Hypothesis: The Changing Relationships of Helicobacter pylori and Humans: Implications for Health and Disease

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1 1523 EDWARD M. KASS LECTURE Hypothesis: The Changing Relationships of Helicobacter pylori and Humans: Implications for Health and Disease Martin J. Blaser Division of Infectious Diseases, Department of Medicine, Vanderbilt University School of Medicine, and Medical Service, Department of Veterans Affairs Medical Center, Nashville, Tennessee Helicobacter pylori has apparently colonized the human stomach since time immemorial and is superbly adapted for persistence. Several genotypes, including cag +, are associated with increased risk of gastric and duodenal diseases. With modern life, for probably the first time in human history, there are large numbers of noncolonized persons. Duodenal ulceration has been present essentially for only 200 years; that its incidence rose just as H. pylori was waning is best explained by changes in gastric microecology. As H. pylori is disappearing, duodenal ulceration and gastric cancer rates are falling. However, more proximal diseases, gastroesophageal reflux (GERD), Barrett s esophagus, and adenocarcinomas of the gastric cardia and lower esophagus, are increasing; colonization with cag + H. pylori strains appears protective against these diseases. Thus, in the 21st century, the continuing decline in H. pylori may lead to the disappearance of duodenal ulcers and distal gastric cancers and toward a marked increase in GERD, Barrett s esophagus, and esophageal adenocarcinoma. It has been 15 years since Warren and Marshall [1] first reported the isolation of Helicobacter pylori. In so doing, they succeeded where pathologists working a century before, who could see the organisms in preparations from the stomach [2], had failed. Since 1983, microbiologists all over the world have been able to isolate H. pylori from the human stomach, and we now know that, once acquired, these organisms generally persist for the life of the host. We also have learned that the presence of these organisms is associated with increased risk for the development of peptic ulcer disease (PUD) [3, 4], noncardia gastric adenocarcinoma [5], and gastric non-hodgkins B cell lymphomas [6]. Consequently, there are many scientists who believe that the only good H. pylori is a dead one [7]. However, H. pylori are not new microbes that recently have parasitized humans, such as human immunodeficiency virus, which may date back!100 years, or even Mycobacterium tuberculosis or measles virus, which probably have affected humans for!15,000 years [8]. There now is much evidence (reviewed in [9, 10]) that H. pylori and related Helicobacter species have been part of the normal microbiota of humans and our ancestors for millions, if not tens of millions, of years or longer. Received 18 December 1998; revised 13 January Presented as the 8th Edward M. Kass Lecture at the 36th annual meeting of the Infectious Diseases Society of America, Denver, 13 November Financial support: NIH (CA-58834, DK-50837, DK-53707); Medical Research Service, Department of Veterans Affairs; and Iris and Homer Akers. Reprints or correspondence: Dr. Martin J. Blaser, Division of Infectious Diseases, Vanderbilt University School of Medicine, 3310 MCN, Nashville, TN (martin.blaser@mcmail.vanderbilt.edu). The Journal of Infectious Diseases 1999;179: by the Infectious Diseases Society of America. All rights reserved /99/ $02.00 Such a long period of cohabitation suggests that there are important adaptations of the microbes to their obligate primate hosts. Similarly, a long association suggests that mutual benefits may have developed for both the microbe and its host and that H. pylori may participate in host processes that we consider physiologic, such as the regulation of gastric secretion [11] and immunologic responsiveness to transient pathogens [12]. According to this model, as with other commensal organisms, including Bacteroides species and a-hemolytic streptococci, H. pylori may exhibit symbiotic or pathogenic properties, depending on the context. Fundamental to a long-shared history is the concept that, for H. pylori to persist through essentially the entire reproductive span of their host, there must be an equilibrium (homeostasis) between H. pylori and humans. In 1990, in Harrogate, England, I first proposed that the equilibrium must include a regulated interaction between H. pylori and its host [13]. Such an equilibrium requires both positive and negative regulation [11, 13, 14], and there already has been microbiologic, pathophysiologic, and mathematical support for this concept [15]. The further extension of this concept [11, 13] is that each population of H. pylori residing in the stomach of its specific human host exists in a unique and dynamic equilibrium, with microbes signaling the host and vice versa. In this model, it is the characteristics of this primary equilibrium that affect such phenomena as epithelial cell cycle events, gastric secretion, and lymphoid proliferation, all of which have an important bearing on clinical outcome. Coevolution may mean that H. pylori colonization has benefits as well as its apparent costs [3, 5, 6, 16, 17], as suggested by recent studies [12].

2 1524 Blaser JID 1999;179 (June) Figure 1. Hypothetical trends in frequency of colonization with multiple Helicobacter pylori strains in developed countries in 3 time periods. During ancient times, when most persons were colonized with H. pylori, most carried several different strains. As industrialization and development proceeded, both frequency of colonization and multiplicity of separate strains declined. Diversity of H. pylori H. pylori are highly polymorphic [18], and, as with other persistent microbes well adapted to humans [19], multiple H. pylori strains may colonize the same host [20, 21]. In part, polymorphism represents point mutation, which appears to occur at high frequency relative to other bacteria [22, 23], as well as chromosomal rearrangement, insertion sequences, and differences in the complement of restriction-modification systems [24 26]. However, there also are allelic variations, including the presence of the cag pathogenicity island [27, 28] and different vaca [29] and icea [30] genotypes that each have clinical relevance [31, 32]. Study of the significance of cag has been advanced the most fully and provides a model for the importance of particular allelic variations. The CagA protein, first related to virulence in 1990 [33, 34], is encoded by a cryptic gene [35, 36] that serves as a marker for the presence of the 37- to 40-kDa cag pathogenicity island [27, 28, 37, 38]. The distinction between strains that are cag or not represents the most fundamental dichotomy among H. pylori strains [39]. We now know that cag and cag strains can circulate in the same population [40] and can even be present in the same host [41, 42]. In Latin America, western Europe, and the United States, only 40% 60% of all strains are cag [31 34], whereas in East Asia most persons carry cag strains [43, 44]. In numerous US, European, and Latin American studies, carriage of a cag strain was significantly associated with duodenal ulceration, atrophic gastritis, and development of noncardia gastric adenocarcinoma (reviewed in [39]) [45 47]. In Asian populations, the same association of cag and enhanced virulence has not been found or is much less clearcut [43, 44]. The reasons for these geographic differences in the significance of cag have not been determined. In studies in Western populations aimed at understanding the mechanisms underlying the observed enhanced association with disease in comparison with cag strains, cag strains induce more epithelial cell injury [34, 48], secrete more proinflammatory cytokines (such as interleukin-8) [48, 49], and have more intense infiltration of the gastric mucosa by neutrophils and mononuclear cells [34, 48] and more rapid development of atrophic gastritis [47] and concomitant changes in gastric secretion [50, 51]. The cag strains are more efficient inducers of epithelial cell NF-kB [52]. In total, cag and cag strains can be considered as having greater or lesser degrees of interaction with their host, respectively [39]. That the more interactive cag strains are associated with a higher prevalence Figure 2. Changing rates of esophageal diseases and Helicobacter pylori incidence in developed countries during the 20th century.

3 JID 1999;179 (June) H. pylori and Disease years just to treat one malady, otitis media [64]. Although treatment of adults with single antibiotics in clinical trials yields low H. pylori eradication rates, many agents have some activity [65]. Even if single antibiotic regimens are only 5% 10% effective in removing H. pylori, their intensive cumulative use in children and in adults [63, 64, 66] might affect H. pylori prevalence. Figure 3. Proposed relationship between the cag genotype and diseases of the upper gastrointestinal tract. In this model, with reference to diseases of the lower stomach and duodenum (e.g., duodenal ulcer and adenocarcinoma), carriage of a cag strain is harmful, since it increases risk of these diseases. Carriage of a cag strain is essentially neutral, with little effect on disease risk compared with not carrying Helicobacter pylori. In contrast, in relation to the upper stomach (cardia) and lower esophagus, carriage of a cag strain appears beneficial, since it is associated with protection against gastroesophageal reflux disease, Barrett s esophagus, and their sequelae. Again, carriage of a cag strain is essentially neutral, presumably because of its low interaction with host tissues [39]. of clinical consequences is consistent with interaction being a central feature of the equilibrium model proposed earlier [11, 13, 15]. Why Has H. pylori Been Declining in the 20th Century? A substantial body of evidence indicates that, over the course of industrialization, the incidence and prevalence of colonization by H. pylori have been progressively declining [53 55]. For an organism that has presumably been colonizing us for millions of years, such a decline is surprising and probably unprecedented. This decline is unlikely to represent surveillance artifact and may represent both diminished acquisition and increased loss. Early childhood crowding is a risk factor for H. pylori acquisition [56], and recent evidence suggests that children of higher birth order (late born) with older siblings within 5 years are at highest risk for acquiring H. pylori [57, 58]. Such studies imply that children are the major amplifier of H. pylori in human populations. One of the most universal features of modernization over the past 200 years has been the progressively falling rates of births per woman and thus diminishing family size and household size [59 62]. If colonized children are the major reservoir relevant to transmission and the optimal window of susceptibility is limited, these demographic changes may be important in explaining the decrease in H. pylori. For the past 50 years, children in developed countries have been receiving antibiotics, and the intensity of antibiotic exposure continues to increase [63]. For example, by 1992, the average US child had received 6 antibiotic courses before age Changing Epidemiology of PUD In contrast to H. pylori, which is ancient, there is substantial evidence (reviewed in [10] that PUD, especially involving duodenal ulcers, is a new disease that began to rise in Europe and the US in the 19th century, when the evidence indicates that H. pylori rates were beginning to fall. After peaking early this century in developed countries, PUD incidence has been falling. We now know that its fall is related to the decreased prevalence of H. pylori colonization, but the more interesting question is why PUD rose at the very time that H. pylori was declining. One possibility is that, along with the decline in the total prevalence of colonization, there also was a decline in the number of distinct H. pylori strains being carried (figure 1). Such a change in multiplicity of the colonizing organisms could affect the equilibrium that the host reaches with its H. pylori populations, leading, on average, to altered acid secretion and/ or to enhanced tendency toward duodenal colonization. Another possibility is that the age when H. pylori is acquired is an important determinant of the ultimate risk for diseases, such as PUD and noncardia gastric cancer [67]. This hypothesis is also based on changes in the equilibria reached between microbial populations and hosts and is consistent with acquisitionage outcome differences observed for other microbial agents (e.g., varicella, hepatitis B, and Epstein-Barr viruses) [68]. Studies of a cohort of Japanese-American men provide support for this hypothesis [67]. Nesse and Williams [69] observed that modern epidemics are most likely to arise from the mismatch between the physiologic design of our bodies and novel aspects of our environment. Changes in the multiplicity of colonizing H. pylori strains and changes in the acquisition age for H. pylori, in essence, reflect changes in the microenvironment (and microecology) of the stomach [10, 11]. In biologic relationships, context is critical [70], which can explain how the same organisms can be associated with differing outcomes. Changing Epidemiology of Esophageal Diseases In 1900, gastric cancer was the leading cause of cancer death in the US and Europe [71]. The marked fall in the incidence of most noncardia gastric adenocarcinoma since then [71] is at least in part due to the decreased prevalence of H. pylori [5]. However, in contrast, the incidence of adenocarcinoma of the gastric cardia and esophagus has been increasing rapidly and

4 1526 Blaser JID 1999;179 (June) Figure 4. Relationships between colonization with Helicobacter pylori and diseases of the upper gastrointestinal tract among persons in developed countries. Essentially all persons colonized with H. pylori develop a host response, generally termed chronic gastritis. Interaction between the host and the particular bacterial population determines clinical outcome. H. pylori colonization increases lifetime risk of developing peptic ulcer disease, noncardia gastric cancer, and B cell non-hodgkins gastric lymphoma (all odds ratios [ORs] 1 1). In contrast, growing evidence indicates that H. pylori colonization protects against development of adenocarcinoma of the esophagus (and related gastric cardia) and premalignant lesions such as Barrett s esophagus ( OR! 1). Although peptic ulcer disease (not due to nonsteroidal anti-inflammatory drugs) and noncardia gastric cancer are declining in developed countries, the incidence of adenocarcinoma of the esophagus is rapidly increasing. alarmingly in the US and in western European countries [72 74]. Why are these cancers becoming more common? Adenocarcinoma of the esophagus and of the gastric cardia are anatomically and nosologically similar and have parallel epidemiologic characteristics, and their increased incidences appear to represent related phenomena [75, 76]. In recent years, the pathogenesis of esophageal adenocarcinoma has been clarified. Gastroesophageal reflux disease (GERD) is the major risk factor for Barrett s esophagus, which in turn is a strong risk factor for esophageal adenocarcinoma [77 79]. We now know that the incidence of GERD, first described in the 1930s, is increasing rapidly in the developed world [76, 80]. Barrett s esophagus, first described in 1950, has had a similar marked increase [81]. Adenocarcinoma of the esophagus, first noted to rise in the 1970s, is now more common in white US men than is squamous cell cancer, and its incidence continues to rise [74]. Relationship of H. pylori to Esophageal Diseases The increase in these diseases has occurred in a temporal relationship that is consistent with its presumed pathogenesis and at the very time that H. pylori incidence and prevalence have been falling (figure 2). Are these events related? Over the past 2 years, a growing body of evidence has accumulated indicating that the presence of H. pylori, particularly cag strains, is protective against these diseases. The key types of evidence may be summarized as follows. GERD is uncommon in countries in which most adults are colonized by H. pylori (especially cag strains) [82]. GERD and its sequelae are increasing in incidence in Western countries [78] as the prevalence of H. pylori (including cag strains) is falling [53 55]. The prevalence of H. pylori is lower in persons with GERD than in controls [83 85]. In patients with duodenal ulcers (who nearly always are colonized by cag strains [31, 32, 86], successful elimination of H. pylori using antimicrobial agents was associated with double the rate of development of reflux esophagitis over a 3-year period compared with subjects who remained colonized [87]. In cohort [88] and case-control [89] studies, carriage of H. pylori was associated with a decreased risk of esophageal and gastric cardia adenocarcinomas. In the case-control study, the entire protective effect was associated with carriage of cag strains [90]. How can we reconcile that cag strains, which appear to be most virulent in relation to diseases of the lower stomach (duodenal ulceration and noncardia gastric adenocarcinoma) [39] (figure 3), are most protective against the more proximal diseases? One hypothesis is that cag strains have little potential for either disease risk or protection since they have little interaction with their hosts [39, 49, 52]. In contrast, cag strains, which are most interactive with their hosts [34, 48 52], would have the highest potential for clinical effect. One particular mechanism for the protective effects of colonization by cag

5 JID 1999;179 (June) H. pylori and Disease 1527 Ecologic Models of Gastric Colonization and Disease Figure 5. Hypothesized relationship between age at acquisition of Helicobacter pylori and risk of adverse clinical consequences. In this model, risk of distal (noncardia) gastric cancer is greatest with earlylife acquisition of H. pylori; duodenal ulcer risk is greatest with later acquisition. Exact ages depicted in the model are not known, and potentially all could occur during childhood. In contrast, lack of colonization with H. pylori, especially caga strains, is associated with enhanced risk of esophageal disease (see text). strains against esophageal disease may involve their enhanced injury to the gastric corpus [48, 50, 91]. Corpus inflammation, efficiently induced by cag strains, may blunt high-level acid secretion [51], which appears necessary for the severity of reflux that leads to Barrett s esophagus. This model, which implies that gastric physiology differs in persons colonized by cag, cag, or no H. pylori strains and that these differences have important clinical ramifications, is completely consistent with the equilibrium models [11, 13, 15] described earlier. Acid secretion is but one facet of gastroesophageal physiology; other aspects worth exploring include motility, pressure, and autonomic function. Interactions with H. pylori: Health and Disease Our earlier model of the relationship between H. pylori colonization and disease [13, 14] now can be modified to include esophageal diseases (figure 4) and can be extended to relate H. pylori acquisition age and clinical outcome (figure 5). In this model, early-life H. pylori acquisition would increase risk for distal gastric adenocarcinoma [67], which was and is highly prevalent in developing countries. Acquisition of H. pylori at older ages (undefined at present) would increase the risk of peptic ulceration. In contrast, failure to acquire H. pylori, which is common in our postmodern societies, would enhance esophageal disease risk. In total, each of these phenomena can be seen as affecting the microecology of the stomach, without invoking either strain or host genotypic differences to explain the changing disease rates during the past 200 years. Nevertheless, either a particular host or bacterial polymorphisms (such as cag positivity) could lead to accentuated risk. A more general or ecologic model is shown in figure 6. When our normal biota colonize in their usual niche [92], we may define that as health (or eutopia ). When they are present in an unusual place, such as when oral streptococci are on heart valves, that leads to disease, which we may call dystopia. When they are absent, such as when broad-spectrum antibiotics eliminate vitamin K producing colonic biota, leading to bleeding diatheses, we may call that atopia. For H. pylori, I propose that gastric colonization represents eutopia, duodenal ulceration represents dystopia, and Barrett s esophagus and its sequelae represent atopia (figure 6B). Extending the model one step further, balanced gastric colonization by cag and cag strains [42] may be termed eucagia, unopposed cag strains in the duodenum could be called dyscagia, and the absence of cag strains would be acagia (figure 6C). These final points are clearly speculative, but such a model is suggested by the emerging knowledge of H. pylori biology. Conclusions During the past years in the US and western Europe, there have been major changes in the epidemiology of many of the major diseases affecting the esophagus, stomach, and Figure 6. Hypothesized relationships between colonization by normal biota (A) and Helicobacter pylori (B, C) and human health and disease.

6 1528 Blaser JID 1999;179 (June) duodenum. These have occurred while the prevalence of H. pylori, probably an ancient inhabitant of the human stomach, has also been changing. If the data presented here, which indicate that H. pylori colonization is protective against esophageal diseases, continue to be confirmed, then elimination of the organism may have risks as well as benefits for human health. Consequently, our clinical approaches to H. pylori will need to change. Of importance, studies of the relation of H. pylori to both health and disease can provide a model for our understanding of the biologic relationships of other persistent biota with their human hosts. From both fundamental and clinical viewpoints, exploration of these interactions should be revealing. Acknowledgments I acknowledge the many important contributions to this work by colleagues Timothy Cover, Murali Tummuru, Smita Sharma, Larry Kerr, Guillermo Pérez-Pérez, Richard T. 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