Helicobacter pylori: "A benign fellow traveler or an unwanted inhabitant"

Abstract

The recent decades have witnessed an alarming increase in the Helicobacter pylori associated diseases worldwide. In spite of this, deficiencies in our knowledge still exist about its exact epidemiology, the optimum method of its diagnosis and indeed about the precise role it plays in gastric carcinogenesis. In the present article, we review the available literature in an attempt to assign a definite role to this unique gastric pathogen. The acquisition of the cag-PAI has undoubtedly altered the understanding of host-microbe interactions, and growing appreciation of other potential determinants viz: vacA, iceA, babA, hrgA etc., may enable us understand the role of this organism and its gradual transition from a commensal to a pathogen. [PUBLICATION ABSTRACT]

Headnote

Abstrac

The recent decades have witnessed an alarming increase in the Helicobacter pylori associated diseases worldwide. In spite of this, deficiencies in our knowledge still exist about its exact epi-demiology, the optimum method of its diagnosis and indeed about the precise role it plays in gastric carcinogenesis. In the present article, we review the available literature in an attempt to assign a definite role to this unique gastric pathogen. The acqui-sition of the cag-PAI has undoubtedly altered the understanding of host-microbe interactions, and growing appreciation of other potential determinants viz: vacA, iceA, babA, hrgA etc., may en-able us understand the role of this organism and its gradual tran-sition from a commensal to a pathogen.

Keywords: Helicobacter pylori, commensal, pathogen.

© 2011 Deccan College of Medical Sciences. All rights reserved.

Helicobacter pylori is a human pathogen that causes chronic gastritis, plays a causative role in gastric and duodenal ulcer and is involved in gastric carcinogenesis. Indeed, the bac-terium has been classified as a definite (Class I) carcinogen of humans1,2. This gram negative gas-tric pathogen is also regarded as being a possible important factor in at least a subset of patients with functional dyspepsia3-5.

Although there appears to be a consensus of opi-nion that the majority of individuals become in-fected with H. pylori during early childhood (around 4 years), there are epidemiological differences between children and adults6,7. In addition to the ac-quisition of H. pylori during childhood, young child-ren also appear to be at increased risk of re-infection or recrudescence following antimicrobial eradication of the organism8.

Many aspects of this unique pathogen still remain elusive. For example, it is still not clear as to why only a subset of infected individuals present with clinically significant disease and related complica-tions. The spectrum of H. pylori disease is so vari-able that it is sometimes difficult to predict clinical outcome (Fig 1). The extensive research on its molecular characterization and genomics was initiated in different parts of the world in order to identify strain specific markers specific for overt manifestations of gastro-duodenal disease, but the equivalent distribution of the genotypes among normal and diseased subjects has not resolved this issue. So, is H. pylori a benign fellow traveler that has been associated with humans since ages or is it an unwanted inhabitant of the gut biota? This article attempts to weigh the currently available evidence.

Historical background of H. pylori's association with humans

Though H. pylori was discovered in 1983, this mi-crobe has been associated with humans since the pre-historic era9. Recent evolutionary studies have shown that Helicobacter pylori has likely been a part of the primitive human biota of the gut10,11. The gut of primordial beasts lacked acid secreting cells (parietal cells) in the stomach12. With the evolution of the first acid secreting stomach around 350 mil-lion years ago, Helicobacter pylori adapted to sur-vive in the acidic milieu via subtle modifications, which allowed them to dwell in the mucus layer close to the mucosal cells, mostly through adapta-tions including urease production, spiral shape, flagella and microaerophily13. Gradually to utilize the nutrients from the gastric mucosa H. pylori ac-quired genes that induced inflammation, but in spite of this these organisms could not at this time pose any menace, as the life span of the host in which they resided was not long enough9,12. In or-der to survive the inflammatory process in the gut Helicobacter pylori gradually upgraded its mechan-isms of survival principally through the elaboration of the enzymes catalase and superoxide dismu-tase (SOD) which protected the bacterium from the toxic effects of the compounds generated by the phagocytes.

The transformation of H. pylori from a silent bug to a gut pathogen

About 150-200 years ago H. pylori seems to have turned into a pathogen. The reasons for this have been a matter of intense debate. Some experts argue that disease of the upper gastrointestinal tract is not because of Helicobacter pylori, but it is a result of change in the host physiology that has occurred with civilization probably due to increased intake of processed food, excess meat, etc.14,15 and this selection pressure forced its adaptation to its particular ecological niche. It is also possible that it was acquisition of 'alien' DNA that altered this relationship8. Other experts argue that gastro-duodenal disease cannot be attributed solely either to Helicobacter pylori or host factors alone, but it is a complex and well coordinated interplay between H. pylori, host genetics, and environmental factors16,17.

During its years as a normal gastric colonizer, H. pylori appeared to offer protection against lethal diarrhoeal diseases of the children18 by mechan-isms such as the heightening of the gastric acid barrier19, priming of the immune response in the stomach20, etc. H. pylori is also believed to reduce the risk of gastro-esophageal reflux disease (GERD) and ultimately esophageal cancer in the infected subjects.

H. pylori virulence determinants involved in bacterial-epithelial interactions

The most accepted hypothesis underlying the gra-dual transition advocates the 'acquisition of the cag pathogenicity island' (cag-PAI) as the major evolu-tionary event that enabled the bacterium to be-come more virulent. Whole genome sequences of four different strains of H. pylori (J99 and ATCC 26695, G27 and HPAG1) isolated from different patients with different disease conditions have pro-vided adequate evidences that cag-PAI has differ-ent G+C content (35%) in contrast to the rest of the genome (39%) thus justifying its foreign origin21. This ~40kb DNA fragment (of unknown origin) is mainly comprised of 30 open reading frames (ORFs). Seven genes of this 'pathogenicity island' (namely hp0524, hp0525, hp0527, hp0528, hp0530, hp0532 and hp0544) are known to share homology to the vir family of genes forming a mul-tiprotein complex apparatus of Type IV secretory machinery (T4SS), that in other prokaryotic spe-cies, functions as a conduit for export of multimeric proteins and nucleoproteins across both the inner and outer bacterial membrane. The cag-PAI in H. pylori is required for both translocation of bacterial proteins into host cells and induction of proinflam-matory cytokine release thus validating the recent findings that the cagA island of genes has biologi-cal significance. This may provide an explanation for the observation that Helicobacter pylori with complete cag-PAI are more interactive with the host than those with partial and complete dele-tions21,22. There are also reports that corroborate various genes of the cag-PAI in H. pylori with dis-ease outcome thus contending that H. pylori with functional cag-PAI could be potentially more harm-ful to humans than those lacking them16,23. If this indeed is the case, can we assume that pre-historic Helicobacters that existed before the ac-quisition of the cag-PAI rendered positive health benefits? Besides the cag-pathogenicity island there are other virulence determinants of H. pylori such as vacuolating associated cytotoxin gene A (vacA), flagellins (flaA &flaB), induced by contact with epithelium gene A (iceA), Helicobacter pylori restriction endonuclease replacing gene A (hrgA), and blood group antigen binding adhesin gene (babA) etc., that have been discovered, that influ-ence disease outcome in infected individuals (Fig 2).

Unsolved conundrums

What was the role of these pathogenic markers? Were they potentially functional before the acquisi-tion of cag-PAI or were they non-contributory to the causation of disease? Did the acquisition of this foreign DNA change the behavior of the other genes? In what way did the cag-PAI alter the ex-pression of the toxins released by the above genes? Further research is required to validate or disprove the long-standing stance in favor of the 'good' Helicobacter pylori that might have existed in the past era. Though the genes of the cag-pathogenicity island are largely responsible for im-parting a virulence trait to Helicobacter pylori they clearly do not tell the complete story. Epidemiolog-ical studies have already confirmed vacA, iceA, hrgA, flagellin genes and other virulence determi-nants as probable risk factors for various gastric diseases independent of the cag-pathogenicity island24,25. Further screening of virulence genes such as vacA, iceA, babA, hrgA, and eludidation of their respective roles pre- and post-acquisition of cag-PAI in pre-historic human gut would enable us to understand the gradual transition of from a commensal to a hostile pathogen.

Conclusion

In conclusion, H. pylori, is a threat that extinguish-es more than a million lives each year, and causes substantial distress to almost all infected individu-als. In spite of its origins as a benevolent fellow traveler this fascinating spiral organism has now evolved as an undesirable commensal dweller of gastric mucosa. Though there exist studies that favor its positive health benefits are there is sub-stantial evidence that implicates its role as a pa-thogen in gastro-duodenal disorders.

Conflict of interest: None

Acknowledgments

We dedicate this article to our beloved Director Late Prof. C.M. Habibullah, a pioneer Gastroenter-ologist, whose inspiration and deep interest in the area of H. pylori encouraged me to work on this pathogen.

References

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