Might helicobacter pylori play a role in allergic or cross-reaction related disorders?

KEYWORDS:

• Helicobacter pylori
• allergy
• atopy
• cross-reaction
• asthma

1. Introduction

Helicobacter pylori (H. pylori) is the most common cause of major gastric benign (chronic active gastritis, peptic ulcer) and malignant disorders (gastric carcinoma, mucosal associated lymphoid tissue lymphoma) [1,2]. However, a link between H. pylori and a large series of extra-intestinal disorders [3] has been ascertained even if with different levels of evidence. Pure atopic reactions, such as urticaria or asthma, have been hypothesized to be associated with H. pylori and this relationship will be herein discussed.

2. Body

A cross-reaction between some components of H. pylori and the immune system has been demonstrated. A representative example could be autoimmune gastritis, in which the similarity of H+,K+-ATPase and bacterial epitopes may lead to the production of antibodies against parietal cells, thus suggesting that bacterial infection may be the trigger of a successive autoimmune mucosal inflammation [4]. Moreover, it has been hypothesized that an infection in childhood with a spontaneous bacterial clearance might be the basis of this event [5].

A suitable example of a positive association between H. pylori and atopy is represented by chronic spontaneous urticaria, a skin disorder characterized by recurrent itchy wheals within a period of almost 6 months. A meta-analysis demonstrated that the prevalence of H. pylori infection was greater in chronic urticaria patients than in controls (odd ratio = 1.66) [6]. Moreover, the same study reported that spontaneous remission of symptoms occurred more frequently in H. pylori negative than in positive patients. An additional remarkable result showed that bacterium eradication doubled the possibility of clinical remission [7].

Several hypotheses have been formulated to explain these findings. In detail, a 21–35 kDa mixed proteic component of H. pylori might stimulate the degranulation of human mast cells [8]. Moreover, some bacterial genes, such as cagA, vacA and nap might codify for specific proteins triggering immune responses, thus enhancing pro-inflammatory pathways [9,10].

Nevertheless, the paradigm of cross reactions might only be partially applied to atopic disorders. In fact, it seems that H. pylori infection fulfills the main features of the so-called ‘hygiene hypothesis’. According to this theory, formulated in 1989 by Strachan, the improvement of hygienic conditions in Western countries has led to a minor exposure to infective agents during childhood [11]. As a consequence, this might have impaired the priming and development of the immune system, thus causing the diffusion of allergic and autoimmune disorders [12]. Therefore, the decline of H. pylori spreading might be hypothesized as a possible background for the diffusion of atopic diseases. Furthermore, interventions such as cesarean delivery, changes in breastfeeding formulas and early antibiotics use have caused a disappearance of ancestral human microbiota [13], in whose context H. pylori could be even considered as a component. Further, considering that the acquisition of H. pylori could occur in early stages of life, presumably by maternal acquisition, this event could not be considered as an environmental exposure, thus supporting the hygiene hypothesis. H. pylori might be protective against allergic disorders. A mechanistic explanation for this phenomenon could be that a persistent gastric infection is associated with dendritic cell activation and induction of T-regulatory lymphocytes, which in turn, results in an increased tolerance toward environmental antigens [12]. Evidences supporting possible mechanisms of the protective role of H. pylori in asthma are provided by studies of basic science in animal models. In this regard, the bacterium has been demonstrated to powerfully re-program dendritic cells (DCs) toward a tolerance-promoting phenotype, thus inducing the production of regulatory Foxp3 + T lymphocytes, which are protective against atopy [14]. On the other hand, in H. pylori infected mice, it has been shown that DC depletion has led to down-regulation of T-regulatory cells with improved airway inflammation [15]. In addition, it has been proven that the urease produced by the bacterium activated NLRP3, a component of cytoplasmic inflammasome in DC and stimulates the TLR2/NLRP3/IL-18 axis, which is a well known pathway protecting against asthma [16]. Additionally, the immune response mediated by Th1 versus Th2 may explain the balance between H. pylori infection and atopy. It is known that the bacterium may elicit a Th1-dependent immune response, over Th2 [17] and express high levels of tumor necrosis factor alpha in the gastric mucosa [18]. This event could prevent the development of a Th2-mediated response, which drives the onset of allergic diseases. In this perspective, Helicobacter pylori neutrophil-activating protein (HP-NAP) is able in vitro to elicit IL-12 and IL-23 production via agonistic interaction with toll-like receptor 2, and to promote Th1 polarization of allergen-specific T-cell responses. Indeed, in a murine model, administration of HP-NAP was able to reduce eosinophilia, IgE and Th2 cytokine levels in bronchoalveolar lavage [19]. Similarly, in ovalbumin (OVA)-induced allergic asthma animal model, HP-NAP reduced the levels of IL-4 and IL-13 (two mediators of atopic response), as well as that of total IgE [20].

These basic data parallel human epidemiologic studies. Indeed, the National Health and Nutrition Examination Survey (NHANES III) 1999–2000 study performed cross-sectional analyses to assess the association between H. pylori and childhood asthma. Bacterial seropositivity was inversely associated with the onset of asthma, especially in the first 5 years of age (odds ratio = 0.58). In addition, H. pylori seropositivity was also inversely related to recent wheezing, allergic rhinitis, dermatitis, eczema, or rash [21]. Further meta-analyses confirmed an inverse correlation of H. pylori infection with atopy [22]. However, these data show a meta-analytic heterogeneity as a relevant drawback due to the different methods for both H. pylori infection and atopy appraisal. On the other hand, few studies supported an opposite deduction and stated that wheezing and allergen specific antibodies were more commonly found in H. pylori [23] and anti-cagA positive subjects [24].

Indeed, the bacterium has inhabited the human stomach for several millennia, and evolutionary and environmental stimuli might have induced a mutual adaptation between guest and host [25,26]. Thus, the possible inhibitory role in asthma onset could represent a ‘strategy’ by which the germ may promote its survival in humans, creating a ‘symbiotic process’.

On these bases, the lesson is difficult to interpret. The hypotheses are quite dissimilar, and results are conflicting. Doubtless, when approaching the field of atopic disorders, it is crucial to remember that each disease has a complex pathogenesis and it is impossible to encase under the same umbrella atopic dermatitis, asthma and urticaria for the truthful differences in clinical manifestations and pathogenetic pathways. In other words, they could be considered as ‘distant relatives’ and therefore, it is pretentious to assert that H. pylori could be a common ancestor.

The results of evidence-based medicine could advocate two main considerations. The first one is that only some disorders, such as chronic urticaria or immune thrombocytopenic purpura, may benefit from H. pylori eradication. In this case, the literature might encourage the treatment of the bacterium, together with specific dermatological or hematological therapy. In this regard, we must note that the pathogenesis of these conditions is complex and multiple predisposing factors are involved. On the other hand, it is known that H. pylori eradication may improve, but not always suppress both disorders. The second consideration is based on the hypothesis that H. pylori infection might alter the composition of gut microbiota, and this event may be a trigger for the onset of atopic diseases [27]. Indeed, the bacterium may increase the diversity index of microbiota composition by inducing a shift from an enterotype characterized by Bacteroides, to one dominated by Prevotella [28]. Moreover, Fusobacterium, Neisseria, Prevotella, Veillonella and Rothia have been positively associated with the presence of H. pylori and related gastric lesions [29]. These evidences have stimulated studies to demonstrate that the eradication of the bacterium may permit the restoration of the microbiota composition. In a recent study, H. pylori eradication induced an increase of Bifidobacteria and an enrichment of some potentially beneficial gut bacteria such as Blautia and Lachnoclostridium [30]. Furthermore, the microbiota composition of children with H. pylori eradication was comparable to non-infected individuals [31]. Therefore, it is reasonable to speculate that a multifaceted pathogenetic mechanism may occur in atopic diseases and novel strategies aiming to modulate the imbalance of microbiota may play a key role [32]. Accordingly, an intervention on the triple bound H. pylori-microbiota-atopy could be invoked to explain this mutual relationship and design future interventional trials aimed to microbiota handling.

In conclusion, despite the fact that H. pylori role has been recognized in both cross reactions and atopy, it needs to be framed in a context characterized by multifactorial events developing over time. Bacterium eradication has been proven to be useful in urticaria, while it seems to exert a protective role in asthma. Lastly, its interaction with intestinal microbiota composition suggests the possibility of an intervention on the triple bound H. pylori-microbiota-atopy. Our hope is to expect future studies to bring further elements of translational medicine.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Acknowledgments

Mrs. Mary Paulene Butts for linguistic revisions.

Additional information

Funding

This paper was not funded.