Leading article risk factors for H pylori acquisition can be Gut: first published as 10.1136/gut.2007.133462 on 14 January 2008. Downloaded from Does Helicobacter pylori protect determined. These include large family size, having parents (especially mothers) against asthma and allergy? carrying H pylori, H pylori-positive older siblings, and household crowding during 18 19 1,2,3 1,4 1,4 childhood. Thus, as disappearance Martin J Blaser, Yu Chen, Joan Reibman begins, the effects compound with each generation, especially as water has The microbes that persistently colonise protects against these disorders and that its become cleaner, family sizes have shrunk, their vertebrate hosts are not accidental.1 disappearance has fuelled their rise. mothers pre-masticate food less, and 20 Although highly numerous and diverse, nutrition has improved. there is specificity by site and substantial Another phenomenon that may con- H PYLORI ACQUISITION AND tribute to H pylori disappearance is the conservation between individuals. The PERSISTENCE genus Helicobacter includes spiral, highly widespread use of antibiotics, especially H pylori is acquired, and may be detected, 21 motile, urease-positive, Gram-negative during childhood. To reliably eradicate H in early childhood usually after the first bacteria that colonise the stomach in pylori requires combinations of two to year of life.5 Transmission is faecal–oral, many mammals. Each mammal has one four antimicrobial agents, but early stu- oral–oral and vomitus–oral.6 Once or more dominant Helicobacter species and dies with monotherapies, including beta- acquired, in the absence of antibiotic they are highly, if not exclusively, host lactam and macrolide antibiotics, showed use, H pylori persists at least for decades, 22 23 species-specific.2 Such observations are eradication rates from 10 to 50%. If and most often for the full life of its host.7 consistent with the hypothesis that when comparable effects occur every time a H pylori strains are highly variable, and ancestral mammals diverged from reptiles child is treated with antibiotics for an several loci affect H pylori–host interac- about 150 million years ago, they con- upper respiratory or skin infection or for tions. In particular, strains with an intact tained ancestral helicobacters, which then otitis media, then the rapid (and com- cag island inject the CagA protein into diverged as their hosts changed. According pounding) decline in H pylori prevalence host gastric epithelial cells;8 this heigh- to this hypothesis, helicobacters represent in childhood in developed countries in tened interaction in relation to cag-nega- ancestral biota (flora) in the mammalian recent decades is not difficult to under- tive strains affects disease risk.910 stomach. The human-adapted strain is H stand. For most of human existence, we have pylori,3 which has not been reproducibly lived in small, intimate groups,11 in which observed in any animals other than CONSEQUENCES OF THE PRESENCE OR our microbiota mingled extensively with humans and other primates.3 ABSENCE OF H PYLORI that of other group members.12 Under the Although we can not reliably estimate By comparing persons with and without conditions of poor hygiene that have http://gut.bmj.com/ the organism, medical scientists have how long H pylori has been in the human predominated for most of human exis- studied the costs and benefits of carrying stomach, its ancestors may have been tence, transmission of gastro-intestinal H pylori. First came the observation that present when our humanoid ancestors microbes has been easily accomplished. the presence of H pylori in the gastric diverged from other primates about four In present-day developing countries in lumen is associated with the presence in million years ago. Consistent with this which such enteric transmission occurs, view are results from phylogeographic the gastric lamina propria of phagocytic H pylori is ubiquitous, with estimates for 24 and immune cells. Warren and Marshall on September 29, 2021 by guest. Protected copyright. studies; strong and consistent evidence its prevalence in adults exceeding 80%; its recognised the association of H pylori with indicates that our ancestors already were presence is possibly nearly universal, these histological findings, which pathol- carrying gastric H pylori when a group when multiple detection methods are ogists call ‘‘chronic gastritis’’;24 25 the that ultimately populated much of the used.713 In populations in which H pylori presence of inflammatory cells leads to world last left Africa, more than 58 000 is highly prevalent, gastric colonisation 4 use of terms implying pathological pro- years ago. In any case, H pylori has been with several distinct strains appears com- cesses. However, as biologists, we believe colonising the stomach of humans since mon.14 at least Paleolithic times. that the collection of immune and inflam- In this paper, we examine the evidence matory cells in the tissue should be concerning the relationship of this ancient H PYLORI IS DISAPPEARING considered as ‘‘the physiological response member of the human microbiota, and Despite the substantial evidence for the to the indigenous microbiota’’ (or PRIM). particularly its absence, with the recent antiquity and ubiquity of H pylori coloni- Similarly, the lamina proprias of the and on-going epidemic of asthma and sation in humans, it now has become mammalian mouth, vagina and colon are related allergic disorders. We discuss the clear that the prevalence of H pylori is populated by phagocytic and immunolo- possibility that gastric H pylori colonisation rapidly decreasing! This is a birth cohort gical cells that respond to the local effect, which began in the early 20th indigenous microbiota. In contrast, 1 Department of Medicine, New York University School of century in many developed countries, and germ-free animals have essentially no 15–17 Medicine, New York, USA; 2 Department of accelerated after World War II. The phagocytic and immune cells in their Microbiology, New York University School of Medicine, effect has been so profound that fewer lamina propria, but ‘‘conventionalising’’ 3 New York, USA; Medical Service, New York Harbor than 10% of children under 10 in the these animals, by restoring their normal Veterans Affairs, Medical Center, New York, USA; 4 United States and in other industrialised biota restores these cells, which is con- Department of Environmental Medicine, New York 26 University School of Medicine, New York, USA countries now are H pylori-positive, com- sidered as the normal histopathology. 15–17 Correspondence to: Dr Martin J Blaser, Department of pared to the historic 70–90% levels. As One difficulty with terming the host Medicine, 550 First Avenue OBV A606, New York, NY a result of this change, occurring around response to H pylori as ‘‘chronic gastritis’’ 10016, USA; [email protected] the developed world to variable extents, is not in the observation, which is correct, Gut May 2008 Vol 57 No 5 561 Leading article but in interpreting the finding as patho- leptin, and is the major site for production Nutrition Survey (NHANES) III, con- logical, and not as physiological. of ghrelin.9 These neurendocrine peptides ducted between 1988 and 1994.59 In the Gut: first published as 10.1136/gut.2007.133462 on 14 January 2008. Downloaded from However, in at least one context PRIM play important roles in mammalian mid-1990s, H pylori and CagA serology also is pathological, since it is associated energy homeostasis, and emerging evi- were performed on stored specimens from with increased risk for development of dence indicates that H pylori status is more than 10 000 NHANES III subjects, peptic ulceration,27 28 and gastric adeno- relevant to their regulation.38 39 with the laboratory workers and statisti- carcinoma and lymphoma.10 29 Further, It thus becomes clear that a generation cians blinded to asthma or atopy status. the highly interactive CagA-positive or more of children in developed countries In 2006, we were able to link 7663 records strains induce the strongest PRIM and have been growing up without H pylori to that contained information on both confer the greatest risk of ulceration and guide or influence these physiological asthma and H pylori status.51 For all carcinoma.10 28 30 Thus, H pylori and the functions, and others not yet described subjects, there was an inverse association PRIM it induces are clearly associated (fig 1). It is predictable that such altered of ever having had asthma with having a with risk of disease, and even fatality. The acid secretion, immunological activation, cagA+ H pylori strain [OR (95% CI) = decline in the incidence of these diseases and neurendocrine regulation have a 0.79 (0.63 to 0.99)], with a stronger in the 20th century is consistent with the variety of consequences. inverse association in those less than the decline in H pylori prevalence. median (43 years) age [0.63 (0.43 to However, it now has become clear that ASSOCIATION WITH ASTHMA AND 0.93)], and no association in the older there is an inverse association between H ALLERGIC CONDITIONS? persons. Similarly, the inverse association pylori and reflux oesophagitis (GORD), In recent years, there has been a rise in the was strongest in those who had asthma and its consequences, including Barrett’s prevalence of asthma, hay fever (allergic onset before the age of 15 years [0.63 oesophagus, and oesophageal adenocarci- rhinitis) and atopy (including eczema) in (0.43 to 0.93)], with no association with 10 noma. Although the gastric PRIM is a developed countries.40 This change, which those with older-onset asthma. Highly risk factor for the development of peptic begins in early childhood, is present across similar trends were observed in relation to ulceration and gastric adenocarcinoma, it many populations in the world, and is allergic rhinitis and allergy symptoms, is inversely associated with the develop- considerable in its extent.