Allelic variation in Helicobacter pylori: progress but no panacea

Helicobacter pylori colonisation in the stomach is associated with increased risk for the development of peptic ulcer disease and non-cardia gastric adenocarcinoma. However, the incidences of these diseases vary in diVerent 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 insuYcient to account for this variation. Alternative hypotheses to explain diVering outcomes include variation in bacterial strains, in host related factors, or in the particular interactions governing the long term equilibrium between H pylori strain populations and the colonised host. In this issue, Kidd et al (see page 499) explore whether H pylori strain diVerences 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. Their population structure indicates that they are freely recombining, which tends to eliminate clonal or allelic variation. Yet, in accordance with previous work, Kidd et al found that important clonal diVerences exist, even within the single geographical locale studied. Three important allelic diVerences are the presence or absence of the cag island, the m1 or m2 alleles of vacA, and the independent s1 and s2 alleles of vacA; s1 can now be divided into s1a, s1b, and s1c. 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 diVerential 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 of H 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, diVerential disease risk associated with particular H pylori alleles is a consequence of particular bacterial adaptations that facilitate colonisation. For example, adaptation (lifestyle) diVerences that exist between cag+ and cag− strains now have been defined experimentally. 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 iceA allelic diVerences to provide a very rough approximation of disease risk. Kidd and colleagues have added to our understanding of H 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 single H 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 that H pylori genotype distribution has geographic clustering, with a very high proportion of South African isolates being cag+ and vacA 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 of cag+ H pylori strains 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 insuYciency to account for disease occurrence diVerences. 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. 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, 10 suggests that certain cagA 3' variants may be markers of particular diseases. However, although helpful for stratifying risk, just as H pylori presence is helpful, the presently known H pylori allelic diVerences are insuYcient to explain fully variation in disease occurrence, and do not suYciently account for geographical variation or temporal changes in disease rates. Rather, the key to understanding H pylori related diseases is likely to be the interaction term between host genotype, host environment, and gastric microbial populations. I have hypothesised that the age at which H pylori is acquired, and the multiplicity of diVerent 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.