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See article on page 499
Helicobacter pyloricolonisation in the stomach is associated with increased risk for the development of peptic ulcer disease and non-cardia gastric adenocarcinoma.1 However, the incidences of these diseases vary in different parts of the world, and these rates have been changing over the past century. It now is clear that the mere presence of H pylori is insufficient to account for this variation. Alternative hypotheses to explain differing outcomes include variation in bacterial strains, in host related factors, or in the particular interactions governing the long term equilibrium betweenH pylori strain populations and the colonised host.2 In this issue, Kiddet al (see page 499) explore whetherH pylori strain differences are related to illness occurrence in South African patients undergoing endoscopy. Why was such a study undertaken?
Despite overall conservation of most genes, H pylori are a highly diverse bacterial species.3Their population structure indicates that they are freely recombining,4 which tends to eliminate clonal or allelic variation. Yet, in accordance with previous work, Kiddet al found that important clonal differences exist, even within the single geographical locale studied. Three important allelic differences are the presence or absence of thecag island, the m1 or m2 alleles ofvacA, and the independent s1 and s2 alleles of vacA 5; s1 can now be divided into s1a, s1b, and s1c.6 Although the boundaries of these alleles are not fully defined and probably shift, their very existence, against the strong pressure of the recombinational tide, indicates their important biological roles for H pylori populations.
It is unlikely that the differential ability to cause disease in humans is responsible for this bacterial variation, as ulcer disease and gastric cancer chiefly occur late in life. Thus, these diseases per se are unlikely to have an important role in aiding the transmission ofH pylori to new hosts that is in any way analogous to the ability of Mycobacterium tuberculosis to facilitate its own transmission by causing cavitary lung disease. More likely, differential disease risk associated with particular H pylori alleles is a consequence of particular bacterial adaptations that facilitate colonisation. For example, adaptation (lifestyle) differences that exist between cag+ andcag− strains now have been defined experimentally.7 It may be that the lifestyle of the colonising bacterial population reflects the summation of all the particular allelic variations. Van Doorn and colleagues have used the combination of cag,vacA, and iceAallelic differences to provide a very rough approximation of disease risk.8
Kidd and colleagues have added to our understanding ofH pylori strain variation and disease in several ways. Firstly, they present evidence indicating that at least 12 (35%) of 34 patients studied were colonised by more than a singleH pylori strain, which extends our understanding of the reservoir for recombination under contemporary circumstances, and further indicates that study of only a single isolate from a patient is suboptimal. Secondly, they confirm thatH pylori genotype distribution has geographic clustering, with a very high proportion of South African isolates being cag+ andvacA s1b. Thirdly, they show that particular genotypes are associated with particular diseases. Their results parallel those from the United States and Europe, but the association of s1b/m1 strains with gastric cancer is new. In particular, this finding emphasises that the particular associations found to date (and those not found), are human population specific. In coming years, investigators will need to categorise such associations in each major population group. For example, although the presence ofcag+ H pyloristrains is associated with both increased ulcer and gastric cancer risk in the USA, Europe, and Latin America, their role in Asia is much more obscure, and their ubiquity in this African population indicates their insufficiency to account for disease occurrence differences. Nevertheless, compared with the absence of H pylori, colonisation by s2 strains seems to have little impact on disease occurrence in this South African population, and in other groups studied.5 ,8 Fourthly, Kidd and colleagues studied size heterogeneity of the cagA 3′ region, a new genotype in relation to disease occurrence. Their work, confirming observations in German and Japanese studies,9 ,10 suggests that certain cagA 3′ variants may be markers of particular diseases.
However, although helpful for stratifying risk, just asH pylori presence is helpful, the presently known H pylori allelic differences are insufficient to explain fully variation in disease occurrence, and do not sufficiently account for geographical variation or temporal changes in disease rates. Rather, the key to understandingH pylori related diseases is likely to be the interaction term between host genotype, host environment, and gastric microbial populations. I have hypothesised11 that the age at which H pylori is acquired, and the multiplicity of different organisms colonising the stomach have important bearing on gastric microecology, and thus, ultimately, on disease risk. Nevertheless, those looking for simple answers about the relations of H pylori and disease undoubtedly will be disappointed; the complexity likely is older than the human race. However, the challenge is great, and the clinic is our laboratory. Clinical researchers, microbiologists, experimental pathologists, and mathematicians each can contribute to solving the puzzle.
Conflict of interest: M J Blaser holds patents relating toH pylori genotypes, serology, and vaccines.