash R.H. Genta R.M. A national study of Helicobacter pylori infection in gastric biopsy specimens.Gastroenterology. 2010; 139: 1894-1901Abstract Full Text Full Text PDF PubMed Scopus (170) Google Scholar relate to these events? Is there a causal relationship between the inverse association of H pylori (and its related conditions), and Barrett's (and its related conditions), and if so, in which direction (A→B, or B→A)? Alternatively, do the findings reflect an underlying process affecting the risk of both (thus, C→A and C→B), or are they just spurious? The large scale and internal consistency of the Sonnenberg et al study argue that the findings are not artifactual. In fact, their findings confirm and extend many other studies over the last decade showing parallel relationships in different populations, and using different techniques of ascertainment.21Chow W.-H. Blaser M.J. Blot W.J. et al.An inverse relation between cagA+ strains of Helicobacter pylori infection and risk of esophageal and gastric cardia adenocarcinoma.Cancer Research. 1998; 58: 588-590PubMed Google Scholar, 22Ye W. Held M. Lagergren J. et al.Helicobacter pylori infection and gastric atrophy: risk of adenocarcinoma and squamous-cell carcinoma of the esophagus and adenocarcinoma of the gastric cardia.J Natl Cancer Inst. 2004; 96: 388Crossref PubMed Scopus (305) Google Scholar, 23de Martel C. Llosa A.E. Farr S.M. et al.Helicobacter pylori infection and the risk of development of esophageal adenocarcinoma.J Infect Dis. 2005; 191: 761-767Crossref PubMed Scopus (97) Google Scholar, 24Islami F. Kamangar F. Helicobacter pylori and esophageal cancer risk: a meta-analysis.Cancer Prev Res. 2008; 1: 329-338Crossref PubMed Scopus (256) Google Scholar, 25Whiteman D.C. Parmer P. Fahey P. Association of Helicobacter pylori infection with reduced risk for esophageal cancer is independent of environmental and genetic modifiers.Gastroenterology. 2010; 139: 73-83Abstract Full Text Full Text PDF PubMed Scopus (106) Google Scholar Although the Sonnenberg et al study was not designed to address the vectors and direction of causality, it should now be clear to all impartial observers that there truly is a reciprocal relationship between H pylori and Barrett's esophagus. How can the relationship be explained? Could GERD and related conditions be causing the loss of H pylori? This is highly unlikely, because GERD usually develops in adults but H pylori is acquired in early childhood. Could the absence of H pylori be predisposing to GERD? As most gastroenterologists know, once acquired, H pylori colonization generally persists for life.26Atherton J.C. Blaser M.J. Co-adaptation of Helicobacter pylori and humans: ancient history, modern implications.J Clin Invest. 2009; 119: 2475-2487Crossref PubMed Scopus (403) Google Scholar unless interrupted by antibiotic treatment or by the development of chronic atrophic gastritis very late in life. Thus, since time immemorial, H pylori has persistently colonized most of the world's population, essentially for their full lifetime26Atherton J.C. Blaser M.J. Co-adaptation of Helicobacter pylori and humans: ancient history, modern implications.J Clin Invest. 2009; 119: 2475-2487Crossref PubMed Scopus (403) Google Scholar; in most cases, however, its presence leads to no symptoms. Indeed, when what we now know as H pylori was recognized in the 19th century by German pathologists, it was essentially universal, and they concluded that it was not worth studying because it was a commensal. 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The only good Helicobacter pylori is a dead Helicobacter pylori.Lancet. 1997; 350: 71Abstract Full Text Full Text PDF Scopus (3) Google Scholar like “test and treat” fail to appreciate this complexity. We clearly need to remove H pylori from persons with peptic ulcer disease and from those who are at substantial risk for gastric cancer, but the latter is an important research frontier; we must understand from whom to eradicate H pylori and when,6Peek R.M. Blaser M.J. Helicobacter pylori and gastrointestinal tract adenocarcinomas.Nature Rev Cancer. 2002; 2: 28-37Crossref PubMed Scopus (1457) Google Scholar before disease is inevitable. However, this is a relatively small segment of the overall population in most localities and is most relevant relatively late in life. But if H pylori protects our esophagus, our airways, and maybe our waistline, should we now begin thinking about giving it back in some form, especially to children, just as pediatricians give live vaccines of persistent microbes today? More than a decade ago, I speculated that doctors will be giving H pylori to the children of the future.49Blaser M.J. Not all Helicobacter pylori strains are created equal: should all be eliminated?.Lancet. 1997; 349: 1020-1022Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar, 50Blaser M.J. Science, medicine, and the future: Helicobacter pylori and gastric diseases.Br Med J. 1998; 316: 1507-1510Crossref PubMed Scopus (243) Google Scholar If we will someday do so, first we must have much deeper knowledge of H pylori, so as to safely restore our ancient companion, maximizing benefit and minimizing risk, and to then be able to eradicate it from the right persons at the right time. Perhaps in such a way, we can curtail these growing epidemics, and before Mother Nature's introduced H pylori-replacements become our new dominant gastric bacteria, without the benefit of millennia of co-evolution and likely to be much less benign. A National Study of Helicobactor pylori Infection in Gastric Biopsy SpecimensGastroenterologyVol. 139Issue 6PreviewWe investigated whether infection with Helicobacter pylori and signs of chronic active gastritis and intestinal metaplasia in gastric biopsy samples were inversely associated with Barrett's metaplasia. Full-Text PDF
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