Gut 1999;45:477–482 477 Commentaries Gut: first published as 10.1136/gut.45.4.477 on 1 October 1999. Downloaded from See article on page 499 Allelic variation in Helicobacter pylori: vacA s1b. Thirdly, they show that particular genotypes are associated with particular diseases. Their results parallel progress but no panacea 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 asso- ciations found to date (and those not found), are human population specific. In coming years, investigators will need Helicobacter pylori colonisation in the stomach is associated to categorise such associations in each major population with increased risk for the development of peptic ulcer dis- group. For example, although the presence of cag+ H pylori ease and non-cardia gastric adenocarcinoma.1 However, strains is associated with both increased ulcer and gastric the incidences of these diseases vary in diVerent parts of cancer risk in the USA, Europe, and Latin America, their the world, and these rates have been changing over the past role in Asia is much more obscure, and their ubiquity in this century. It now is clear that the mere presence of H pylori is African population indicates their insuYciency to account insuYcient to account for this variation. Alternative for disease occurrence diVerences. Nevertheless, compared hypotheses to explain diVering outcomes include variation with the absence of H pylori, colonisation by s2 strains in bacterial strains, in host related factors, or in the seems to have little impact on disease occurrence in this particular interactions governing the long term equilibrium South African population, and in other groups studied.58 between H pylori strain populations and the colonised Fourthly, Kidd and colleagues studied size heterogeneity of host.2 In this issue, Kidd et al (see page 499) explore the cagA 3' region, a new genotype in relation to disease whether H pylori strain diVerences are related to illness occurrence. Their work, confirming observations in Ger- occurrence in South African patients undergoing endos- man and Japanese studies,910 suggests that certain cagA 3' copy. Why was such a study undertaken? variants may be markers of particular diseases. Despite overall conservation of most genes, H pylori are However, although helpful for stratifying risk, just as H a highly diverse bacterial species.3 Their population struc- pylori presence is helpful, the presently known H pylori ture indicates that they are freely recombining,4 which allelic diVerences are insuYcient to explain fully variation tends to eliminate clonal or allelic variation. Yet, in accord- in disease occurrence, and do not suYciently account for ance with previous work, Kidd et al found that important geographical variation or temporal changes in disease rates. clonal diVerences exist, even within the single geographical Rather, the key to understanding H pylori related diseases locale studied. Three important allelic diVerences are the is likely to be the interaction term between host genotype, presence or absence of the cag island, the m1 or m2 alleles host environment, and gastric microbial populations. I have http://gut.bmj.com/ of vacA, and the independent s1 and s2 alleles of vacA5;s1 hypothesised11 that the age at which H pylori is acquired, can now be divided into s1a, s1b, and s1c.6 Although the and the multiplicity of diVerent organisms colonising the boundaries of these alleles are not fully defined and prob- stomach have important bearing on gastric microecology, ably shift, their very existence, against the strong pressure and thus, ultimately, on disease risk. Nevertheless, those of the recombinational tide, indicates their important bio- looking for simple answers about the relations of H pylori logical roles for H pylori populations. and disease undoubtedly will be disappointed; the It is unlikely that the diVerential ability to cause disease in complexity likely is older than the human race. However, on September 24, 2021 by guest. Protected copyright. humans is responsible for this bacterial variation, as ulcer the challenge is great, and the clinic is our laboratory. disease and gastric cancer chiefly occur late in life. Thus, Clinical researchers, microbiologists, experimental pa- these diseases per se are unlikely to have an important role in thologists, and mathematicians each can contribute to aiding the transmission of H pylori to new hosts that is in any solving the puzzle. way analogous to the ability of Mycobacterium tuberculosis to facilitate its own transmission by causing cavitary lung Conflict of interest: M J Blaser holds patents relating to H pylori genotypes, disease. More likely, diVerential disease risk associated with serology, and vaccines. particular H pylori alleles is a consequence of particular bac- M J BLASER terial adaptations that facilitate colonisation. For example, Division of Infectious Diseases, adaptation (lifestyle) diVerences that exist between cag+ and Vanderbilt University School of Medicine and 7 Department of Veterans AVairs Medical Centre, cag− strains now have been defined experimentally. It may A-3310 Medical Centre North, be that the lifestyle of the colonising bacterial population Nashville, TN 37232–2605, USA reflects the summation of all the particular allelic variations. email: [email protected] Van Doorn and colleagues have used the combination of 1 Blaser MJ. The changing relationships of Helicobacter pylori and humans: cag, vacA, and iceA allelic diVerences to provide a very J Infect Dis − 8 implications for health and disease. 1999;179:1523 300. rough approximation of disease risk. 2 Blaser MJ, Kirschner D. Dynamics of Helicobacter pylori colonization in relation to the host response. Proc Natl Acad Sci USA 1999;96:8359−64. Kidd and colleagues have added to our understanding of 3 Go MF, Kapur V, Graham DY, et al. Population genetic analysis of Helico- H pylori strain variation and disease in several ways. Firstly, bacter pylori by multilocus enzyme electrophoresis: extensive allelic diver- sity and recombinational population structure. J Bacteriol 1996;178:3934– they present evidence indicating that at least 12 (35%) of 34 8. patients studied were colonised by more than a single H 4 Suerbaum S, Maynard Smith J, Bapumia K, et al. Free recombination within pylori Helicobacter pylori. Proc Nat Acad Sci USA 1998;95:12619–24. strain, which extends our understanding of the reser- 5 Atherton J, Cao P, Peek RM, et al. Mosaicism in vacuolating cytotoxin alleles voir for recombination under contemporary circumstances, of Helicobacter pylori: association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem 1995;270:17771–7. and further indicates that study of only a single isolate from 6 van Doorn L-J, Figueirdo C, Megraud F, et al. Geographic distribution of a patient is suboptimal. Secondly, they confirm that H pylori vacA allelic types of Helicobacter pylori. Gastroenterology 1999;116:823–30. 7 Blaser MJ. The interaction of cag+ Helicobacter pylori strains with their genotype distribution has geographic clustering, with a very hosts. In: Hunt RH, Tytgat GNJ, eds. Helicobacter pylori, basic mechanisms to high proportion of South African isolates being cag+ and clinical cure. Dordrecht: Kluwer, 1998:27–32. 478 Nightingale 8 Van Doorn L, Figueiredo C, Sanna R, et al. Clinical relevance of the cagA, 10 Yamaoka Y, Kodama T, Kashima K, et al. Variants of the 3' region of the vacA and iceA status of Helicobacter pylori. Gastroenterology 1998;115:58–66. cagA gene in Helicobacter pylori isolates from patients with diVerent H. 9 Rudi J, Kolb C, Maiwald M, et al. Diversity of Helicobacter pylori vacA and pylori-associated diseases. J Clin Microbiol 1998;36:2258–63. cagA genes and relationship to VacA and CagA protein expression, 11 Blaser MJ. Helicobacters are indigenous to the human stomach: duodenal cytotoxin production and associated diseases. J Clin Microbiol 1998;36: ulceration is due to changes in gastric microecology in the modern era. Gut Gut: first published as 10.1136/gut.45.4.477 on 1 October 1999. Downloaded from 944–8. 1998;43:721–7. See article on page 559 Short bowel, short answer? from their stoma.14 This is because of loss of normal daily intestinal secretions (about 4 litres/24 hours), rapid gastric emptying and rapid small bowel transit.15 If a patient has less than 100 cm jejunum remaining and a stoma he/she is The paper by Jeppsen et al (see page 559) shows that likely, as a minimum, to need long term parenteral saline.14 glucagon-like peptide-2 (GLP-2) concentrations are low in This requirement does not reduce with time.3 Patients patients lacking an ileum and colon. This is not an with a retained colon do not have these problems and, unexpected finding as the L cells that produce GLP-2 are owing to functional adaptation, nutrient absorption situated in the ileum and colon. GLP-2 is an enterocyte usually improves with time. To explain the diVerences specific growth hormone that in mice causes small and between the two types of patient, measurements of various large bowel villus/crypt growth and increases small and gastrointestinal hormones have been made with interest large bowel length and weight. In mice it also reduces body focusing upon those produced by the ileum and colon. weight loss and restores mucosal integrity after dextran Peptide YY, which like GLP-2 is produced by the L cells induced colitis. In pigs it reduces gastric antral motility.1 of the ileum and colon, slows gastric emptying and small The deficiency of GLP-2 in patients with a jejunostomy bowel transit and may be responsible for the “ileal” and may explain why these patients show no evidence of struc- “colonic” brakes. Peptide YY serum values are high in 2–4 patients with a retained colon and low in patients with a tural or functional intestinal adaptation over time.