COMMENTARY

Helicobacter pylori: Friend or Foe?

David A. Johnson, MD, FACG, FACP

Disclosures

July 09, 2008

Corley DA, Kubo A, Levin TR, et al
Gut. 2008;57:727-733

Abstract

Relationship Between Helicobacter pylori Infection and Gastric Atrophy and the Stages of the Oesophageal Inflammation, Metaplasia, Adenocarcinoma Sequence: Results From the FINBAR Case-control Study

Anderson LA, Murphy SJ, Johnston BT, et al
Gut. 2008;57:734-739

Abstract

Does Helicobacter pylori Protect Against Asthma and Allergy?

Blaser MJ, Chen Y, Reibman J
Gut. 2008;57:561-566

Abstract

Editor's Note: Dr. Johnson's summary and commentary collaboratively address these 3 reports on the potential influence of Helicobacter pylori infection in GERD and related complications of Barrett's esophagus and esophageal adenocarcinoma, as well as expanded implications for asthma and atopy.

Summary

The existing studies that have evaluated the link between H pylori infection and Barrett's esophagus have been conflicting, but the majority have suggested a lower prevalence association. However, almost all of the studies have involved patients undergoing endoscopy and there has been a lack of appropriate controls (non-endoscopy cases).

The first report is a case-control study that evaluated serologic data for H pylori and its CagA (cytotoxin-associated gene protein A) protein in 318 patients with a new diagnosis of Barrett's esophagus and compared this with 312 patients with uncomplicated gastroesophageal reflux disease (GERD) and 299 matched control patients.

The prevalence of H pylori infection was 11.7%, 9.6%, and 22.7% in the Barrett's esophagus, GERD, and control populations, respectively. An inverse prevalence association was evident for H pylori antibody status and the risk for Barrett's esophagus (odds ratio [OR]: 0.42; 95% confidence interval [CI]: 0.26-0.70). There were no differences between long-segment Barrett's esophagus (≥ 3 cm) and shorter-segment Barrett's esophagus. The risk for Barrett's esophagus was lower among patients with CagA+ status (OR: 0.08; 95% CI: 0.02-0.35). H pylori was not an independent risk factor for Barrett's esophagus compared with GERD controls, particularly when adjusted by logistic regression for GERD symptoms (OR: 0.71; 95% CI: 0.36-1.38).

The second report by Anderson and colleagues is a case-control study from Ireland that involved 224 patients with Barrett's esophagus, 230 patients with GERD, and 260 population-based control subjects. These investigators used data and samples from the FINBAR (Factors Influencing the Barrett's Adenocarcinoma Relationship) study.

Serologic evidence of H pylori and CagA status was determined for all subjects, and pepsinogen I and II levels were measured. Gastric atrophy was diagnosed if the pespsinogen I/II ratio was < 3. Seropositivity for H pylori was inversely associated with Barrett's esophagus, esophageal adenocarcinoma, and gastroesophageal reflux: OR 0.35 (95% CI: 0.22-0.56), OR 0.49 (95% CI: 0.31-0.76), and OR 0.42 (95% CI: 0.27-0.65). Although gastric atrophy was uncommon, there was an inverse relationship with Barrett's esophagus, nonjunctional esophageal adenocarcinoma, and GERD (0.23 [95% CI: 0.05-0.96]), OR 0.34 [95% CI: 0.10-1.24], OR 0.27 [95% CI: 0.08-0.88]), respectively. The inverse relationships between H pylori infection and Barrett's esophagus, esophageal adenocarcinoma, and GERD remained significant despite adjustment in the gastric atrophy-negative patients.

Epidemiologic data have revealed an increase in the prevalence of asthma, hayfever, and other atopic disorders in industrialized nations. Although there are many extrinsic environmental allergens that may be implicated in this increased prevalence, a change in the indigenous microflora may also be a cause. Twelve recent cross-sectional and 4 case-control studies have shown an inverse relationship between asthma/atopy and H pylori seropositivity. In the third report, Blaser and colleagues also validated these findings using 2 separate analyses of the National Health and Nutrition Examination Survey (NHANES) database. They showed this inverse relationship with H pylori to be particularly strong for children with onset of asthma before 15 years of age (OR: 0.63; 95% CI: 0.43-0.93).

There are several potential causal mechanisms by which H pylori infection might induce a protective effect against asthma/atopy. First, if H pylori reduces acid production and related GERD, it may reduce any related asthma. However, this would not explain any effects on atopy or related conditions. H pylori does have a role in immunologic sensitization, in particular with respect to regulatory T cells, which may have systemic modulatory activities. Additionally, H pylori inflammation may affect immunomodulatory activity, specifically through changes in ghrelin and leptin production, which may in turn affect the overall immunoregulatory response. Furthermore, because H pylori can affect the autonomic nervous system response, causality for atopic conditions would be plausible.[1]

Viewpoint

The first report by Corley and colleagues is the first study to use an appropriately controlled community population base to evaluate the association between Barrett's esophagus and H pylori. The strong inverse relationship suggests that H pylori infection may be protective against Barrett's esophagus. The mechanism mediating this association is not known, but there are several possible explanations. The most likely reason is that H pylori infection can lead to gastric atrophy, in particular with the more virulent strains (CagA+). Gastric atrophy and reduced acid secretion should lessen GERD risk. Clearly, the biologic role of H pylori infection in the development of gastrointestinal disease is complex and includes other well-associated conditions: peptic ulcer disease and gastric cancer. Prior reports have noted an inverse relationship between Barrett's esophagus-related dysplasia and H pylori status.[2]This present study takes the inverse relationship back to a more basic link with Barrett's esophagus itself.

The second report by Anderson and colleagues suggests that although H pylori seropositivity is clearly associated with gastric atrophy, this does not fully explain the association with the complications of GERD, notably Barrett's esophagus and esophageal adenocarcinoma. If H pylori infection was the only protective mechanism against Barrett's esophagus and esophageal adenocarcinoma, there should be no inverse association with H pylori in gastric atrophy-negative patients. Accordingly, there may be other mechanistic explanations. Clearly, however, there is strong evidence that there is a significant risk reduction for Barrett's esophagus and esophageal adenocarcinoma in patients with serologic evidence of H pylori infection. These data add support to the increasing evidence to suggest a protective role for H pylori in the GERD-related complications of Barrett's esophagus and esophageal adenocarcinoma. This is one more reason to screen for H pylori infection only when you are ready to eradicate and thereby ready to treat -- and only as deemed appropriate by consensus standards.

The third report by Blaser and colleagues is an extremely provocative study that takes the association of H pylori beyond the implications of peptic disease or gastric cancer. It is likely that the numerous and diverse microflora that populate the human digestive tract are not by chance; as with all "Darwinian models," the central theme is "survival of the fittest." Phylogeographic evidence from more than 58,000 years ago supports that H pylori colonized the stomach of humans.[3] Despite the antiquity of this association, there is clear evidence that the prevalence of H pylori is decreasing. In the United States and other industrialized nations, the current prevalence of H pylori infection in children younger than 10 years has decreased from 70%-90% to less than 10%.[4] There is substantial evidence now to support the inverse association between H pylori and childhood asthma, allergic rhinitis, and atopy. Furthermore, a "dose response" association is suggested, as the strongest association is evident in patients with Cag A+ infections, the more virulent strain of H pylori, which also has a stronger association with the risk for gastrointestinal disease (ulcers, gastric cancer).

Clearly, the interactions of H pylori in the GI system are complex, but the potential protective influences of this infection hopefully introduce a new awareness to perhaps temper the overzealous rush to diagnose and treat. Perhaps we have come full circle: from "shoot to kill" to an emerging campaign to "save the bug."

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