Helicobacter pylori: A Beneficial Gastric Pathogen?

Since Helicobacter pylori (H. pylori) is the first successful culture three decades ago, ongoing perspectives regarding the relationship between the bacterium and human health have changed radically (1, 2). Apart from tremendous studies performed during the last years, there are still many debates regarding the unclear rationale for existence of such bacteria in human stomach (3, 4). Basically, due to the beneficiary effects of H. pylori colonization (regression in child asthma and other allergic disorders), it has been concluded that H. pylori is a common flora or at least harmless bacterium (5–10), Conversely, because of the causative role of H. pylori in certain digestive diseases such as duodenal ulcer and gastric cancer, other reports are quite contradictory (11–13). A large number of discussions led to a consensus regarding presence of H. pylori in the human stomach (5, 11, 14, 15). Our knowledge about biology of H. pylori suggests that the bacterium is highly adapted to stay in gastric mucosa for long time (1, 16). Indeed, living in lower surface of gastric mucosa, with no bacterial competition, provided a novel place to survive. Moreover, H. pylori is able to multiply freely due to the protective effects by mucosal layer. Thus, H. pylori had an opportunity to thrive in stomach over the course of tens of thousands of years of co-evolution with humans (17). Additionally, the high frequency of mutation in the genome also led to higher chances of survival, and natural selection helped them to remain and cause chronic infection (18). Determining whether H. pylori is beneficial or detrimental in human stomach has been a challenging area of research in gastroenterology (5, 11, 19, 20). In this article, we aim to elucidate various aspects of this persistent colonization of this beneficial infection. 
 
H. pylori: Carried by human over the history 
It seems that H. pylori is an old recognized bacterium, which is not clinically comparable with new discovered infectious agents such as human immunodeficiency virus (HIV). In other words, HIV was introduced to human hosts <50 years ago. Given a long period of H. pylori colonization in the human stomach, mutual benefits obliged both partners to adapt themselves in order to establish stable symbiosis. It has been firmly established that H. pylori first subverts innate immunity and then modulates the adaptive immune system (blocking the activation of both B and T cells) (21–23). As a result, cagA and vacA, the main bacterial products, will inhibit B cell and T cell proliferation, respectively. Accordingly, immune response in the stomach is silenced against digested microbes (24, 25). Undeniably, the stomach, with its harsh acidic condition, is a container for many digested microbes every day. Possibly, regulation and modulation of immune response arose after microbial exposure to H. pylori colonizing the stomach (24, 25). Our current understanding of the strategies used by this pathogen to make a lifelong colonization, disclosed that maybe for our old ancestors having this bacteria in the stomach happened initially by accident, but due to natural selection, H. pylori made a set of adaptations, enabling the bacterium to survive and also thrive in the surface of human gastric epithelial cells. To everyone’s surprise, after millions years of living in human stomach, H. pylori became a strategic member of our microbiome (26). Undoubtedly, it is no exaggeration to say that both host and the bacterium are following a constant beneficial relationship, which is quite unique in biological world. After long period of H. pylori gastric colonization, it has evolved into a highly adaptable persistent bacterium, obtaining all necessary features of the most successful human pathogen.


INTRODUCTION
Since Helicobacter pylori (H. pylori) is the first successful culture three decades ago, ongoing perspectives regarding the relationship between the bacterium and human health have changed radically (1,2). Apart from tremendous studies performed during the last years, there are still many debates regarding the unclear rationale for existence of such bacteria in human stomach (3,4). Basically, due to the beneficiary effects of H. pylori colonization (regression in child asthma and other allergic disorders), it has been concluded that H. pylori is a common flora or at least harmless bacterium (5)(6)(7)(8)(9)(10), Conversely, because of the causative role of H. pylori in certain digestive diseases such as duodenal ulcer and gastric cancer, other reports are quite contradictory (11)(12)(13). A large number of discussions led to a consensus regarding presence of H. pylori in the human stomach (5,11,14,15). Our knowledge about biology of H. pylori suggests that the bacterium is highly adapted to stay in gastric mucosa for long time (1,16). Indeed, living in lower surface of gastric mucosa, with no bacterial competition, provided a novel place to survive. Moreover, H. pylori is able to multiply freely due to the protective effects by mucosal layer. Thus, H. pylori had an opportunity to thrive in stomach over the course of tens of thousands of years of co-evolution with humans (17). Additionally, the high frequency of mutation in the genome also led to higher chances of survival, and natural selection helped them to remain and cause chronic infection (18). Determining whether H. pylori is beneficial or detrimental in human stomach has been a challenging area of research in gastroenterology (5,11,19,20). In this article, we aim to elucidate various aspects of this persistent colonization of this beneficial infection.

H. PYLORI : CARRIED BY HUMAN OVER THE HISTORY
It seems that H. pylori is an old recognized bacterium, which is not clinically comparable with new discovered infectious agents such as human immunodeficiency virus (HIV). In other words, HIV was introduced to human hosts <50 years ago. Given a long period of H. pylori colonization in the human stomach, mutual benefits obliged both partners to adapt themselves in order to establish stable symbiosis. It has been firmly established that H. pylori first subverts innate immunity and then modulates the adaptive immune system (blocking the activation of both B and T cells) (21)(22)(23). As a result, cagA and vacA, the main bacterial products, will inhibit B cell and T cell proliferation, respectively. Accordingly, immune response in the stomach is silenced against digested microbes (24,25). Undeniably, the stomach, with its harsh acidic condition, is a container for many digested microbes every day. Possibly, regulation and modulation of immune response arose after microbial exposure to H. pylori colonizing the stomach (24,25). Our current understanding of the strategies used by this pathogen to make a lifelong colonization, disclosed that maybe for our old ancestors having this bacteria in the stomach happened initially by accident, but due to natural selection, H. pylori made a set of adaptations, enabling the bacterium to survive and also thrive in the surface of human gastric epithelial cells. To everyone's surprise, after millions years of living in human stomach, H. pylori became a strategic member of our microbiome (26). Undoubtedly, it is no exaggeration to say that both host and the bacterium are following a constant beneficial relationship, which is quite unique in biological world. After long period of H. pylori gastric colonization, it has evolved into a highly adaptable persistent bacterium, obtaining all necessary features of the most successful human pathogen.

GERD AND H. PYLORI : A GOOD EXAMPLE OF BENEFICIAL EFFECTS
Gastroesophageal reflux disease (GERD) incidence has been increased mostly in developed communities where H. pylori infection is almost effectively eradicated (27,28). GERD is the main risk factor for Barrett's esophagus, and it has been associated with another deadly gastroduodenal carcinoma called "esophageal adenocarcinoma" (3,5). However, the relationship between GERD and H. pylori remains incompletely defined (29). Several studies suggested that eradication of H. pylori infection in the setting of duodenal ulcer disease would result in an increase in GERD symptoms (3,30). In other words, an inverse association of H. pylori infection with decreased rate of this sort of disease was a challenging topic in new gastroenterology (14,(31)(32)(33). Of note, GERD and its sequelae, which include Barrett's esophagus and esophageal adenocarcinoma, is decreasing in countries in which most individuals are infected by H. pylori (15,34,35). Actually, not only has worldwide H. pylori prevalence changed in recent decades but also other environmental factors affecting on human health such as socioeconomical levels, diet, and vaccination were drastically changed (10,17). If so, H. pylori is confronting with different situation rather than before.

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Remarkably, H. pylori can undergo drastic genetic change through each generation, while human genes do not change frequently. As a result, frequent genetic changes in H. pylori helped the bacterium to adapt quickly (18). Remarkably, slower adaptation in humans deteriorates longtime established equilibrium between H. pylori and human. Because of this, elimination of H. pylori as permanent resident of human microbiome would not be the first option to deal with gastroduodenal diseases. According to what explained about GERD and H. pylori as a protective effect, the long cohabitation in our stomach calls for more deep studies to elucidate microbiota and human health. GERD is the best example of disease, which became more frequent after starting the H. pylori treatment (34). Indeed, after antibiotic usage against H. pylori and, of course, its eradication in Western countries, a constant equilibrium between H. pylori and human health disappeared. Interestingly, in Northeastern Malaysia, the low prevalence of H. pylori infection was frequently reported (36)(37)(38). As general rule, one expects that frequency of diseases such as asthma and GERD should be relatively low rather than the findings of expected inverse association were not found (39)(40)(41). Actually, the association between H. pylori infection and certain diseases such as GERD and asthma risk can be affected by geographical and genetic differences (37,41). As a result, there is a complex and mostly undetermined associations between human microbiome and health; accordingly, all attempts to change this arranged biological system can exacerbate certain diseases. Undoubtedly, we need to eradicate virulent H. pylori in people with adverse clinical manifestations, but this conclusion cannot be generalized to all H. pylori positive subjects.

FUTURE OF H. PYLORI
The interesting relation between H. pylori and humans has shown that gastric acidic condition and human immune responses, which resulted in highly adaptable microbe. Currently, half of the world population is carrying strains that can survive and multiply in human gastric mucosa. Nowadays, available data about microbiota are sharply increasing; hence, one can expect to elucidate more details about this mysterious part of our bodies. In fact, experiments, which determine an actual association between H. pylori and microbiota, can increase our knowledge regarding this persistent resident of our stomach. Strikingly, both approaches, (i) bacterial eradication for asymptomatic individuals and (ii) global vaccination programs do not seem necessary in current clinical setting. Alternatively, we can suggest to only eradicating H. pylori in patients with adverse clinical presentations. In the end, with continuing current approach against H. pylori, we will lose this old ancient member of our microbiota; an event, which we are not fully aware of its drawbacks.

ACKNOWLEDGMENTS
The contents of the paper are the sole responsibility of the author and do not necessarily represent the official views of any institute or organization.