Helicobacter in the developing world

Helicobacter pylori infection has a worldwide distribution, and it has distinct epidemiological features in developing countries. In contrast to that in developed countries, H. pylori infection in developing countries seems to be nearly universal, beginning in early childhood. Children become infected in the first few months of life; in some communities as many as 50% of the children are infected by the age of 5 years, and up to 90% are infected by the time they reach adulthood. In some developing countries with improvements in industrialization, socioeconomic conditions, and hygiene, infection rates are lower. The incidence of H. pylori infection, determined indirectly, also suggests a rate several times higher than that in developed countries. Marked differences in H. pylori seroprevalence have been observed between various ethnic and racial groups. Although the mode of transmission of H. pylori remains uncertain, evidence suggests person-to-person transmission occurs.

Epidemiological Features of Helicobacter pylori Infection in Developing Countries

Helicobacter pylori is a gastric pathogen that chronically infects more than half of all people worldwide (for reviews see references 48 and 64) and constitutes a major cause of peptic ulcer disease and an early risk factor for gastric cancer. It may also contribute to childhood malnutrition and increase the risk or severity of infection by other gastrointestinal pathogens such as Vibrio cholerae, especially in developing countries (18, 19). It appears to be one of the most genetically diverse of bacterial species, because DNA fingerprinting can distinguish any given isolate from most others (5, 56) and because of the ∼3 to 5% DNA sequence divergence typically found in essential genes from unrelated strains (3, 29). This mutational diversity is enhanced by a rich history of interstrain recombination (29, 40, 54). In contrast, most other well-studied bacterial species characterized to date are much more strongly clonal (see, e.g., references 28, 31, and 53).

The observed genetic diversity implies a lack of population-wide selection for just one or a few universally most fit H. pylori genotypes. Some of this may reflect preferential transmission within families and among people in close contact, not in large epidemics (11, 24, 50). Such a pattern means that no individual strain would compete simultaneously against many others (12, 38, 55). H. pylori diversity would also be enhanced if humans differ in traits that are important to individual strains (e.g., specificity or strength of immune and inflammatory responses or availability of receptors used for H. pylori adherence [26, 33]).

There are also indications of significant geographic differences among strains. For example, only one-half to two-thirds of U.S. and European strains carry the cag pathogenicity island (PAI), a 40-kb DNA segment many of whose genes seem to help induce interleukin 8 and thereby a strong and potentially damaging inflammatory response; such strains are recovered preferentially from persons with overt disease (4, 8, 9, 17). In contrast, nearly all east Asian strains carry the cag PAI independent of disease status (34, 47). Similarly, somewhat more than half of U.S. and European strains carry toxigenic (vacAs1) alleles of the vacuolating cytoxin gene, with other strains carrying nontoxigenic (vacAs2) alleles (in general, vacAs1 strains carry the cag PAI (65); nearly all east Asian strains carry vacAs1 alleles. Potentially more significant in terms of host interaction and evolution were findings that east Asian and Western strains differ markedly in DNA sequence motifs in the vacA and cagA genes (3, 34, 35, 46, 58, 62), since the proteins these genes encode probably each interact directly with host factors (CagA protein is translocated to host cells and is tyrosine phosphorylated in them but is not needed for interleukin 8 induction) (7, 45, 51). Even though less geographic partitioning was found in a sampling of housekeeping genes (3, 58), it is not clear whether the regional differences in cagA and vacA alleles reflect natural selection, random genetic drift including founder effects, or both during H. pylori evolution. It is noteworthy in this context that the two strains whose genome sequences have been determined (6, 57) and compared to better understand H. pylori genetic diversity (23) are from ethnic European patients (26695 from the United Kingdom [6]; J99 from a Caucasian in Pulaski, Tenn. [57; T. L. Cover, personal communication]) and thus may not be fully representative of H. pylori worldwide.

We began studies of genotypes of H. pylori strains of India, motivated by the differences between strains of east Asia and the West found to date and a sense that the peoples of the vast Indian subcontinent (some one-fifth of all humanity) may have been sufficiently isolated during much of human history to have allowed the emergence of a distinct H. pylori gene pool (37, 42, 63). It is well established that H. pylori infection and peptic (especially duodenal) ulcer disease are very common in India (1, 36, 44, 52) and that a large fraction of strains may be resistant to metronidazole (Mtzr) (2), but to our knowledge there has been very little analysis to date of the genotypes of the underlying H. pylori strains (20). Here we identify several markers that help distinguish H. pylori strains from Calcutta from those of east Asia and the West.

Distinctiveness of Genotypes of Helicobacter pylori in Calcutta, India

Helicobacter pylori is one of the human pathogens with highest prevalence around the world; yet, its principal mode of transmission remains largely unknown. The role of H. pylori in gastric disease and cancer has not been established until the end of the 20th century. Since then, its epidemiology has been extensively studied, and an accruing body of literature suggests that not all humans are equally at risk of infection by this gut pathogen. Here, we briefly review the different epidemiological aspects of H. pylori infection with emphasis on those factors related to human poverty. The epidemiology of H. pylori infection is characterized by marked differences between developing and developed countries, notably among children. In addition, congruent lines of evidence point out to socioeconomic factors and living standards as main determinants of the age-dependent acquisition rate of H. pylori, and consequently its prevalence. These data are alarming in the light of the changing global climate and birth rate, which are expected to change the demography of our planet, putting more children at risk of H. pylori and its complications for years to come.

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Helicobacter pylori: a poor man's gut pathogen?

Helicobacter pylori infection is a major cause of upper gastrointestinal disease throughout the world. Colonization begins in childhood, although little is known about its age of onset, rate, or mode of colonization. Our aim was to identify the age of acquisition of H. pylori colonization in Gambian children. A cohort of 248 Gambian children aged 3 to 45 months was studied at intervals of 3 months for 2 years, using the 13C-urea breath test, specific IgM and specific IgG serology. The prevalence of positive breath tests rose from 19% at 3 months of age to 84% by age 30 months. Elevated specific IgG and IgM antibody levels were associated with positive breath tests, although there was discrepancy between breath test results and serology, particularly IgG serology, during the 1st year of life. Neither IgG nor IgM serology could be validated as reliable diagnostic tools for infant H. pylori colonization compared with the 13C-urea breath test. Reversion to negative breath test, in association with declining specific antibody levels, occurred in 48/248 (20%) of children. On the assumption that the 13C-urea breath test is a reliable index of H. pylori colonization, we conclude that the infection is extremely common from an early age in Gambian children. Transient colonization may occur. Previous studies relying on serodiagnosis may have significantly underestimated the true early prevalence of colonization in the developing world, where the target age for intervention studies is probably early infancy.

Helicobacter pylori colonization in early life.

AlthoughH. pylori is well established as an etiological agent of type B gastritis and a predisposing factor for peptic ulcer, knowledge about its transmission is unclear. In this study we examined the prevalence ofH. pylori infection in the family members of index infants infected with this organism as indicated by positive [13C]-urea breath test (UBT). We performed UBT among family members of 15 predominantly breastfed infants, eight with and seven withoutH. pylori infection. Infection rates were 82% and 91% in family contacts of the infected and noninfected infants respectively, the average infection rate being 85%, which is rated to be high. There was no difference in infection rates among the parents of the infected and noninfected infants. Fifty percent and 70% families belonging to infected and noninfected infants, respectively, were found to have all members infected withH. pylori. No evidence of sex predilection of infection was found. We conclude that in communities with high prevalence ofH. pylori infection, there is almost an equal infection rate among the family contacts of infected and noninfected infants, suggesting that environmental factors may be more important than intrafamilial transmission.

Mohammad M. Rahman

Papers

Prevalence of Helicobacter pylori infection in infants and family contacts in a poor Bangladesh community.