Unintended consequences of Helicobacter pylori infection in children in developing countries

Abstract

Helicobacter pylori infection is predominantly acquired early in life. The prevalence of the infection in childhood is low in developed countries, whereas in developing countries most children are infected by 10 y of age. In poor resource settings, where malnutrition, parasitic/enteropathogen and H. pylori infection co-exist in young children, H. pylori might have potentially more diverse clinical outcomes. This paper reviews the impact of childhood H. pylori infection in developing countries that should now be the urgent focus of future research. The extra-gastric manifestations in early H. pylori infection in infants in poor resource settings might be a consequence of the infection associated initial hypochlorhydria. The potential role of H. pylori infection on iron deficiency, growth impairment, diarrheal disease, malabsorption and cognitive function is discussed in this review.

Keywords: :

• Helicobacter pylori
• children
• hypochlorhydria
• iron deficiency
• diarrhea
• growth retardation
• malabsorption
• cognitive impairment
• developing countries

Introduction

Helicobacter pylori colonizes the stomach of more than a half of the world’s population and its acquisition occurs predominantly in early childhood, especially in preschool age.¹ In developed countries, the prevalence of H. pylori infection is low in childhood whereas in developing countries most children are infected by 10 y of age.^1,2 In some settings such as Peru shanty towns over 70% of infants are infected in the first year of life^3,4 but in other similar settings in South America H. pylori infection occurs between 1–5 y of age.^2,4 In poor resource settings where the infection co-exists with other morbidities such as malnutrition and parasitic and enteropathogen infections, H. pylori infection in young children may have potentially more diverse clinical outcomes than in developed countries, and include not only iron deficiency or iron deficiency anemia but growth retardation, diarrheal disease, malabsorption and impaired cognitive function.

This review focuses on the impact of childhood H. pylori infection in poor resource settings. With rapidly falling levels of H. pylori infection in children in developed countries, childhood H. pylori infection in developing countries, where infection in early childhood remains high, should now be the urgent focus of future research. Importantly, the extra-gastric manifestations of H. pylori infection as a consequence of the initial hypochlorhydria associated with H. pylori infection⁵ have been little investigated in developing countries. The potential role of H. pylori on iron deficiency, growth impairment, diarrheal disease, malabsorption and cognitive function is discussed in this review. Although these are all potential extra-gastric manifestations of H. pylori infection, recent evidence points to the importance of hypochlorhydria⁶ and proinflammatory IL-1β gene cluster polymorphisms⁷ in iron deficiency in H. pylori infected children. The consequences of hypochlorhydria in early H. pylori infections in infants in poor resource settings may also be central to increased diarrheal disease, growth impairment, malabsorption and impaired cognitive function (Fig. 1). H. pylori infection in developing countries could be initiating a vicious cycle of events in infants,⁵ the global impact of which on childhood morbidity may be diverse, and largely a consequence of extra-gastric manifestations of H. pylori infection.

Figure 1. Potential multiple outcomes of childhood H. pylori infection in developing countries. Infection with H. pylori is frequent in children in developing countries.²H. pylori infection is accompanied by a period of hypochlorhydria for several months. Hypochlorhydria in H. pylori infected children has been associated with iron deficiency.⁶ Polymorphisms in IL-1β gene cluster may control the extent and duration of hypochlorhydria with initial H. pylori infection. Pro-inflammatory polymorphisms in the IL-1β gene cluster in H. pylori infected children are associated with hypoferritinaemia and reduced hemoglobin concentrations.⁷ The period of hypochlorhydria associated with H. pylori infection in poor resource settings is a potential window for the acquisition of other enteric infections and diarrheal disease.^90,91 The clinical consequences and potential synergism between H. pylori infection and diarrheal disease in poor resource settings will promote not only malnutrition and growth impairment, but also cognitive impairment.¹⁵⁰ The hypochlorhydria induced by H. pylori infection may also result in alterations in the gut microbiota and contribute to small intestinal permeability changes and malabsorption, thus also impacting on malnutrition and growth impairment.

H. pylori and Iron Deficiency

Iron deficiency (ID), the most common nutritional disorder in the world, affects 20–50% of people globally,^8-11 iron deficiency anemia (IDA) being the final stage in the spectrum of a persistent negative iron balance. In developing countries, anemia represents a major public health problem and approximately 50 percent of all cases are due to ID.^9,11 Factors including low iron intake, low dietary iron bioavailability and gastrointestinal parasite infections contribute to the high frequency of ID/IDA in developing countries.^11,12 In childhood/adolescence the increased requirement for iron due to growth, expansion of red cell mass and menstrual blood loss in adolescent females favors the development of ID/IDA.^11,13,14 In childhood, iron deficiency has been associated with deficits of immune, cognitive and motor function.^11,15,16 Clinically advanced IDA is associated with reduced growth, increased susceptibility to infectious diseases and increased mortality.^10,17

The first descriptions of an association between IDA and H. pylori infection in children were case reports published in 1991 by Blecker et al.¹⁷ of a 15-y-old girl with a chronic active hemorrhagic gastritis associated with H. pylori infection and in 1993 by Dufour et al.¹⁹ of a 7-y-old boy with H. pylori chronic antral gastritis without hemorrhage. These two patients had IDA that was refractory to iron therapy in the boy.¹⁹ Eradication of H. pylori without iron supplementation resulted in reversion of the anemia in both cases. Since then, other case reports and series of cases have demonstrated an improvement in iron parameters after eradication of H. pylori in children.^20-22

Epidemiological studies

Several observational epidemiological studies in children demonstrating an association between H. pylori infection and lower serum ferritin concentrations and/or increased prevalence of iron deficiency^23-28 have reinforced the association between H. pylori infection and impaired iron status. Studies conducted in developed^23-27 and developing²⁸ countries showed lower serum ferritin concentrations^23,24,26,27 and/or higher proportion of ID or IDA^25-28 in H. pylori-positive than in H. pylori-negative children.

Of note, in a large cohort of 937 pubescent children in South Korea,²³a higher H. pylori-positive serology rate in those with either hypoferritinemia or ID/IDA was largely restricted to girls, which might be explained by lower iron storage in females. In 1040 children and adolescents²⁹ and in nearly 700 school-aged Alaskan children,²⁵ where H. pylori status was evaluated by ELISA or ¹³C urea breath test (¹³C-UBT), an increased risk for low serum ferritin concentrations²⁹ or increased prevalence of ID in children older than 8 y of age²⁵ was observed in H. pylori infected than in non-infected children. Cardenas et al.²⁶ by evaluating 1,771 children and adolescents among 7,462 subjects from the 1999–2000 USA National Health and Nutrition Examination Survey (NHANES) showed that positive serology for H. pylori was associated with decreased levels of serum ferritin and hemoglobin and increased risk for IDA. The authors estimated that 32.3% of the cases of IDA and 13.6% of ID in the United States might be related to H. pylori infection. In poor resource settings the contribution of H. pylori to ID may well be greater.

In a cross-sectional study evaluating symptomatic South-American children undergoing upper gastrointestinal endoscopy, H. pylori infection was also a significant predictor of low serum ferritin and hemoglobin concentrations.³⁰ Negative correlations between mean cell volume (MCV) and mean cell hemoglobin (MCH) values and the degree of antral and corpus inflammation were also observed in the Brazilian and Chilean children.³⁰ An association between H. pylori infection and reduced serum ferritin levels was also found in children from Turkey undergoing endoscopy.³¹

Other studies in children have failed to demonstrate associations between H. pylori infection and iron/anemia parameters.^32-35 Explanations include differences in study design, inclusion/exclusion criteria, number and age of the evaluated children, H. pylori diagnosis criteria and adjustment for confounding factors. For instance, very few studies have investigated children undergoing endoscopy for upper gastrointestinal symptoms,^30,31,36 a strategy which permits better evaluation of H. pylori status and the exclusion of common causes of iron deficiency such as gastrointestinal bleeding, peptic ulcer disease, extensive erosions and celiac disease. Exclusion of female adolescents with heavy menstrual blood loss,³⁰ an important determinant of iron status in young women, and intestinal parasitic infections^6,30 that lead to blood loss have not been adopted by all authors. Exclusion of subjects with enteric parasitic infection is vital in studies on H. pylori infection and iron deficiency in developing countries. The choice of diagnostic methods for H. pylori infection may also contribute to disagreement among the studies. Indirect methods such as serology have a low accuracy rate for the diagnosis of H. pylori in young children.³⁷

Interventional clinical trials

The strongest evidence for a cause-and-effect comes from interventional trials in children from developed^38-40 and developing countries^41-44 or from low socioeconomic populations in a developed country⁴⁵ that demonstrated an improvement of the anemia after H. pylori eradication. A series of therapeutic trials in children without iron replacement in South Korea demonstrated improvement of hemoglobin and/or ferritin levels after H. pylori eradication.^38-40 In a controlled, household-randomized trial in rural Alaska, Fagan et al.,⁴² by evaluating 176 native school-age children, demonstrated higher ferritin concentrations in children who remained H. pylori negative at 40 mo after H. pylori eradication therapy than in children who were re-infected with H. pylori, or who were untreated for H. pylori. Eradication of H. pylori in 110 Hispanic children of low socio-economic level aged 3 to 10 y without ID was accompanied by 3-fold increased serum ferritin baseline values.⁴⁵ However, Sarker et al.⁴⁶ did not observe differences in the hemoglobin concentrations and iron parameters between Bangladeshi children with IDA or ID in whom H. pylori was eradicated and children who remained H. pylori-positive in the three months-follow-up.

Two meta analyses studies including 16 and 8 randomized controlled trials^47,48 conducted in Asian children and adults, and one trial in Alaska,⁴⁷ compared the effect of oral iron supplementation alone, or in combination with H. pylori eradication therapy, on hematological parameters in patients with iron deficiency anemia. The meta analyses indicated eradication of H. pylori with oral iron significantly increased hemoglobin, serum ferritin^47,48 and serum iron⁴⁷ from baseline compared with oral iron therapy alone. The meta analyses confirm that oral iron alone has no beneficial effect on serum iron, hemoglobin and serum ferritin in the absence of H. pylori eradication. This indicates that gastric H. pylori infection is perturbing the normal physiological mechanisms of iron absorption.

An important question is whether eradication of H. pylori infection to improve iron status in children in developing countries could have adverse effects. Recent important studies in Tanzanian children indicate that the iron status influences Plasmodium falciparum malaria risk.⁴⁹ Iron deficiency was associated with significantly reduced parasitemia and severity of malaria and malaria-associated mortality.⁴⁹ In areas of high malaria risk H. pylori may have a beneficial role protecting from severe parasitaemia. H. pylori eradication in such areas for iron deficiency should only be undertaken in associated with effective malaria control.

Mechanisms of ID/IDA due to H. pylori infection

The mechanisms by which H. pylori infection might cause ID/IDA have not been well defined. Increased blood loss due to H. pylori-induced gastric lesions, deficient iron absorption due to decreased gastric acidity/gastric juice ascorbic acid concentrations and iron uptake by H. pylori have been proposed.

Erosive gastritis

Occult blood loss due to chronic erosive/hemorrhagic gastritis was one of the first supposed mechanisms of ID in H. pylori infection.¹⁸ However, it does not appear to be the most relevant factor because neither gastric bleeding lesions are frequently found in H. pylori-positive children undergoing endoscopy,^19,20,38,40 nor is the faecal occult blood test positive in the patients.^19,40

Deficient iron absorption and reduced gastric juice ascorbic acid

Another proposed mechanism promoting ID in H. pylori infection involves deficient iron absorption due to decreased gastric acidity.^5,50 Gastric acid is essential for iron absorption as it reduces ferric iron to the more soluble and absorbable ferrous iron form.⁵⁰ It has been demonstrated that H. pylori infected children have significantly lower basal and stimulated acid output than uninfected children and that eradication of H. pylori infection improves gastric acid output.⁵¹ In addition, in Chilean children infected with H. pylori an association between hypochlorhydria and low serum iron and transferrin was observed.⁶

Initial H. pylori infection is accompanied by a period of hypochlorhydria of variable duration.^52-54 This could be linked to increased concentrations of IL-1β and TNF-α, potent inhibitors of gastric acid secretion by parietal cells,⁵⁵ in the gastric mucosa of H. pylori infected adults and children.^56-58 Similar perturbations in gastric acid secretion occur in animals following infection with gastric Helicobacter species.^59,60 In the study of Takashima et al.⁶⁰ in gerbils, treatment with recombinant IL-1 receptor antagonist reversed the hypochlorhydria induced by H. pylori infection implicating the IL-1B gene cluster in the hypochlorhydric response to H. pylori. Clinically the duration of hypochlorhydria is variable but experimental human infection studies indicate hypochlorhydria can extend for several months.⁶¹ Data from infants in Gambia, using a non-invasive urinary test of gastric acid secretion,⁶² similarly indicate H. pylori infected infants have extended periods of hypochlorhydria.⁶³

As H. pylori infection is mainly acquired in childhood,¹ it is plausible that infected children with hypochlorhydria may be at increased risk of developing ID/IDA. In fact, a recent study evaluating a cohort of symptomatic Brazilian children undergoing upper gastrointestinal endoscopy⁷ demonstrated that the concentration of gastric IL-1β was inversely associated with blood ferritin and hemoglobin concentrations, suggesting that in the early phase of H. pylori infection, high gastric secretion of IL-1β inhibits acid secretion and impairs the absorption of iron. IL1β could also participate in the impairment of iron absorption by upregulating hepcidin as demonstrated in vivo.^64,65 However, association between the serum concentrations of hepcidin and H. pylori infection has not been observed.⁶⁶

In long-term chronic H. pylori infection in adults, hypochlorhydria resulting from development of gastric atrophy with loss of parietal cells is considered an important mechanism of iron deficiency.^67,68 Gastric corpus atrophy in H. pylori infected adults is more frequently observed in carriers of the IL1 gene cluster polymorphisms.⁵⁷ In Brazilian children it was demonstrated that hemoglobin and hematocrit values are lower in carriers of IL1RN polymorphic alleles than in children with the wild genotype.⁷ High gastric secretion of IL-1β in the former group might cause more severe hypochlorhydria in the acute phase of H. pylori infection that is mainly acquired in early childhood.

Decreased gastric juice ascorbic acid concentrations have also been considered to contribute to deficient iron absorption in H. pylori-infected patients. Ascorbic acid maintains iron stability by chelating ferric iron as well as participating in the maintenance of iron in the more absorbable ferrous form.⁵⁰ Baysoy et al.⁶⁹ demonstrated decreased gastric juice ascorbic acid concentrations in H. pylori positive children, especially in those infected with cagA-positive strains. However, there were no differences in ascorbic acid concentrations between H. pylori infected children with, and without, IDA. However, an association between low gastric juice ascorbic acid and IDA in adults infected by H. pylori has been demonstrated.⁶⁷

Finally, H. pylori-positive children⁶⁹ and adults⁷⁰ with IDA have more frequently a pattern of gastritis with corpus involvement that is accompanied by decreased gastric acid secretion that could impair iron absorption. Baysoy et al.⁶⁹ observed lower serum iron concentrations in infected children with pangastritis than in those with antral gastritis.

Iron-uptake by H. pylori

H. pylori has a high affinity uptake system to scavenge iron from the host with many proteins, such as FeoB, FrpB, iron-repressible outer membrane proteins (IROMPs), Pfr and NapA involved in the transport/storage of the metal,^71-76 and the Fur protein, encoded by the fur gene, involved in ferric uptake regulation.⁷⁷ The sources of iron that H. pylori utilizes during colonization are not clear, but uptake of ferrous iron by FeoB^75,76 and heme uptake by heme/hemoglobin-binding proteins such as FrpB2^76,78 and IROMPs^72,79 have been demonstrated.

Iron uptake from host transferrin^76,80 and lactoferrin⁷³ have also been described. In the process of iron acquisition from transferrin, the virulence factors, VacA and CagA, are involved in the relocation of the transferrin/transferrin receptor from the basolateral to the apical surface of the gastric epithelial cell where the iron can be utilized by H. pylori.⁸¹ Importantly, experimental studies indicate that only CagA-positive H. pylori strains are able to colonize iron deficient gerbils.⁸¹ This raises the intriguing question of whether the high prevalence of cag pathogenicity island (cag PAI) positive H. pylori strains in many developing countries is a consequence of high levels of iron deficiency in the respective populations.

It seems that some H. pylori strains have enhanced iron-uptake activity as demonstrated by Yokota et al.⁸² who compared strains isolated from patients with IDA to those from patients without IDA. The authors postulated that the high ability of H. pylori to uptake iron might be a causative factor for iron-deficiency anemia. Corroborating this finding, the expression of IROMPs under iron restricted conditions is higher in H. pylori strains isolated from patients with IDA than from those without IDA.⁷⁹

The proteomic profiles of H. pylori strains isolated from patients with IDA seems to be different from those isolated from patients without IDA,⁸³ suggesting that polymorphisms in genes that encode proteins involved in H. pylori iron acquisition might influence the development of ID in the host. The Thr70-type polymorphism in napA that encodes a bacterioferritin-like protein was associated with enhanced Fe iron uptake and occurred more frequently in strains isolated from Japanese patients with, than in those without, iron-deficiency.⁸⁴ Other polymorphisms in the napA gene have also been more frequently observed in strains isolated from IDA Korean adolescents.⁸⁵ Polymorphisms in the H. pylori feoB gene⁸⁶ that encodes FeoB, a high-affinity cytoplasmic membrane Fe⁺² transporter protein, were reported to associate with IDA in Korean children, but not in adult Japanese patients. Polymorphisms in other Helicobacter genes such as pfr⁸⁷ that encodes a prokaryotic ferritin and fur,⁸⁴ a transcription repressor of iron acquisition systems, were not significantly associated with IDA.

High lactoferrin concentrations, which decreased after eradication of H. pylori, were observed in the gastric mucosa of H. pylori positive Korean adolescents with IDA compared with those without anemia, or in non-infected adolescents with IDA.⁸⁸ This points to lactoferrin sequestration in the gastric mucosa as another potential mechanism of iron deficiency associated with H. pylori infection.

H. pylori and Diarrheal Disease

The importance of gastric acid in preventing enteric infections is well established.^89,90 Although some bacterial pathogens are less susceptible to gastric acid,⁹¹ hypochlorhydria increases the risk of several infections including cholera,⁹² typhoid and non-typhoidal salmonellosis⁹³ and enteric viruses.⁹⁴ In developed countries pharmacological induced hypochlorhydria is a recognized risk factor for Clostridium difficile-associated diarrhea.⁹⁵

In developing countries where enteric infections are endemic, the hypochlorhydria associated with initial H. pylori infection in infants and children, which can last several months, may be a critical window for acquisition of other enteropathogens and diarrheal disease (Fig. 1). Few studies have examined the impact of initial H. pylori infection in infants and children on diarrheal disease. Early studies in Gambian infants identified an association between H. pylori seropositivity and chronic diarrhea.⁹⁶ In Lima, Peru H. pylori seroconverting infants and children had increased diarrhea days and diarrhea episodes in the year after H. pylori infection than uninfected children.⁹⁷ Interestingly, the effects of H. pylori on diarrheal disease were greatest in the two months after infection,⁹⁷ the period when post-infection hypochlorhydria would be most evident.

The risk of co-infection with specific enteropathogenic infections in H. pylori positive children and/or adults has also been investigated in developing countries. In Peru H. pylori positivity has been associated with increased Vibrio cholerae infection in young children under 10 y of age⁹⁸ and adults with chronic atrophic gastritis,⁹⁹ the latter study emphasing the important protective role of gastric acidity. In contrast, studies in Bangladeshis involving both children and adults have found no increase in cholera in H. pylori infected subjects;¹⁰⁰ however, evaluation of gastric pathology was not undertaken and the period of acute H. pylori infection was not specifically evaluated. H. pylori infection has also been associated with increased Shigella infection in young children¹⁰¹ and Salmonella typhi in adults.¹⁰²

In contrast to the studies in Peru⁹⁷ and Gambia,⁹⁶ a study in Thai children did not observe an association between H. pylori infection and increased diarrheal disease.¹⁰³ Furthermore, studies in adults in two developed countries, USA and Germany, found a negative association between H. pylori infection and gastroenteritis.^104,105 The conflicting results between developed and developing countries is unsurprising given the contrasting exposure to enteric pathogens and differing availability of clean water and sanitation. Further studies are required in infants and children to assess the role of H. pylori in childhood diarrheal disease in developing countries.

H. pylori and Growth Retardation

There is considerable variation in the results of studies evaluating the effect of H. pylori infection on growth in children. Cross-sectional studies in different countries points to the presence^24,106-113 or absence^114-121 of association. There are other studies demonstrating associations only in the presence of iron-deficiency or dyspeptic symptoms.^122,123 However, almost all longitudinal studies analyzing growth velocity, considered a more sensitive indicator of health status than weight and height,¹²⁴ point to association.^124-128 Recently, new evidence on the role of H. pylori infection on growth emerged from the studies of Mera et al.¹²⁹ and Yang et al.¹³⁰ who demonstrated a beneficial effect of eradication of H. pylori on the growth of children from Colombia and China, respectively. However, only one study¹²⁷ has examined childhood growth in the first two years of life, when the greatest impact of infection on growth is expected to occur and no birth-cohort studies have been conducted until recently.

Most of the cross-sectional studies evaluating differences in the height-for-age, weight-for-age, or the frequency of short stature, according to H. pylori status are from developing countries. In most studies, no adjustment for genetic factors and socioeconomic status, which are known to influence childhood growth, was done. Association between H. pylori infection and short stature was observed in prepubescent girls from a low income community in northeast Brazil,¹¹⁰ in Egyptian children¹¹¹ and in children from low resource setting in Mexico.¹¹² Results of studies from Turkey are controversial: a negative effect of H. pylori infection on growth^31,108,113 and no association,^117,119 or associations only in children with recurrent abdominal pain¹²³ were observed. Absence of an association between height and H. pylori infection were described in Alaska native children;¹¹⁸ in African refugee children from Australia;¹²⁰ in dyspeptic children from Iran¹²¹ and in children from Guatemala.¹¹⁶

In developed countries, studies from Italy,¹⁰⁶ Germany,¹⁰⁷ and Japan¹⁰⁹ also point to negative effects of H. pylori infection on growth in childhood. However, no difference in the prevalence of H. pylori infection could be detected in Italian children with short stature^114,115 as well as no difference in the weight and height could be demonstrated in children from UK after adjusting for socioeconomic factors.¹³¹

Longitudinal cohort studies evaluating children from Colombia^124,126,132 and Ecuador¹²⁸ demonstrate reduction on the velocity of growth associated with acquisition of H. pylori infection as diagnosed by urea breath test and stool antigen test. Of note, the associations remained significant after controlling for confounding variables linked to socio-economic status.

Bravo et al.¹²⁶ demonstrated that the deceleration of growth velocity occurs one to two months after acquisition of the infection, independently of the age of the children, and the final effect of H. pylori infection on the growth velocity was 0.5 cm/year. Mera et al.¹³² observed that the reduction on growth velocity was significant for up to 6 mo after acquisition of H. pylori and after 8 mo the cumulative difference between H. pylori-positive and -negative children was 0.25 cm. In the study of Goodman et al.¹²⁴ H. pylori-positive children grew an average of 0.022 cm/month slower than the non-infected children. Egorov et al.¹²⁸ observed a reduction in the linear growth velocity of 9.7 mm/year in children with new H. pylori infection compared with uninfected children and 6.4 mm/year compared with children with chronic H. pylori infection.

Reduction in growth velocity associated with acquisition of the infection, evaluated by urea breath test and controlled for socioeconomic and demographic variables, in two cohorts of children from Gambia was transiently observed in children who acquired H. pylori infection early, at 3/6 mo of age, but reduced growth velocity was no longer detected when the children were 5 to 8 y old.¹²⁷ In developed countries, Patel et al.,¹²⁵ by evaluating 554 Scottish children, demonstrated that the growth of H. pylori-positive girls after four years follow-up was significantly lower than that of the uninfected girls.

Recently, two interventional studies^129,130 demonstrated that eradication of Helicobacter pylori increases childhood growth. In Colombia, the authors showed that although no difference in the height between H. pylori-positive and -negative children could be detected at baseline, in the 3.7 y follow-up, treated but not untreated children were 2.98 cm taller, after adjusting for demographic and socioeconomic variables.¹²⁹ In another study, Yang et al.¹³⁰ found that Taiwanese children with successful eradication of the bacterium had higher height and weight than the non-infected ones.

The mechanism by which H. pylori causes growth impairment in children remains to be investigated. Whether growth failure is a direct effect of the H. pylori-induced inflammation or a consequence of indirect effects such as infection-induced anorexia, H. pylori-associated intestinal permeability changes/malabsorption or diarrheal disease is unclear. The likelihood is both direct and indirect effects will contribute to growth impairment. Experimental studies on inflammation induced animal models of colitis indicate IL-6, which suppresses insulin-like growth factor (IGF-1), mediates growth failure.¹³³ Further studies are required to determine whether IL6 -174 G/C promoter polymorphisms associated with growth failure in children with Crohn disease¹³³ impact on growth impairment in infants/children with H. pylori infection.

Does H. pylori Infection Contribute to Malabsorption?

Mucosal small intestinal enteropathy and associated chronic permeability changes in infants in developing countries are considered a major factor in growth retardation.¹³⁴ The precise mechanisms of small intestinal mucosal damage contributing to malabsorption and its association with diarrhea and growth retardation has long been debated and subject of recent comprehensive reviews.^135,136 To date no specific pathogens have been associated with enteropathy and malabsorption. The hypochlorhydria associated with initial H. pylori infections in infants in developing countries may result in establishment of small intestinal bacterial flora and lead, via microbial disturbances of intestinal barrier function, to changes in small intestinal permeability (Fig. 1). Whether such changes in intestinal microbiota resolve following restoration of normal acid secretion in H. pylori infected infants is unknown. While several recent studies have investigated changes in the gut microbiota in the first few years of life,¹³⁵ the changes in gut microbiota associated with H. pylori infection in poor resource settings is unknown.

Recent experimental studies in H. pylori infected mice have shown, using ex vivo techniques to measure jejunal intestinal permeability to ⁵¹Cr-EDTA and ¹⁴C-mannitol, that small intestinal permeability is significantly increased in H. pylori infected mice compared with uninfected controls.¹³⁷ Interestingly, eradication of infection in mice did not significantly improve permeability at two months post-eradication. Clinical studies indicate H. pylori infection in adults also increases intestinal permeability compared with H. pylori negative controls.¹³⁸

The extent and duration of hypochlorhydria in infants and children on initial H. pylori infection may vary with the cag PAI status of the colonizing H. pylori strain as well as polymorphisms in the IL-1β gene cluster.⁶ In both animal models¹³⁹ and symptomatic adults^140,141 cag PAI strains are more likely to colonize the corpus mucosa with associated inflammation. In developed countries both increases, and changes in composition, of gastric non-H. pylori microbiota occur in H. pylori infected adults who have reduced acid secretion as a consequence of corpus atrophy, or following pharmacological treatment with proton pump inhibitors.¹⁴² Similar changes in both gastric and small intestinal microbiota during the hypochlorhydric phase following initial H. pylori infection in infants in poor resource settings are entirely possible, but remain to be investigated.

Recent exciting studies in Malawian children have identified using discordant monozigous twin pairs for kwashiorkor that the metabolism of gut microbiota and local diet are key to malnutrition.¹⁴³ Gnotobiotic mice given stool samples obtained from children with kwashiorkor became malnourished on Malawian diet but changed gut microbiota and gained weight on ready-to-use therapeutic food (RUTF).¹⁴³ Furthermore, a recent double blind placebo controlled study in Malawian infants aged 6 to 59 mo with kwashiorkor highlighted the importance of gut microbiota in malnutrition. Antibiotic therapy, together with RUTF, significantly reduced mortality and increased weight gain in children with malnutrition being superior to RUTF and placebo.¹⁴⁴ These important recent studies suggest antibiotic manipulation of the gut microbiota, which contributes to malnutrition, has occurred. This raises the important question of whether antibiotics are targeting specific gut pathogens which contribute to malnutrition.¹⁴⁵ While normal H. pylori eradication therapy requires two antibiotics and acid suppressant proton pump inhibitors,¹⁴⁶ in H. pylori infected infants and young children with hypochlorhydria, antibiotic treatment alone would be sufficient for H. pylori eradication. At high pH the gastric mucous barrier is decreased increasing the gastric permeability of antibiotics.¹⁴⁷ This raises the intriguing question of whether reduced mortality and weight gain following antibiotic treatment in children with malabsorption in the study of Trehan et al.¹⁴⁴ was a consequence of H. pylori eradication, restoration of normal acid secretion and loss of small intestinal microbiota mediating permeability changes. In H. pylori positive pre-school children in Bangladeshi suppressed basal and stimulated gastric acid output is restored after successful eradication of H. pylori.⁵¹ The restoration of gastric acid secretion after eradication of H. pylori infection may result in changes to gut microbiota relevant to reduced malabsorption. Future studies should aim to address whether antibiotic treatment in children with severe malabsorption in poor resource settings is changing their H. pylori status. Recent studies have validated non-invasive diagnostic ¹³C urea breath tests and stool antigen assays for detection of H. pylori infection in infants in developing countries.⁴ This provides the necessary validated tools for non-invasively determining H. pylori status in infants in developing countries and addressing the impact of this infection on globally important potential extra-gastric manifestations of H. pylori infection in infants in developing countries.

Does H. pylori Infection in Children Impair Cognitive Function?

Gastrointestinal parasitic infections and early diarrheal disease^148-150 in infancy in developing countries have been reported to impact negatively on later cognitive function in childhood and school performance in developing countries. Similarly, it has long been established that iron deficiency in infancy is associated with later impairment of cognitive function.^151,152 The potential role of H. pylori infection in infancy on cognitive function has not been investigated in developing countries. Given the association of H. pylori infection with iron deficiency, as well as frequent other enteric infections and diarrheal disease in poor resource settings, investigations on direct or indirect effects of H. pylori infection on cognitive impairment would be challenging and require large longitudinal birth cohorts to be examined for cognitive function at school age.

Muhsen et al.¹⁵³ have recently assessed the cognitive function of school age children in the Israeli Arab population, who have high levels of H. pylori infection although living in a developed country. Children from three villages of differing socioeconomic status were studied. H. pylori infection in children in the high socioeconomic village was independently associated with impaired cognitive function at early school age assessed by both full-scale Intelligence Quotient (IQ) score and also reduced non-verbal IQ and verbal IQ scores.¹⁵³ In the low socioeconomic village an association between H. pylori infection and cognitive impairment was not observed, probably due to high levels of H. pylori infection. Further studies are required to evaluate the association of H. pylori infection with cognitive impairment particularly in developing countries. Recent longitudinal birth cohorts of infants in South America of defined H. pylori status, and with known diarrheal episodes and growth over the first two years of life⁴ will be valuable populations in which to analyze the contribution of H. pylori infection to cognitive function in the children at school age. The association of H. pylori with impaired cognitive function is not confined to developing country populations as H. pylori seropositivity has recently been linked with poor cognition in adults in the United States.¹⁵⁴

Conclusions

The extra-gastric manifestations of H. pylori infection in children in developing countries are likely to be substantially greater than in developed countries and thus constitute a major public health problem. Childhood H. pylori infection in poor resource settings has been largely under investigated and further studies are required on the impact of H. pylori infection on growth impairment, diarrheal disease and cognitive impairment. Knowledge on host and bacterial factors contributing to iron deficiency in H. pylori infection in developing countries is increasing but further studies on host and bacterial polymorphisms are required in developing countries. The last Maastricht Florence Consensus Report (Maastricht IV)¹⁵⁵ recommends treating H. pylori-positive patients with IDA after the exclusion of the other common causes of the disease. Gastric carcinoma is an important cause of death in developing countries. Recently it was demonstrated that iron deficiency accelerates H. pylori-induced gastric carcinogenesis by enhancing deployment and function of the pilus component of the cag PAI type 4 secretion system, as well as upregulating proteins involved in survival and persistence of the bacterium.¹⁵⁶ It thus would be interesting also to consider eradication of H. pylori in those infected children without anemia, but with decreased serum ferritin. With high levels of antibiotic resistance in developing countries and significant H. pylori re-infection risk,¹⁵⁷ the optimum future strategy will be vaccination.

Acknowledgments

DQ and JEC were funded under the Sixth Framework Programme of the European Union, Project CONTENT (INCO-DEV-3–032136), “Evaluation and Control of Neglected Mucosal Enteric Infections in Childhood”

Disclosure of Potential Conflicts of Interest

No potential conflict of interest was disclosed.