de Sablet, T. et al. Phylogeographic origin of Helicobacter pylori is a determinant of gastric cancer risk. Gut 60, 1189-1195

Division of Gastroenterology, Hepatology, and Nutrition, Vanderbilt University School of Medicine, MRBIV, Room 1030C, 2215 Garland Avenue, Nashville, TN 37232, USA.
Gut (Impact Factor: 14.66). 02/2011; 60(9):1189-95. DOI: 10.1136/gut.2010.234468
Source: PubMed


Helicobacter pylori colonises the stomach in half of all humans, and is the principal cause of gastric cancer, the second leading cause of cancer death worldwide. While gastric cancer rates correlate with H pylori prevalence in some areas, there are regions where infection is nearly universal, but rates of gastric cancer are low. In the case of Colombia, there is a 25-fold increase in gastric cancer rate in the Andean mountain (high risk) region compared to the coastal (low risk) region, despite similarly high (∼90%) prevalence of H pylori in the two locations. Our aim was to investigate the ancestral origin of H pylori strains isolated from subjects in these high- and low-risk regions and to determine whether this is a predictive determinant of precancerous lesions.
Multi-locus sequence typing was used to investigate phylogeographic origins of infecting H pylori strains isolated from subjects in the Pacific coast and Andes Mountains in the state of Nariño, Colombia. We analysed 64 subjects infected with cagA+ vacA s1m1 strains. Gastric biopsy slides from each individual were scored for histological lesions and evaluated for DNA damage by immunohistochemistry.
We show that strains from the high-risk region were all of European phylogeographic origin, whereas those from the low risk region were of either European (34%) or African origin (66%). European strain origin was strongly predictive of increased premalignant histological lesions and epithelial DNA damage, even in the low-risk region; African strain origin was associated with reduced severity of these parameters.
The phylogeographic origin of H pylori strains provides an explanation for geographic differences in cancer risk deriving from this infection.

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Available from: Luis Eduardo Bravo, Jun 25, 2014
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    • "For example, in many African and South Asian countries, the low incidences of gastric cancer in the presence of almost universal rates of H. pylori infection remain a source of much speculation, and have been referred to collectively as the " African enigma " and the " Asian enigma " (Holcombe, 1992; Campbell et al., 2001; Ghoshal et al., 2007). In Latin America, where H. pylori strains native to Amerindian populations have been largely displaced by European strains (Dominguez-Bello et al., 2008; Correa and Piazuelo, 2012), the predominantly Amerindian populations living at high altitudes suffer disproportionately from gastric cancer relative to other populations with similar infection rates (de Sablet et al., 2011; Torres et al., 2013). These and other points of evidence raise the possibility that the pathogenicity of a given H. pylori strain may vary with human genomic variation, and that some individuals may be better adapted to their infecting strains than others. "
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    ABSTRACT: A major goal in infectious disease research is to identify the human and pathogenic genetic variants that explain differences in microbial pathogenesis. However, neither pathogenic strain nor human genetic variation in isolation has proven adequate to explain the heterogeneity of disease pathology. We suggest that disrupted co-evolution between a pathogen and its human host can explain variation in disease outcomes, and that genome-by-genome interactions should therefore be incorporated into genetic models of disease caused by infectious agents. Genetic epidemiological studies that fail to take both the pathogen and host into account can lead to false and misleading conclusions about disease etiology. We discuss our model in the context of three pathogens, Helicobacter pylori, Mycobacterium tuberculosis and human papillomavirus, and generalize the conditions under which it may be applicable.
    Frontiers in Genetics 08/2014; 5:290. DOI:10.3389/fgene.2014.00290
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    • "Overall, the low incidence of gastric cancer in African and South Asian countries might be explained, at least in part, by the different genotypes of H. pylori circulating in different geographic areas. Intriguingly, a recent report on cagA-positive strains in Colombia showed that all strains from high-risk regions of GC belong to hpEurope, whereas hpEurope and hpAfrica1 strains coexist in the low-risk regions [15]. In addition, subjects infected with hpEurope strains of H. pylori showed higher histopathological scores than those infected with hpAfrica1 strains. "
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    ABSTRACT: Background A recent report has shown that the phylogenetic origin of Helicobacter pylori based on multi-locus sequence typing (MLST) was significantly associated with the severity of gastritis in Colombia. However, the potential relationship between phylogenetic origin and clinical outcomes was not examined in that study. If the phylogenetic origin rather than virulence factors were truly associated with clinical outcomes, identifying a population at high risk for gastric cancer in Colombia would be relatively straightforward. In this study, we examined the phylogenetic origins of strains from gastric cancer and duodenal ulcer patients living in Bogota, Colombia. Methods We included 35 gastric cancer patients and 31 duodenal ulcer patients, which are considered the variant outcomes. The genotypes of cagA and vacA were determined by polymerase chain reaction. The genealogy of these Colombian strains was analyzed by MLST. Bacterial population structure was analyzed using STRUCTURE software. Results H. pylori strains from gastric cancer and duodenal ulcer patients were scattered in the phylogenetic tree; thus, we did not detect any difference in phylogenetic distribution between gastric cancer and duodenal ulcer strains in the hpEurope group in Colombia. Sixty-six strains, with one exception, were classified as hpEurope irrespective of the cagA and vacA genotypes, and type of disease. STRUCTURE analysis revealed that Colombian hpEurope strains have a phylogenetic connection to Spanish strains. Conclusions Our study showed that a phylogeographic origin determined by MLST was insufficient for distinguishing between gastric cancer and duodenal ulcer risk among hpEurope strains in the Andean region in Colombia. Our analysis also suggests that hpEurope strains in Colombia were primarily introduced by Spanish immigrants.
    PLoS ONE 08/2014; 9(8):e105392. DOI:10.1371/journal.pone.0105392 · 3.23 Impact Factor
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    • "Chronic Helicobacter pylori-induced gastritis in humans can progress to gastric atrophy, intestinal metaplasia and dysplasia with increased risk for gastric adenocarcinoma [1]. Epidemiologic evidence in humans and data from rodent models support that gastric carcinogenesis is multifactorial, influenced by host genetics [2], hormones [3], H. pylori virulence properties [4], environmental co-factors [5] [6] and co-infections with enterohepatic Helicobacters [7] [8] or helminths [9]. Higher prevalence of helminth infections in H. pylori infected children was suggested to potentially lower the life-time risk for gastric adenocarcinoma [9], with serologic evidence that life-long exposure through adulthood to a variety of parasites impacts inflammatory responses to H. pylori [10]. "
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    ABSTRACT: Higher prevalence of helminth infections in H. pylori infected children was suggested to potentially lower the life-time risk for gastric adenocarcinoma. In rodent models, helminth co-infection does not reduce Helicobacter-induced inflammation but delays progression of pre-malignant gastric lesions. Because gastric cancer in INS-GAS mice is promoted by intestinal microflora, the impact of Heligmosomoides polygyrus co-infection on H. pylori-associated gastric lesions and microflora were evaluated. Male INS-GAS mice co-infected with H. pylori and H. polygyrus for 5 months were assessed for gastrointestinal lesions, inflammation-related mRNA expression, FoxP3+ cells, epithelial proliferation, and gastric colonization with H. pylori and Altered Schaedler Flora. Despite similar gastric inflammation and high levels of proinflammatory mRNA, helminth co-infection increased FoxP3+ cells in the corpus and reduced H. pylori-associated gastric atrophy (p<0.04), dysplasia (p<0.02) and prevented H. pylori-induced changes in the gastric flora (p<0.05). This is the first evidence of helminth infection reducing H. pylori-induced gastric lesions while inhibiting changes in gastric flora, consistent with prior observations that gastric colonization with enteric microbiota accelerated gastric lesions in INS-GAS mice. Identifying how helminths reduce gastric premalignant lesions and impact bacterial colonization of the H. pylori infected stomach could lead to new treatment strategies to inhibit progression from chronic gastritis to cancer in humans.
    Microbes and Infection 04/2014; 16(4). DOI:10.1016/j.micinf.2014.01.005 · 2.86 Impact Factor
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