Humans have been infected with Helicobacter pylori since they left Africa more than 58,000 years ago, according to genetic sequence analysis Citation[1]. Estimates suggest that half the world is infected with the bacteria, with an especially high rate of infection in Asia Citation[2]. In 1984, Barry Marshall and Robin Warren discovered that H. pylori was the cause of peptic ulcers and gastritis Citation[3]; since then, the way we think about and treat peptic ulcer disease and gastric malignancies has been completely revolutionized. H. pylori is the first thing we think of and search for before discussing additional diagnoses. Two decades of work have gone into developing effective vaccines for the bacteria, and since it affects half the world, a global vaccination program to eradicate it seems to make sense.
Main issue: is H. pylori good or bad?
In 2007, an NIH workshop on H. pylori research brought forward a panel of experts to discuss directions for future research on H. pylori and concluded that H. pylori is harmful to a small subset of patients, but that there is enough evidence to suggest that it is also beneficial. Infection with H. pylori is asymptomatic in approximately 85% of individuals, while 15% develop symptomatic peptic ulcer disease, and less than 1% go on to develop gastric cancer Citation[4]. Negative correlations with asthma Citation[5], eczema Citation[6] and gastrooesophageal reflux disease Citation[7] have been found, but the responsible mechanism remains to be elucidated. These observations suggest that H. pylori may also have a protective effect against the development of autoimmune disease.
Negative assocciation with inflammatory bowel disease
Epidemiological studies indicate that inflammatory bowel disease (IBD) is more prevalent in areas with lower rates of H. pylori colonization, such as the USA Citation[8]. On the other hand, there is a steady rise in the incidence of IBD in H. pylori-endemic regions that corresponds to the beginning of anti-H. pylori therapy for peptic ulcer disease Citation[9]. These observations have led to a number of studies investigating the association between H. pylori infection and IBD.
Our laboratory recently published a meta-analysis showing a negative correlation with IBD: 27.1% of IBD patients showed evidence of H. pylori infection compared with 40.9% patients in the control group Citation[10]. These data suggest that there are protective benefits of H. pylori infection against the development of IBD. However, long-term studies investigating the effect of eradication of H. pylori on the development of IBD are warranted.
Like the asthma and obesity studies, there existed no mechanistic studies to explain this correlation. Commonly cited as the explanation for this negative association is the hygiene hypothesis: cleaner conditions early in life lead to a higher incidence of autoimmune diseases later in life by suppressing natural development of the immune system. H. pylori infection is more prevalent in developing parts of the world with poor hygiene. Since poor sanitary conditions are thought to play a role in the lower rates of IBD in these parts of the world, H. pylori infection is widely believed to be a marker of poor hygiene in one’s birthplace, and not a direct contributor to protection against IBD.
Mechanisms
Helicobacter pylori infection triggers a unique inflammatory response in which the infection persists despite the activation and recruitment of T and B lymphocytes, phagocytic cells and other immune cell populations Citation[11]. This suggests that H. pylori infection may induce immune tolerance, favoring its persistence in the stomach. To investigate further the H. pylori–IBD connection, the direct influence of H. pylori infection on the host immune system needs to be elucidated. This cannot be performed in the clinical setting given that environmental hygiene is a strong confounding factor. Thus, we carried out this study in a mouse model of H. pylori infection and experimental colitis. We first showed that H. pylori infection can protect against Salmonella typhi-induced experimental colitis Citation[12]. Higher IL-10 in the mesenteric lymph nodes could explain the protective mechanism. We employed a mouse model of H. pylori infection and showed that induction of Tregs by H. pylori appears to be a major adaptation to evade host immunity Citation[13]. H. pylori alters the dendritic cell-polarized Th17/Treg balance toward a Treg-biased response, resulting in suboptimal Th17 response and failure to eradicate the offending pathogen. This mechanism may also explain the negative correlation that exists between H. pylori infection and the incidence of IBD, a condition in which Th17 may play a pivotal role. Arnold et al. provided more evidence that H. pylori infection enhances the Treg response and thus limits the severity of asthma in a mouse model Citation[14]. In subsequent studies we further demonstrated that H. pylori DNA decreases proinflammatory cytokine production by dendritic cells and attenuates dextran sodium sulfate-induced colitis in mice. We showed that H. pylori DNA, which has been found in the colon and stool of infected patients Citation[15,16], has immunoregulatory properties Citation[17]. H. pylori DNA suppresses type 1 interferon and IL-12 production from mouse bone marrow-derived dendritic cells, possibly owing to its high immunoregulatory sequence to immunostimulatory sequence ratio. This may explain why the systemic levels of type 1 interferon were found to be lower in H. pylori-colonized patients than noncolonized controls Citation[17]. We also showed that the administration of isolated H. pylori DNA significantly ameliorated the severity of experimental colitis in mice.
Clinical implications
Clinical studies clearly demonstrate that eradication of H. pylori infection significantly reduces the incidence of peptic ulcer disease and its complications. This supports the recommendation by the NIH that H. pylori is harmful to a small subset of patients and should be appropriately treated. However, because of immune tolerance conferred by H. pylori infection, its elimination from the body in asymptomatic patients may not be a good idea. Up to 50% of patients may experience mild side effects associated with antibiotic treatment Citation[18]. Furthermore, treatment fails in approximately 25% of patients Citation[19], so widespread use of antibiotics may result in future antibiotic-resistant strains. Therefore, we recommend that only symptomatic patients or asymptomatic family members of gastric cancer patients should be tested and treated. Unless treatment is considered, if the result is positive, physicians should not test the patient for H. pylori.
Research implications
We know that H. pylori causes ulcers, but do all strains of H. pylori cause ulcers? Most people count all H. pylori strains as ‘bad’, but it is possible that some strains are more harmless than others. More research needs to be conducted on differences between strains before we blacklist all of them. In addition, we know that Asian populations have an especially high incidence of gastric cancer, but no convincing theory exists as to why. If we can understand why some people experience symptoms while others remain asymptomatic, then we may be more efficient at treating the infection and even providing H. pylori-based treatments for chronic inflammatory conditions.
Conclusion
It is good to recognize that H. pylori causes serious symptoms in 15% of those infected, but it is also essential to consider the remaining 85% of H. pylori carriers: quite possibly, the bacterium is protecting these people from chronic inflammation, a burgeoning problem in today’s steadily advancing society. Before eradicating the bacteria, the beneficial effects of H. pylori and differences between strains need to be examined more thoroughly to make sure we are not eliminating a potential, albeit hidden, ally that has lived with us for more than 58,000 years. By treating those who are unaffected, we could be unwittingly breeding susceptibility to a host of serious chronic inflammatory problems; however, by properly harnessing H. pylori’s veiled benefits (i.e., its DNA), we may be able to obtain all the advantages without any of the complications. If we look at H. pylori as a good bacterium with bad side effects as opposed to a bad bacterium with good side effects, perhaps we can gain something from this bug.
Financial & competing interests disclosure
John Y Kao is a consultant for Otsuka America Pharmaceutical, Inc. The authors have no other 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 apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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