Helicobacter pylori (H. pylori) is present in roughly 50% of the human population worldwide and infection levels reach over 70% in developing countries. The infection has classically been associated with different gastro-intestinal diseases, but also with extra gastric diseases. Despite such associations, the bacterium frequently persists in the human host without inducing disease, and it has been suggested that H. pylori may also play a beneficial role in health. To understand how H. pylori can produce such diverse effects in the human host, several studies have focused on understanding the local and systemic effects triggered by this bacterium. One of the main mechanisms by which H. pylori is thought to damage the host is by inducing local and systemic inflammation. However, more recently, studies are beginning to focus on the effects of H. pylori and its metabolism on the gastric and intestinal microbiome. The objective of this review is to discuss how H. pylori has co-evolved with humans, how H. pylori presence is associated with positive and negative effects in human health and how inflammation and/or changes in the microbiome are associated with the observed outcomes.

Helicobacter pylori (H. pylori) infects approximately 50% of the human population worldwide and the infection could reach more than 70% in developing countries[1,2] The consequences of infection have been associated with the development of different gastro-intestinal diseases, such as gastric ulcers, gastric cancer, mucosa-associated lymphoid tissue (MALT) lymphoma and biliary tract cancer[3]. Moreover, H. pylori infection has also been associated with extra gastric diseases, such us ischemic heart diseases[4], type 2 diabetes mellitus[5], anemia[6], adverse metabolic traits in obese subjects[7] and insulin resistance[8], to mention but a few.

Despite the existence of such associations, these diseases occur only in a small percentage of infected people, suggesting that the bacteria frequently persists in the human host without inducing any obvious signs of disease, and it has been suggested that H. pylori may also play a beneficial role in human health[9-14]. Indeed, recent studies indicate that the decreasing incidence of H. pylori in the developing world is paralleled by an increase in the incidence of allergies and autoimmune diseases[15]. Furthermore, the absence of H. pylori has been linked to elevated incidence of diseases, such us multiple sclerosis and celiac disease, among others[16-18].

Several studies have focused on understanding the local and systemic effects triggered by this bacterium in order to understand how H. pylori can produce such diverse effects in the human host. One of the best-characterized mechanisms involved in such effects is likely to be the damage to the host induced by local and systemic inflammation[19]. However, more recently, studies are beginning to focus on the effects of H. pylori and its metabolism on the gastric and intestinal microbiome[20-23]. This emerging field of interest could explain, at least in part, the wide variety of effects that are currently attributed to the presence of H. pylori in the human body.

In this review, we discuss such gastric and extra-gastric effects of H. pylori and the possible mechanisms involved.

H. pylori is a Gram-negative bacterium whose presence in the stomach of infected individuals is linked to the development of several gastric diseases, such as chronic gastritis. Although it is estimated that 50% of the world population is infected by H. pylori, only a small percentage of infected patients develop more severe pathologies, such as ulcers (10%-15%) and stomach adenocarcinomas (less than 1%)[1,2], the latter representing 15.4% of the cancers produced by infectious agents worldwide in 2012[24]. These values suggest that while relevant to the development of severe diseases, including gastric cancer, this pathogen could also play other roles in the human host.

It is now well established that H. pylori has been a highly prevalent pathogen in humans for over sixty thousand years and that infection occurs mainly in the intimate family environment or through vertical transmission[25]. These continuous infections and contact with other bacterial strains promoted the existence of a large number of mutations and genetic variability among bacteria due to horizontal transfer of information[26-28]. The emerging differences have been characterized particularly with respect to geographic distribution and such studies have revealed that the observed genomic alterations allow H. pylori to survive in different microenvironments[29,30]. Moreover, these genetic modifications are thought to have lead to the emergence of less virulent strains, which may explain the low percentage of patients affected with serious pathologies, such as adenocarcinomas[31].

The events during human evolution associated with initial acquisition H. pylori are thought to have been the development of agrarian practices, as evidenced by the presence of DNA remnants in the H. pylori genome, such as the vir genes of Agrobacterium tumifaciens[32]. Also population migration is likely to have contributed to the acquisition of genes or genomic islands important for H. pylori virulence. One of them is the cagPAI genomic island, where cagA is one of the most important virulence genes associated with an increase in the activation of pro-inflammatory pathways and the production of pro-inflammatory cytokines in the stomach mucosa[33,34]. According to genomic analyses of H. pylori, European colonization trips to South America may have contributed to the acquisition of cagA by indigenous people living in the Andes, who possessed H. pylori without a functional cagA gene[30,35]. Moreover, other studies analyzing South American populations, such as the Colombians, have determined that the mountain people with greater similarity to the native people of that region have a higher incidence of gastric cancer compared with residents of coastal towns, who were more strongly influenced by the colonization of African migrant populations. Currently, this sector of the population has a low incidence of gastric cancer associated with H. pylori infection[36,37].

However, it has been observed that although in certain populations positive CagA strains are more numerous (as in parts of Eastern Asia), there are specific characteristics that make it unlikely for them to spread to the rest of the world, such as Western countries, with fewer positive CagA strains. These observations suggest that “fitness traits” exist, which aid in the survival of the bacteria in different hosts, in addition to other well-known factors, like difference in the lifestyles, socioeconomic levels and diet of the host population[38]. Japan, for example, has the highest rate of gastric cancer worldwide, associated with the highest presence of CagA (57%); however a lower seroprevalence is observed compared to other populations[39]. In contrast, despite the high prevalence of H. pylori in India, a low rate of gastric cancer is registered (known as the “Indian Enigma”). One of the main hypotheses seeking to explain this enigma is that the higher rate of enteric infections in more poorly developed countries could boost the immune system and limit the consequences of H. pylori infection. In addition, the high diet content of peppers, which represent an important ingredient in the Indian diet, may protect against H. pylori infection[40]. In conjunction, these examples support the hypothesis that a variety of factors contribute to the fitness of H. pylori in different human host populations.

Therefore, bacterial and host fitness are very relevant in H. pylori infection. In particular, host genetics likely affect the progression of pathologies associated with H. pylori infection. Indeed, specific polymorphisms in genes coding for cytokines, such as IL-1β, IL-8, IL-10 and TNF-α, are associated with an increase in the pro-inflammatory responses, greater colonization and infection, as well as an increased risk of gastric cancer[41-45]. Also, polymorphisms in innate immunity genes, such as the toll-like receptor 4 (TLR4), are relevant because TLR4 is implicated as a receptor responsible for H. pylori induced signaling in gastric epithelial cells. Moreover, epigenetic changes due to hypermethylation in the promoter regions of tumor suppressor genes, such as LOX, HAND1 and APC, and the alteration as well as deregulation of microRNAs (miRs) are associated with a higher prevalence of gastric cancer following H. pylori infection[46,47].

Despite clearly representing a human pathogen, evidence is available suggesting that this bacterium could also be considered a commensal bacteria in the human host. This notion is supported by the simple observation that the bacteria is present in so many individuals, yet generates relatively few symptoms or pathologies. This raises the issue as to whether to refer to H. pylori as a commensal or pathogen, because pathologies are likely not only to be associated with specific traits of H. pylori, but also with a series of specific conditions in the human host.

H. pylori has been found as part of the normal oral microbiota and part of the microbiota of the stomach in the absence of inflammation[48,49]. In addition, it has been reported that H. pylori infection is not associated with the onset of the gastric cancer, but rather with its recurrence and chronicity[50]. Moreover, the presence of H. pylori in the stomach microbiota may result in changes in the normal microbiota[21,23].

In this context, it is worth mentioning that several studies have attributed positive effects to H. pylori infection. These include the suppression of bacteria that cause tuberculosis (Mycobacterium tuberculosis), protection against asthma, Crohn’s disease, esophageal reflux, diarrheal diseases, as well as esophageal cancer[9-14]. This controversy has led to the discussion whether eradication of H. pylori is recommendable to help restore the host’s health status, or if alternative strategies should be developed to control virulence of the bacteria, thereby avoiding the appearance of ulcers and adenocarcinomas without eliminating the positive effects that this bacterium may have [51]. With this in mind, it is not surprising that H. pylori is so widely studied and considered a relevant target in many therapies.

H. pylori infection triggers several adaptative cellular mechanisms in host cells that may favor gastric cancer development and progression[108]. However, whether the disease develops or not and the final outcome are thought to depend largely on the extent of inflammation promoted by the bacteria in the host during the pre-neoplastic process[109]. Indeed, chronic inflammation is a common causative event associated with the development of several types of cancer[110,111] and, as was demonstrated in animal models, H. pylori infection is considered the major factor responsible for gastric epithelial damage and deregulation of signaling leading to irreversible epigenetic changes in the gastric mucosa, a consistent hallmark observed during the gastric carcinogenic cascade[19,109]. Initially, H. pylori-related studies focused on identifying the virulence factors implicated in these processes. Those factors epidemiologically associated with a higher risk of developing gastric cancer were tested in vitro and shown to induce signaling pathways associated with exacerbated inflammatory responses. For example, strains harboring particular vacA and cagA allele variants were found to induce elevated inflammatory responses in infected cells[112]. However, this seemingly simple scenario rapidly transited to a more complex one when epidemiological data revealed that in certain ubiquitously infected populations no correlation with elevated gastric cancer incidence was detected, as is the case for the so-called African enigma[113] where only a minor percentage of infected patients progress to develop cancer. To date, experimental studies have clarified that final disease outcome depends not only on the contribution of certain bacterial virulence factors, but also on host susceptibility, diet and environmental factors[114]. Here, it is important to mention that co-existence with the bacteria is not only to be viewed negatively (see previous and following chapters), bearing in mind that since the prevalence of the infection has declined in developed countries over the last decades, several disorders have emerged as a consequence of the lack of exposure to H. pylori[115]. Human beings have co-evolved with the bacterium and gastric as well as extra-gastric physiology has been conditioned to such association[116]. In order to persist in the gastric niche, H. pylori have evolved mechanisms necessary to evade and to attenuate the innate and adaptive immune systems by several mechanisms, including those implicated in evasion of recognition by pattern recognition receptors, inhibition of phagocytic killing, inhibition of killing by ROS and nitric oxide, among others[117]. Particularly, antigenic phase variation, modulation of adhesion molecules, immune inhibition by VacA protein and lipopolysaccharide (LPS) have been widely described[118]. Moreover, additional mitigating local mechanisms mediated by bacterial enzymes exist. For instance, it was recently reported that the expression of a cholesterol-α-glucosyltransferase reduced cholesterol levels in gastric epithelial cells, blocking IFN-γ signaling, a classical Th1 cytokine[119]. Notably, this enzyme is present in most Helicobacter species and cholesteryl α-glucosides are also involved in resistance to antibiotics[120], interference with phagosome trafficking[121], H. pylori type IV secretion system function[122] and immune evasion by inhibiting T-cell activation[123]. On the other hand, H. pylori superoxide dismutase (SOD) has been shown to suppress the production of pro-inflammatory cytokines during in vivo infection by reducing oxidative stress. Thus, SOD from H. pylori can inhibit the production of pro-inflammatory cytokines during in vivo infection[124]

Additionally, H. pylori deregulates adaptive immune responses by interfering with antigen presentation and modulation of T-cell responses[117,118]. Eradication of H. pylori has revealed the importance of this modulation of the immune response in preventing the development of extra-gastric immune and inflammatory disorders, such as gastroesophageal reflux disease, childhood asthma and allergy, as well as metabolic disorders[15,52,54]. Although in most of the cases correlations are derived from cross-sectional studies, the most experimentally validated preventive association is the appearance of childhood asthma[115,125]. Moreover, innate immune responses are also involved, given that bronchial epithelial cells, mast cells, basophils, natural killer T cells and dendritic cells (DC) also produce inflammatory mediators[52]. This harmful effector response is modulated by CD24+CD25+ regulatory cells (Treg) present in the lung, which secrete anti-inflammatory cytokines, such as IL-10 and transforming growth factor beta (TGF-β), preventing or modulating the Th2 responses to allergens[126]. Tregs of healthy individuals shift allergen-specific immune responses toward tolerance, thereby preventing the development of asthma and other allergic disorders[52]. Also in animal models of infection, the importance of dendritic cells in H. pylori-specific adaptive immune responses was noted. Particularly tolerance induction[52,127], Treg skewing and Th17 suppression observed in mice occurred in a cagA- and vacA-independent manner[128]. Chronic exposure to H. pylori impairs dendritic cell function and inhibits Th1 development[129]. Also, H. pylori-mediated protection was linked to IL-10-secretion by peripheral blood Treg cells[130].

The importance of these immune cells has been validated in experimental animal models of infection or induced asthma. For instance, blocking CD24+CD25+ Treg cells by a CD25-neutralizing antibody abrogated Treg cell tolerance promoted by H. pylori infection and enhanced pulmonary inflammation following albumin induced asthma[131]. Also, KO animals for IL-10, TGF-β or animals depleted of Tregs, develop gastritis to an elevated extent in response to H. pylori infection. Although these animals are able to clear the infection, pre-neoplastic lesions develop since Th1 responses predominate[52]. Together, these results indicate that tolerance rather than immunity protects against H. pylori-induced gastric pre-neoplastic lesions[132]. Accordingly, decreased Treg cell function is associated with an increase in peptic ulcer development upon H. pylori infection[133].

A currently unresolved question is how H. pylori promotes tolerance in distant organs such as the lung? A recent study showed that systemic and mucosal pre-administration of recombinant neutrophil-activating protein prevented ovalbumin-induced allergic asthma in mice, indicating that secreted virulence factors may be responsible[134]. What determines the balance between tolerance or elimination of an exacerbated Th1 type chronic inflammation could be explained in part by host hyperreactivity to allergens or bacterial infection. In this respect, pro-inflammatory cytokine polymorphisms are generally thought to participate in the genesis of gastric and other types of cancer[109] and interleukin family cytokines, like IL-1β and IL-18, have emerged as central mediators of mucosal inflammation[135]. On the other hand, virulence factors can determine the type of response. For instance, blocking the TLR4 in a mouse model using a specific antibody prior to H. pylori infection, was shown to reduce the number of T-cell effectors (Th1 and Th17) and diminish the immune response[136]. In agreement with this observation, activation of TLR4 signaling was reported to be associated with gastric cancer progression by inducing mitochondrial ROS production[137]. Moreover, type I H. pylori (cag PAI+ and vacuolating toxin A+, VacA+) LPS exhibited a stimulatory effect on TLR4 signaling followed by mitogen oxidase 1 activation in cultured gastric pit cells through the lipid A portion of LPS[138]. In a similar study, LPS from some H. pylori strains were shown to act as TLR4 antagonists, which may contribute to more beneficial clinical outcomes of H. pylori infection in host individuals[139]. Additionally, H. pylori LPS from type I, but not type II strains, promotes cytotoxicity in cultured gastric mucosal cells[140]. Conversely, TLR2 mediates H. pylori-induced tolerogenic immune responses[141] and TLR9 signaling has anti-inflammatory effects during the early phase of H. pylori-induced gastritis in mice[142]. Also, additional virulence factors have been implicated in immune response suppression or tolerance, such as the suppression of dendritic cells by OipA in vitro[143], promotion of immune tolerance by VacA-mediated inhibition of T-cell proliferation and antigen-presentation[59]. Also, bacterial gamma-glutamyl transpeptidase[59] and outer membrane vesicles inhibit T-cell responses[144,145]. Furthermore, H. pylori infection has been associated inversely with IBD. Experimental immuno-regulatory properties of the H. pylori genome and particularly the immuno-regulatory sequence TTTAGGG was demonstrated to down-regulate dendritic cell-mediated production of pro-inflammatory cytokines both in an in vitro and in vivo model[146].

As discussed above, H. pylori infection has been associated both positively and negatively with the development of gastric and non-gastric diseases. Disease development is often linked to chronic inflammatory responses induced by H. pylori, as was discussed in the previous section. However, it is now becoming increasingly clear that H. pylori also induces changes in the host by altering the microbiome. This aspect will be covered in the following paragraphs.

The harsh gastric environment is thought to represent a key limitation to the complexity of the stomach microbiota[147]. This assumption, together with limitations imposed by culture-dependent strategies for bacterial identification, has historically leaded to an underestimation of the biodiversity in the stomach. In this context, the gastric microbiota was initially considered to include only a very select group of taxa, including mainly Veillonella spp., Lactobacillus spp., and Clostridium spp., besides -of course- H. pylori[148-151]. Nonetheless, with the development of more sophisticated 16S rRNA-based bacterial identification techniques, we now have gleaned deeper insight to the complexity of the gastric microbiome. Accordingly, an increasing number of publications describe greater ecosystem diversity in the stomach and, importantly, correlate the presence of H. pylori with variations in the composition of the microbiome[23,48,152-156]. Bik et al[152] identified taxa, such as Caulobacter, Actinobacillus, Corynebacterium, Rothia, Gemella, Leptotrichia, Porphyromonas, Capnocytophaga, TM7, Flexistipes, and Deinococcus in the normal microbiome. Alternatively, Li et al[155] showed that the most common genera in gastric biopsies from both normal and non-H. pylori gastritis individuals were Prevotella, Neisseria, Haemophilus, and Porphyromonas. Later, Delgado et al[153] also identified Propionibacterium, Lactobacillus and Streptococcus as dominant genera in healthy samples.

Regarding the effect of H. pylori on the gastric microbiome, there is still some controversy. No effect on either diversity and/or evenness in community members between H. pylori-positive vs H. pylori-negative samples were observed at the phylum level[152]. Likewise, in a mouse model of H. pylori infection, neither acute nor chronic H. pylori infection altered the murine gastric microbiota[157]. Similarly, others described that, although when present H. pylori dominates the microbiome, only minor differences in community structure were observed in stomach biopsies from H. pylori-positive and negative subjects[158]. However, others have shown that the presence of H. pylori dramatically reduces the diversity of the gastric microbiota[20,21,23] and modifies the microbiome by increasing the relative abundance of Proteobacteria, Spirochetes and Acidobacteria, while decreasing Actinobacteria, Bacteroidetes and Firmicutes[156]. Similar results were reported by Thorell et al[30], who performed a meta-transcriptomic analysis and reported higher levels of Firmicutes, Bacteroidetes, and Actinobacteria in subjects with low levels of H. pylori. Such discrepancies might be due to inter-subject variations, since the gastric microbiome seems to be sensitive to exogenous factors, such as diet and lifestyle, as has been shown by the analysis of monozygotic twins[159].

Interestingly, while the experimental inoculation of H. pylori into an established community in rhesus monkeys, did not affect the community membership or structure[160], pre-infection of mice with H. pylori did alter the microbiota structure in the stomach[22]. Therefore, the time-point in life when H. pylori is acquired is another aspect to be considered in the discrepancies reported for H. pylori-associated microbiome variations. Differences in both diversity and community composition were also observed in the stomachs of H. pylori-infected vs H. pylori-negative children and also in comparison to adults, regardless of the H. pylori status[161]. Thus, early acquisition of the bacterium is likely to shape the microbiome by inducing local modifications in the stomach environment. One of these effects is driven by the production of ammonia and bicarbonate from urea[162,163]. Such compounds may serve as substrates for other bacteria[164], in addition to altering the stomach pH[162,163], which facilitates the colonization by other species, such as nitrogen-reducing bacteria[165]. Moreover, H. pylori-induced increases in the stomach pH favor the migration to the stomach of some bacterial taxa that are usually restricted to the intestinal tract (Bacteroides and Clostridia) in mice[166]. Interestingly, the effect of H. pylori on acid secretion depends on the pattern of gastritis that is induced[167]. In predominantly antral gastritis, the production of gastric acid is increased (hyperchlorhydria)[168], while in predominantly corpus gastritis, acid production decreases (hypochlorhydria)[169]. Thus, microbiome shifts may differ in both cases. In fact, hyperchlorhydria increases microbial diversity in the stomach[170] and it has been implicated in the development and progression of cancer (reviewed by Espinoza et al 2018[171]). Additionally, the viscosity of the gastric mucus layer decreases when the pH increases[172], making it easier for other microorganisms to colonize the epithelium. Finally, H. pylori can directly alter the mucus barrier by modulating the expression of stomach mucins[173].

As illustrated above, all these environmental modifications in the stomach may impact on the local microbiome, as well as induce changes in the entire gastrointestinal tract, since these are dynamic compartments between which fluids are exchanged and therefore microbes can easily migrate from one gastrointestinal segment to another[174]. Some of these H. pylori-mediated downstream effects in other compartments include impairment in the absorption of iron and vitamin B12 in the intestine[175,176], and alterations in carbohydrate and amino acid metabolism of the host[177]. Interestingly, besides the direct effect of H. pylori in the stomach/intestine, also the immune response triggered by the bacterium could affect the local microbiome, as well as bacterial populations at more distal sites in the human body.

Regarding the effect of H. pylori-mediated immune mediators in the microbiome, there are some contradictory reports. No statistically significant differences in the microbiota were found in CagA-positive (n = 10) compared to CagA-negative (n = 10) biopsies from human subjects[178]. Therefore, the increased production of pro-inflammatory cytokines mediated by CagA appears not to have an effect on the microbiome in this model. Nonetheless, as the sample cohort was small in that study, this question probably needs to be re-evaluated in larger groups of samples. In contrast, in a transgenic Drosophila model of CagA expression, CagA was sufficient to alter midgut host microbiota[179]. Additionally, a series of reports demonstrated differences in the intestinal microbiome related to the presence of H. pylori both in humans[180] and mice[22]. Moreover Schulz et al[158] correlated the presence of H. pylori in human individuals with modifications in the microbiome of the duodenum and the oral cavity. More specifically, Heimesaat et al[181] demonstrated that chronic infection of Mongolian gerbils with H. pylori resulted in changes in some specific genera, including increased abundance in the large intestine of Akkermansia, which is involved in mucus degradation. These changes were accompanied by variations in the expression of immunity-related genes in both the stomach and the lung, with stronger effects in the former. The authors speculated that early community shifts could reflect changes in the niche microenvironment (e.g., altered gastric pH), while later shifts might be driven by the cumulative changes in the immune/inflammatory response triggered by H. pylori. These effects could also be observed at distant sites in the host organism and be driven by other members of the Helicobacter genus. For instance, natural colonization of the mouse digestive tract with Helicobacter hepaticus leads to a shift in gut microbiota, which generates subclinical inflammation and a drastic impairment of the control of Mycobacterium tuberculosis growth by the immune system[182].

It is likely that H. pylori might affect mucosal diseases at distant sites via its effects on immune cells that traffic through lymphatic vessels. H. pylori also induces a shift in the immune response toward an induction of Treg cells, mediated by VacA and GGT[59,161,183,184]. Treg cell responses are important in differentiating between self and foreign antigens, i.e., immunological tolerance. This effect could be involved in H. pylori persistence in the stomach, and also could contribute to suppressing gastric inflammation, which may explain reduced gastric disease severity in H. pylori-positive children compared to H. pylori-positive adults[161]. Such effects have been linked to alterations in the stomach physiology and its microbiota, as well as to progression of extra-gastric diseases, such as asthma[59], celiac disease[17], ischemic heart diseases, insulin resistance, Type 2 diabetes mellitus, periodontal diseases, among others (see previous sections and references listed in Table 1).

Interestingly, as was stated above, H. pylori is part of a complex microbiota in the stomach and its presence has been linked to modifications in the microbiome at other sites in the body. Therefore, it is reasonable to speculate that other community members could also contribute to changes observed following H. pylori infection of the host. Indeed, direct bacteria-bacteria interaction was described by Khosravi et al[185] between H. pylori and Streptococcus mitis, in which H. pylori transit from spiral to coccoid-shaped cells that are more resistant to stressing conditions. The exact effect of this conversion on disease progression remains to be elucidated. Also, antimicrobial molecules produced by Lactobacillus spp have been shown to be active against H. pylori strains[186-189]. Therefore, bidirectional communication and modulation between H. pylori and other community members occur, and the combination of all these interactions will be reflected in the host health status. The question as to how the microbiota shapes the immune system and how this affects its response to some diseases has been broadly discussed in the literature (see for instance, Hooper et al[190] 2012). Therefore, modifications in the microbiome induced by early acquisition of H. pylori[161] may also determine the host immune status and, as a consequence, the development of a number of systemic diseases. This is relevant, since Rolig et al[191] reported that when the microbiota is altered by antibiotic treatment, the H. pylori-triggered inflammation is reduced.

In summary, H. pylori has a strong effect in the stomach microenvironment and also on the host immunological status, leading to shifts in the microbiome at different sites of the body. These shifts are involved not only in the pathogenesis of gastric diseases, but also in some of the non-gastric H. pylori-related diseases that were discussed in this review. The question as to whether the bacterium is acquired early on or later in life is a key point when analyzing such effects, as H. pylori has been reported to co-evolve with its host, shaping the immune system and consequently, the microbiome. Therefore, a better understanding of the exact mechanisms involved in such effects, as well as the H. pylori-induced microbiome shifts that may be related to the development of specific diseases, will likely be useful to predict and hopefully prevent H. pylori-associated diseases. Ideally, one would aspire to achieving this goal while at the same time preserving the beneficial effects that H. pylori-host co-habitation appears also to offer.