The results of this meta-analysis suggest that colonization of the stomach with CagA-positive strains of H. pylori may protect against EAC.
has co-existed with modern humans since their origin (60
), and once it could be found in the stomachs of most humans. With advances in sanitation and use of antibiotics, however, this bacterium is rapidly disappearing from human populations (61
), especially in Western countries. In the United States, for example, data from the third National Health and Nutritional Examination Survey (1988 – 1991) showed that serum samples from 57% of the population older than 70 years of age, versus 17% of the population between 20–29 years of age, were positive for IgG antibodies against H. pylori
). More recent data from the National Health and Nutritional Examination Survey 1999–2000 show a positive IgG seroprevalence of only 5% in children younger than 10 years of age who were born in the 1990’s (63
). Given that H. pylori
colonization in most people occurs before the age of 10 (64
), these numbers show a substantial decline in H. pylori
in a period of 70 years. This decrease mostly reflects a cohort effect (65
), rather than eradication of H. pylori
in individuals over time.
With changes in the prevalence of H. pylori
incidence rates of diseases caused, or prevented, by this organism change. H. pylori
is a known cause of noncardia gastric cancer (66
). Incidence rates of this cancer have been sharply declining in most parts of the world in the past few decades (7
). In contrast, rates of EAC have steeply increased in Western countries during this same period (13
). Once a rare cancer, EAC now constitutes approximately half of all esophageal cancer cases in some Western populations (11
). Our results suggest that CagA-positive strains of H. pylori
which constitute the majority of H. pylori
strains, may protect against EAC, and that increasing EAC rates may be partly due to the decline of H. pylori
in human populations. In parallel with EAC rates, the incidence rates of gastric cardia adenocarcinoma, another cancer inversely associated with H. pylori
), are increasing in some Western countries (67
). However, it is unclear whether this latter inverse association is real or it merely reflects misclassification of EAC for gastric cardia adenocarcinoma (33
). Another observation consistent with the hypothesis that H. pylori
disappearance is contributing to the increased EAC rates is that EAC rates are still low in most developing countries (9
), where H. pylori
is still common.
may decrease risk of EAC by reducing acid production in the stomach and hence reducing acid reflux to the esophagus (19
). It may also reduce EAC risk by decreasing the production of the hormone ghrelin, which is mostly secreted from the stomach and stimulates appetite (70
). A reduction in the level of ghrelin may lead to lower rates of obesity, an important risk factor for EAC (71
The protective association of H. pylori
with EAC or gastric cardia adenocarcinoma may be part of a broader phenomenon. The long history of co-existence of this organism with humans, despite its disease-causing potential, may suggest that H. pylori
also has some beneficial effects to humans (61
), including possible roles in reducing diarrheal diseases and asthma (63
). Therefore, in this article, we have used the term H. pylori
“colonization”, rather than “infection”, to describe the presence of H. pylori
living in the stomach. The reciprocal link of H. pylori
with both EAC and asthma may be due to lower acid reflux, which is a risk factor for both diseases, or it could be due to modulation of the hormones leptin and ghrelin, which have immunoregulatory effects (reviewed in (72
The decline of H. pylori
colonization can only partly explain the sharp increase in EAC incidence rates. With an OR of 0.5, even if H. pylori
entirely disappeared, EAC incidence could increase at most by two-fold, so part of the nearly 4-fold increased incidence observed in some populations (67
) must be due to other reasons. Recent epidemiologic studies have found three important risk factors for EAC, namely gastroesophageal reflux, obesity, and smoking (14
). Whether, and how much, a change in the prevalence of these factors has contributed to the surge of EAC cases in the past few decades is still debated.
We conducted several analyses to examine the robustness of the association between H. pylori and EAC. The point estimate of the OR for each individual study in the meta-analysis was lower than one, and there was little heterogeneity among these studies. Subgroups analyses also showed remarkably consistent ORs. When data analysis was limited to population-based studies; to studies from Western or Eastern countries; to studies that used serological tests to determine exposure; to studies that matched for age; to larger studies; or to studies that included Barrett’s esophagus in their diagnostic criteria; the summary OR remained lower than 0.60. When we used adjusted estimates, the summary OR was 0.50. Therefore, the results were quite robust. Likewise, using the broader definition of H. pylori positivity had very little or no impact on the results. We did not find any evidence for publication bias, using funnel plots or formal statistical tests.
CagA-positive strains of H. pylori
have been disappearing faster than the CagA-negative ones (76
). Interestingly, the inverse association between H. pylori
and EAC was seen only with CagA-positive strains. Forest plots showed that this pattern was consistent across studies. It should be noted, however, that only five of the 13 selected studies could be used for comparing the effects of CagA-positive and CagA-negative strains. Therefore, more studies may still be needed to confirm this pattern. As discussed earlier, CagA-positive strains confer higher risk of noncardia gastric cancer than CagA-negative strains (18
). Therefore, CagA-positive strains may also have stronger associations with other diseases that are caused, or prevented, by H. pylori
. CagA protein can be delivered into gastric epithelial cells, and it may increase the risk of gastric cancer by increasing the turnover of the gastric epithelium (17
). CagA-positive strains are also more likely to have the s1 allele of vacA
which encodes a molecule that affects epithelial cells (77
) and may increase gastric cancer risk (78
), and are also more likely to express the babA
product, which controls adherence of H. pylori
organisms to Lewisb
antigens on gastric epithelial cells (77
). The biological reasons for the inverse association between CagA-positive H. pylori
and EAC need to be further investigated.
We found no overall association between H. pylori and ESCC risk. However, the point estimates differed substantially and qualitatively among studies, resulting in large heterogeneity indices. Limiting studies to population-based studies, studies from Western or Eastern countries, studies that used serological tests, studies that matched for age, or using adjusted results made little change in summary estimates and did not reduce heterogeneity. Therefore, the source of the observed heterogeneity is unclear. Gastric colonization with CagA-positive strains was not associated with ESCC risk. Compared to H. pylori-negative subjects, CagA-negative strains were associated with a marginally significant increased risk of ESCC. However, the bulk of the data for this latter analysis came from only two studies, and further studies are needed to make more definitive conclusions. An association was observed in studies from Western countries when we used the broader definition of H. pylori positivity. Again, there were only four studies in this analysis, and further data are needed to have more confidence in the results.
One other meta-analysis has previously examined the association between H. pylori
and esophageal cancer (79
). Our meta-analysis differs from this previous evaluation in several respects. One difference is the choice of published articles. The two meta-analyses share only 6 papers that examined the association between H. pylori
and EAC, and only 4 papers that examined the association between H. pylori
and ESCC. We excluded several of the publications used in the previous meta-analysis because they included duplicate data from the same study; we substituted newer papers from some studies; and we included several additional recent studies. We also conducted multiple subgroup analyses to examine the robustness of our data to the choice of study methods and other factors. We also examined the effects of CagA-positive and CagA-negative strains of H. pylori
separately versus H. pylori
-negative subjects, rather than comparing CagA-positive subjects versus all other subjects. Despite these differences, both meta-analyses found that H. pylori
protects against EAC and is not significantly related to ESCC risk. Also both meta-analyses found that the association of H. pylori
with EAC was largely homogeneous across studies, but there was substantial and statistically significant heterogeneity in results with respect to ESCC.
Strengths of this meta-analysis include the evaluation of 19 published studies with a large number of cases and controls, presenting multiple subgroup analyses, and using several methods to examine study heterogeneity and publication bias. This meta-analysis also has limitations. Combining observational studies conducted in different populations with various qualities of design to obtain summary ORs and 95% CIs can sometimes be misleading (80
) and summary statistics need to be interpreted with caution (81
). However, as mentioned above, at least for EAC, there was little evidence of heterogeneity, and the results were robust to multiple subgroup analyses.
In conclusion, we found an inverse association between CagA-positive strains of H. pylori and risk of esophageal adenocarcinoma. The prominent decline of H. pylori colonization, especially CagA-positive strains, may be responsible for part of the recent increase in esophageal adenocarcinoma rates in Western countries.