Does Helicobacter pylori protect against asthma and allergy?

Introduction

The microbes that persistently colonize their vertebrate hosts are not accidental (1). Although highly numerous and diverse, there is specificity by site and substantial conservation between individuals. The genus Helicobacter includes spiral, highly motile, urease-positive, gram-negative bacteria that colonize the stomach in many mammals. Each mammal has one or more dominant Helicobacter species and they are highly, if not exclusively, host species-specific (2). Such observations are consistent with the hypothesis that when ancestral mammals diverged from reptiles about 150 million years ago, they contained ancestral helicobacters, which then diverged as their hosts changed. According to this hypothesis, helicobacters represent ancestral biota (flora) in the mammalian stomach. The human-adapted strain is H. pylori (3), which has not been reproducibly observed in any animals other than humans and other primates (3).

Although we can not reliably estimate how long H. pylori has been in the human stomach, its ancestors may have been present when our humanoid ancestors diverged from other primates about four million years ago. Consistent with this view are results from phylogeographic studies; strong and consistent evidence indicates that our ancestors already were carrying gastric H. pylori when a group that ultimately populated much of the world last left Africa, more than 58,000 years ago (4). In any case, H. pylori has been colonizing the stomach of humans since at least Paleolithic times.

In this paper, we examine the evidence concerning the relationship of this ancient member of the human microbiota, and particularly its absence, with the recent and on-going epidemic of asthma and related allergic disorders. We discuss the possibility that gastric H. pylori colonization protects against these disorders and that its disappearance has fueled their rise.

H. pylori acquisition and persistence

H. pylori is acquired, and may be detected, in early childhood usually after the first year of life (5). Transmission is fecal-oral, oral-oral, and vomitus-oral (6). Once acquired, in the absence of antibiotic use, H. pylori persists at least for decades, and most often for the full life of its host (7). H. pylori strains are highly variable, and several loci affect H. pylori-host interactions. In particular, strains with an intact cag island inject the CagA protein into host gastric epithelial cells (8); this heightened interaction in relation to cag-negative strains affects disease risk (9,10).

For most of human existence, we have lived in small, intimate groups (11), in which our microbiota mingled extensively with that of other group members (12). Under the conditions of poor hygiene that have predominated for most of human existence, transmission of gastro-intestinal microbes has been easily accomplished. In present-day developing countries in which such enteric transmission occurs, H. pylori is ubiquitous, with estimates for its prevalence in adults exceeding 80%; its presence is possibly nearly universal, when multiple detection methods are used (7, 13). In populations in which H. pylori is highly prevalent, gastric colonization with several distinct strains appears common (14).

H. pylori is disappearing

Despite the substantial evidence for the antiquity and ubiquity of H. pylori colonization in humans, it now has become clear that the prevalence of H. pylori is rapidly decreasing! This is a birth cohort effect, that began in the early 20^th century in many developed countries, and accelerated after World War II (15–17). The effect has been so profound that fewer than 10% of children under 10 in the United States and in other industrialized countries now are H. pylori-positive, compared to the historic 70–90% levels (15–17). As a result of this change, occurring around the developed world to variable extents, risk factors for H. pylori acquisition can be determined. These include large family size, having parents, (especially mothers) carrying H. pylori, H. pylori-positive older siblings, and household crowding during childhood (18,19). Thus, as disappearance begins, the effects compound with each generation, especially as water has become more clean, family sizes have shrunk, mothers pre-masticate food less, and nutrition has improved (20).

Another phenomenon that may contribute to H. pylori disappearance is the widespread usage of antibiotics, especially during childhood (21). To reliably eradicate H. pylori requires combinations of two to four antimicrobial agents, but early studies with monotherapies including beta-lactam and macrolide antibiotics showed eradication rates from 10–50% (22, 23). If comparable effects occur every time a child is treated with antibiotics for an upper respiratory or skin infection or for otitis media, then the rapid (and compounding) decline in H. pylori prevalence in childhood in developed countries in recent decades is not difficult to understand.

Consequences of the presence or absence of H. pylori

By comparing persons with and without the organism, medical scientists have studied the costs and benefits of carrying H. pylori. First, came the observation that the presence of H. pylori in the gastric lumen is associated with the presence in the gastric lamina propria of phagocytic and immune cells (24). Warren and Marshall recognized the association of H. pylori with these histological findings, which pathologists call ”chronic gastritis” (24, 25); the presence of inflammatory cells leads to use of terms implying pathological processes. However, as biologists, we believe that the collection of immune and inflammatory cells in the tissue should be considered as “the physiologic response to the indigenous microbiota” (or PRIM). Similarly, the lamina proprias of the mammalian mouth, vagina, and colon are populated by phagocytic and immunologic cells that respond to the local indigenous microbiota. In contrast, germ-free animals have essentially no phagocytic and immune cells in their lamina propria, but “conventionalizing” these animals, by restoring their normal biota restores these cells, which is considered as the normal histopathology (reviewed in 26).

One difficulty with terming the host response to H. pylori as “chronic gastritis” is not in the observation, which is correct, but in interpreting the finding as pathological, and not as physiological. However, in at least one context PRIM also is pathological, since it is associated with increased risk for development of peptic ulceration (27, 28), and gastric adenocarcinoma and lymphoma (10, 29). Further, the highly interactive CagA-positive strains induce the strongest PRIM and confer the greatest risk of ulceration and carcinoma (10, 28, 30). Thus, H. pylori and the PRIM it induces are clearly associated with risk of disease, and even fatality. The decline in the incidence of these diseases in the 20^th century is consistent with the decline in H. pylori prevalence.

However, it now has become clear that there is an inverse association between H. pylori with reflux esophagitis (GERD), and its consequences, including Barrett’s esophagus, and esophageal adenocarcinoma (10). Although the gastric PRIM is a risk factor for the development of peptic ulceration and gastric adenocarcinoma, it is inversely associated with the development of these esophageal diseases, and the more interactive CagA-positive strains are associated with the strongest inverse effects (10). Thus, a paradigm exists of a host-microbial interaction that in some cases may promote pathological conditions, whereas in other cases may be protective from pathology. This is not a simple concept for most physicians, but in fact fits well with Rosebury’s definition of an “amphibiont” as a microbe that could be pathogen or symbiont, depending on context (31). The phenomenon of “amphibiosis” can be used to characterize our indigenous microbiota (32), in which, for example, residential oral alpha-hemolytic streptococci protect against oral invaders, but also can cause endocarditis.

Effects of H. pylori on human physiology

The stomach is an organ with multiple functions; H. pylori and its induced PRIM affects at least three of these. First, the stomach secretes acid, which is under complex regulatory control, involving autonomic innervation, and the neurendocrine peptides, gastrin and somatostatin. It is evident that H. pylori status affects this homeostasis (9). Second, the stomach has adaptive immunologic activity in terms of both T- and B-cell function (33–37). The H. pylori-positive and the H. pylori-free stomachs are immunologically different, not only in terms of H. pylori-specific responses (36), but in more general responses as well (37), and including a far greater population of regulatory T-cells (33–35). Third, the stomach produces leptin, and is the major site for production of ghrelin (9). These neurendocrine peptides play important roles in mammalian energy homeostasis, and emerging evidence indicates that H. pylori status is relevant to their regulation (38, 39).

It thus becomes clear that a generation or more of children in developed countries have been growing up without H. pylori to guide or influence these physiological functions, and others not yet described (Figure 1). It is predictable that such altered acid secretion, immunologic activation, and neurendocrine regulation have a variety of consequences.

Figure 1.

Changes in gastric physiology as the ancient (H. pylori–colonized) stomach is becoming the post-modern (H. pylori–free) stomach. Representative references are cited.

Association with asthma and allergic conditions?

In recent years, there has been a rise in the prevalence of asthma, hay fever (allergic rhinitis) and atopy (including eczema) in developed countries (40). This change, which begins in early childhood, is present across many populations in the world, and is considerable in its extent. A perturbation of such magnitude must be environmentally caused, and some of the leading candidates include exposure to tobacco smoke, air pollution, allergens, exogenous infections and microbial substances in the environment, as well as obesity (40–42)

In addition to these exogenous causes, an alternative hypothesis could relate to a change in our indigenous microbiota (1). As such, it is plausible to consider H. pylori, since its well-documented disappearance is extensive and involves developed country populations (15–17). Further, the disappearance of H. pylori has preceded the rise in asthma, but are they related?

Table 1 summarizes 12 recent cross-sectional and 4 case-control studies in which the relationships of H. pylori with asthma, atopy, allergic rhinitis, and/or eczema were examined (43–57). In general, the cross-sectional studies, involving a variety of populations and somewhat differing definitions of atopy and asthma, show significant inverse relationships of these conditions with H. pylori. The published case-control studies, in general much smaller in scale, do not show any significant direct or inverse relationships (Table 1). However, a case-control study we conducted in New York showed an inverse relationship between H. pylori, especially cagA+ strains, with asthma and atopy (58).

Table 1.

Association of H. pylori and asthma, allergic rhinitis, and atopic disease from prior literature

CROSS-SECTIONAL STUDIES
Author, year (reference)	Location	Study population	Age (years)	H. pylori measure	Definition of outcome	Major findings: Condition and OR (95% CI) in relation to H pylori+
Matricardi, 2000 (43)	Caserta, Italy	1659 Italian male military cadets	17–24	IgG ELISA	Total IgE Atopy: logRU > 1.2 Non-atopic: logRU < 0	Atopy For H pylori, T gondii, Hep A 1 vs. 0 2 or 3 vs. 0	0.70 (0.52–0.94)* 0.37 (0.22–0.63)*
Kosunen, 2002 (44)	Vammala, Finland	326 and 319 healthy subjects in 1973 and 1994, respectively	15–54	IgA & IgG ELISA	Atopy: any IgE >0.35 IU/mL	Atopy In 1973: In 1994:	0.97 (0.46–2.05) 0.20 (0.05–0.71)*
McCune, 2003 (45)	Bristol, England	3244 healthy subjects	20–59	13C-urea breath test	Current medications for the disorders: asthma (inhalers), allergic rhinitis (antihistamines), and eczema (topical corticosteroids)	Asthma: Allergic rhinitis: Eczema: Any of the three:	0.78 (0.59–1.05) 0.60 (0.36–1.00)* 0.29 (0.06–1.26) 0.70 (0.54–0.91)*
Linneberg, 2003 (46)	Denmark	1101 subjects	15–69	IgG ELISA	Self-reported allergic rhinitis Specific IgE to 6 allergens Atopy: any IgE >0.35 kU/L	Atopy Allergic rhinitis:	0.78 (0.57–1.08) 0.74 (0.51–1.07)
Jarvis, 2004 (47)	East Anglia, England	907 randomly invited from 15,000 young adults	20–44	IgG ELISA	Self-reported symptoms in the prior year suggestive of hay fever and asthma Total IgE and specific IgE to house dust mite, cat, grass, Cladosporium, and birch	Hay fever/nasal allergies: Wheeze with no cold: Allergy to grass: Allergy to >1 allergens:	1.01 (0.70–1.52) 0.80 (0.51–1.24) 0.65 (0.43–0.99)* 1.13 (0.81–1.59)
Radon, 2004 (48)	Northern Germany	321 with blood samples from 930 randomly selected from 3112 inhabitants	18–44	IgG ELISA, IgG CagA	Specific IgE against a panel of aeroallergens Atopy: any IgE>0.70 kU/L	Atopy:	0.70 (0.39–1.28)
von Hertzen, 2006 (49)	Eastern Finland, Western Russia	Healthy adults; 790 from Finland, 387 from Russia	25–54	IgG ELISA	Skin prick testing with a panel of 11 common airborne allergens Atopy: any wheal diameter ≥ 3 mm	Atopy, in Russians: In Finns:	0.55, p < 0.01*1 0.72, p = 0.53 1
Janson, 2007 (50)	Iceland, Sweden, Estonia	1249 healthy adults	Mean 42	IgG ELISA	Detection of specific Atopy: any IgE >0.35 kU/L Self-reported hay fever, asthma in the prior year	Atopy: For IgG antibodies to ≤3 specified infectious Atopy: Allergic asthma: Allergic rhinitis:	0.57 (0.43–0.77)* 0.70 (0.52–0.94)* 0.55 (0.34–0.89)* 0.59 (0.42–0.83)*
Chen, 2007 (51)	USA	7663 adults	20–90; Mean, 43	IgG ELISA, IgG CagA	Self-reported asthma and hay fever (current and lifetime) Skin sensitization tests	OR in relation to CagA+ Ever asthma: Onset age ≤ 15:	0.79 (0.63–0.99)* 0.63 (0.43–0.93)*
Herbarth, 2007 (52)	Germany	2487 children	Mean 6	13C-urea breath test	Lifetime physician-diagnosed eczema	Eczema:	0.37, p < 0.01*1
Shiotani, 2007 (53)	Japan	777 university students	Mean 19	IgG ELISA	Self-reported atopic dermatitis, bronchial asthma, allergic rhinoconjunctivitis, urticaria	Any allergic disease: Ever asthma: (in ≤19 years)	0.60 (0.40–0.90)* 0.65 (0.45–1.06)
Chen, 2007 (54)	USA	7412 adults	3–85, Mean 25	IgG ELISA	Self-reported asthma and hay fever (current and lifetime)	Current asthma: (in ≤ 13 years) Early childhood: (onset < 5 years)	0.41 (0.24–0.69)* 0.58 (0.38–0.88)*

CASE-CONTROL STUDIES
Author, year (reference)	Location	Study population	Age (years)	H. pylori measure	Definition of outcome	Major findings: Condition and OR (95% CI) in relation to H pylori+
Matricardi, 2000 (43)	Caserta, Italy	240 atopic cases and 240 non-atopic controls	17–24	IgG ELISA	Total IgE Atopy: logRU > 1.2 Non-atopic: logRU < 0	Atopy:	0.76 (0.47–1.24)
Bodner, 2000 (55)	Grampion, Scotland	97 cases and 208 controls	39–45	IgG ELISA	Skin & specific IgE tests Atopy: weal ≥ 3 mm, or any IgE > 0.35 IU/ml Self-reported adult-onset wheeze and asthma	Wheeze: Wheeze and asthma: Atopy:	1.20 (0.70–2.20) 0.50 (0.20–1.50) 0.90 (0.60–1.60)
Tseng, 2000 (56)	Hong Kong	90 cases with stable asthma and 97 controls	Mean 43	IgG ELISA	Current asthma diagnosed by ATS guidelines	Asthma:	1.55 (0.83–2.90)
Jun, 2005 (57)	Japan	46 cases with asthma, and 48 healthy controls	Mean 52	IgG ELISA IgG CagA	Current asthma diagnosed by ATS guidelines	Compared with healthy controls Asthma: For CagA+ Asthma:	1.10 (0.45–2.69) 1.20 (0.39–3.69)

^*P < 0.05

¹CI was not estimated because information on covariates is not available; the study reported a p-value adjusted for covariates only.

^•P < 0.05

To consider the findings of the cross-sectional analyses, we focus on two other studies that we conducted (51, 54). We first examined a large, publicly available database from the National Health and Nutrition Survey (NHANES) III, conducted between 1988 and 1994 (59). In the mid-1990’s, H. pylori and CagA serology were performed on stored specimens from more than 10,000 NHANES III subjects, with the laboratory workers and statisticians blinded to asthma or atopy status. In 2006, we were able to link 7,663 records that contained information on both asthma and H. pylori status (51). For all subjects, there was an inverse association of ever having had asthma with having a cagA+ H. pylori strain (OR (95% CI) = 0.79(0.63–099), with a stronger inverse association in those less than the median (43 years) age (0.63(0.43–0.93), and no association in the older persons. Similarly, the inverse association was strongest in those who had asthma onset before the age of 15 years (0.63(0.43–0.93), with no association with those with older-onset asthma. Highly similar trends were observed in relation to allergic rhinitis and allergy symptoms, with some inverse relationships also occuring in persons with cagA-negative H. pylori strains. We also linked records for 2,386 persons who had skin tests performed for pollens and molds, and who had H. pylori status ascertained (51). For 4 of the 6 antigens tested, there were inverse associations in persons with cagA+ strains, especially those below the median age. Thus, we found inverse associations between H. pylori, especially cagA+ strains, with asthma and related allergic disorders, especially involving younger individuals, and with early life disease onset.

Because of these findings, we sought independent assessment of the relationships. We then examined the subsequent survey, NHANES 1999–2000 (60). For that study, we found 7,412 subjects who had data on asthma and related conditions as well as on H. pylori status; no testing for cagA status had been performed. The median age in this study was 25, and because our prior results highlighted asthma with early age of onset, we focused on children less than 20 years old. We found significant inverse associations of H. pylori positivity with early onset of asthma and allergic rhinitis in children and teens under 20, as well as ever having had asthma and current asthma in children 3–13 years old(54). H. pylori also was inversely related to having recently had wheezing, allergic rhinitis, and dermatitis, eczema, or rash. These two large, cross-sectional, independent studies show highly consistent results across asthma and related allergic disorders, and extend the prior studies which were more limited in sample size, age range of study populations, as well as data on potential confounders, H. pylori strains, and age of onset of asthma (Table 1).

Biological plausibility for H. pylori to play a protective role against asthma

H. pylori status could be causally related to asthma and its related disorders, with colonized persons having a partial protection. Considering the Bradford Hill criteria (61) provides evidence that supports such a causal role. First, the secular trend is consistent and reverse causation in not likely; H. pylori is disappearing while asthma incidence is rising. Importantly, the decline in H. pylori acquisition, beginning early in the 20^th century, precedes the increase in asthma. However, all of the epidemiological studies to date are cross-sectional or case-control studies, and not prospective. Nevertheless, it is not likely that asthma and related disorders could themselves be leading to the disappearance of H. pylori. Once acquired early in life, if not treated with antibiotics, H. pylori persists at least for decades, if not for life. The cross-sectional studies could measure an effect of asthma, or of its treatment. For example, if asthmatics receive more antibiotics than non-asthmatics, that could reduce H. pylori prevalence. However, the specificity of the inverse association with early life asthma and not with long-standing asthma seen in adults is one argument against that proposition.

Second, a dose-response relationship between exposure and disease is present. Studies of differences among H. pylori strains show the strongest effects for cagA+ strains, in terms of risk of disease (ulcers, gastric cancer) or protection from disease (GERD and esophageal adenocarcinoma). A similar dose-response to that related to GERD is present with asthma, with cagA+ strains having the strongest inverse association (54, 58). Third, as shown in Table 1, a variety of cross-sectional studies show protective effects, suggesting consistency of the data. The increasing number of these studies, especially our two large, independent, and population-based studies, point toward a correct association. Nevertheless, that not all studies, especially the case-control studies, show this inverse association could indicate that there is population-based specificity for the observation, and/or differences in study design.

Fourth, is the role of specificity; asthma is considered as predominantly allergic or not. The strong inverse associations with H. pylori are present for asthma and other allergic disorders consistent with the allergic (atopic) spectrum. In addition, the inverse association with H. pylori appears stronger for childhood-onset asthma. There may be etiologic differences between childhood-onset and adulthood-onset asthma. Childhood asthma often remits during adolescence, although many of these patients in remission have relapses during young adulthood (62). Consistently, the case-control studies of H. pylori and current asthma in adults did not find any association (Table 1). The effect of H. pylori may be less important in adult-onset asthma, since the risk factors may be much more heterogeneous than in childhood asthma. In addition, asthma in adults may be new onset, persistent from childhood, or exacerbated from childhood asthma. Although commonly associated with atopy, adult asthma is more complex and onset may be complicated by environmental exposures (e.g. tobacco, occupation) (63, 64). Finally, the misclassification of current status of asthma and H. pylori could be more serious in adults. Since the misclassifications of asthma and H. pylori status do not depend on one another, it is non-differential, which would lead to a bias toward the null.

Fifth, the inverse association is coherent with our knowledge, and there is no evidence of plausible competing theories or rival hypotheses. One possibility is that H. pylori status, while related to asthma risk, is merely a marker for other phenomena. For example, early life antibiotic use (65, 66) that eliminates H. pylori carriage also could eliminate one or more other microbes that actually are the protective agents. There are insufficient data at present to rule out this possibility. Several studies that have evaluated multiple infections suggest their additive effect in the etiology of asthma (43, 50) (Table 1). In addition, the inverse association between H. pylori and asthma is independent of indicators of socioeconomic status, age, gender, ethnic background, smoking status, and hepatitis A infection (51). An independent phenomenon that makes asthma more likely and H. pylori carriage less likely could be underlying the inverse association. Such a phenomenon could be due to enhancement of Th-2 immunity due to another microbe, for example, and a consequent effect on H. pylori status could provide a maker of risk. Sixth, mechanisms exist (see below) that could explain a protective effect. In total, there is considerable biological plausibility for a protective role of H. pylori (especially cagA+) strains toward asthma and related disorders.

Mechanisms by which gastric H. pylori colonization might affect asthma risk

In the simplest statement, it is increasingly clear that the gastric physiology of the H. pylori-positive and negative subjects differs (9, 20, 67). Several non-exclusive mechanisms could be playing a role. First, if H. pylori, is actually protecting against GERD (10), it also could protect against asthma, since some proportion of asthma is due to GERD (68); this component may actually be underestimated (69). However, this mechanism is unlikely to be sufficient to explain protective H. pylori effects in hay fever and atopic dermatitis. Second, the constellation of asthma, atopy, hay fever, and skin sensitization suggests immunologic mediation. H. pylori-positive persons have a gastric population of immunocytes, including regulatory T-cells (33–36), that is largely or completely absent from H. pylori-negative subjects. Such cells may have systemic immunomodulatory activities. Recent studies indicate an interaction of H. pylori colonization with Mycobacterium tuberculosis, with colonization associated with the maintenance of tuberculosis latency (70), again pointing to a global immunomodulatory role. A third mechanism may relate to the effects of H. pylori-induced inflammation on gastric hormonal levels (9). Both leptin and gastrin have immunomodulatory activities as well as intermediary effects on energy homeostasis (71, 72). There is increasing evidence that H. pylori gastric colonization affects both ghrelin and leptin production (38, 73) which thus would affect the immunoregulatory environment. Finally, H. pylori’s effects on the autonomic nervous system might play a role. Individual differences in the host-microbial interaction could account for differential risk and disease expression. Prospective studies that evaluate the influence of H. pylori on both indicators of causal intermediates and asthma risk will help delineate the mechanisms.

Conclusions

For probably the first time in human history, generations of children are growing, without H. pylori in their stomachs, guiding the development of their immunologic capabilities, their hormonal regulation of energy homeostasis, and their regulation of gastric acidity (Figure 1). The loss of this ancient, dominant, and persistent member of the normal biota of humans would be predicted to have consequences, and there now is much information about the beneficial and deleterious aspects of this change on gastrointestinal tract health and disease (1, 10, 77, 78). However, increasing evidence is pointing to extra-intestinal manifestations of the disappearance of H. pylori, including disorders of energy homeostasis (38, 39) and asthma. An inverse association of H. pylori and childhood asthma, allergic rhinitis, and atopy is becoming increasing obvious. Although this may represent an epiphenomenon as part of a more general change in human microecology (1), there is substantial biological plausibility for a role of the disappearance of H. pylori and the rise of these allergic disorders of children. Nevertheless, if H. pylori, and especially cagA status, only is a marker for asthma risk, it could become useful for clinical and epidemiological studies. These questions are of sufficient importance that confirmatory and prospective studies in different populations should be done.

Clearly, the interactions of H. pylori are complex, somewhat host-specific, and certainly incompletely understood. Ten years ago, one of us predicted that doctors of the future will have the tools to perform relevant phenotyping and genotyping of young children and then take the appropriate stocks of H. pylori from their pharmacy and deliberately colonize that child with that strain (or combination of strains) most likely to optimize their life-long health (79). The continuing beneficial associations of H. pylori with reduction of risk for esophageal diseases (including malignancy), now with asthma and atopy, and possibly with obesity and diabetes (9, 38, 39), should be considered in H. pylori treatment and intervention plans, and move that earlier prediction closer to reality.

It is possible that for most individuals, H. pylori is beneficial in childhood and more deleterious later in life. Within such a paradigm, a public health framework for H. pylori introduction and eradication can be envisioned.