Helicobacter pylori infection, nutrition and growth of West African infants

TMNSKTIONS OF THEROYALSOCIETYOF TROPICALMEDICINEANDHVGIENE(1995) 89, 347-350

Royal Society of Tropical Medicine and Hygiene Meeting at Manson House, London, 16 February Aspects of Helicobacterpylori developed world Helicobacterpylori

infection,

infection

nutrition

347

1995

in the developing

and growth

of West African

and infants

Lawrence T. Weaver Department of Human Nutrition, University of Glasgow, Yorkhill Hospitals, Glasgow, G3 SSJ, Scotland, UK

Abstract Helicobacter pylon is probably the commonest bacterial infection of humankind. In adults, colonization of

the stomach is associatedwith chronic gastritis and duodenal ulcer disease.However, children in the developing world acquire H. pylori soon after birth, and there is evidence that it plays a part, through suppression of the gastric acid barrier, in the pathogenesis of the syndrome of diarrhoea, malnutrition and growth failure. Infants born of mothers who secretemilk with high levels of anti-H. pylori immunoglobulin A (IgA) antibody acquire the infection later than those born of mothers with low specific antibody levels. Enhancement of maternal breast milk anti-H. pylori IgA levels may protect infants from H. pylon infection during the vulnerable weaning period when many are susceptible to enteric infections, leading to recurrent diarrhoea and adverseconsequenceson nutrition and growth. Keywords:

Helicobacterpylori, childhood malnutrition, immunoglobulin A

Childhood malnutrition and growth failure Throughout the world most infants show satisfactory weight gain during the early months of exclusive breast feeding. However, in many parts of the developing world this is followed by a period of growth faltering associated with episodes of diarrhoea, which coincides with the introduction of weaning foods (WEAVER,1994).By one year old most Gambian infants, for instance, are less than 80% of their expected weight-for-age. In some children repeated episodesof acute diarrhoea lead to persistent diarrhoea, resulting in severemalnutrition and growth failure. Defective and inadequate gastrointestinal function appears to be central to the pathogenesis of childhood malnutrition and growth failure. A vicious cycle between gut failure and malnutrition leads inexorably to progressive growth faltering in a large proportion of young children of the developing world. Prolonged injury of the small intestinal mucosa is present in many infants and children with recurrent diarrhoea, malnutrition and growth failure. The spectrum of mucosal change can range from ‘normal’ to total villous atrophy (SULLIVAN et al., 1991). It has been well documented in The Gambia that weaning foods, introduced first at a median age of 3 months, are frequently contaminated with enteropathogenic bacteria, particularly if they are allowed to stand for any appreciable length of time after preparation (ROWLAND et al., 1978). There is evidence that impairment of defence against ingested microbial and food antigens may play a part in the genesis of the diarrhoeamalnutrition syndrome. Defences against enteric infections Gastric acid is the primary non-immune barrier against ingested enteric pathogens, and a major regulator of the small bowel flora. Childhood malnutrition is associated with diminished or absent gastric acid secretion, and renutrition is not always accompanied by a return to normal gastric acid output (GILMAN et al., 1988). Immunoglobulin (Ig) A is the primary immune defence against enteric antigens that reach the small intestinal mucosa. Ingested by the infant in colostrum and milk, IgA acts at the epithelial surface to exclude ‘foreign’ microbial and food-borne antigens. The functioning of these 2 defences may play a key role in the rate of acquisition and natural history of Helicobacterpylori infection in childhood. Helicobacterpylori infection in early life H. pylon’ infection is probably the commonest bacterial

infection of humankind (HOLCOMBE et al., 1992). In Europe, and elsewherein the industrialized world, H. pylon’ is the principal causeof gastroduodenal diseasein adults, but in the developing world it may play a central part in initiating enteric infections in early life. The prevalence of H. pylori infection increases with agein all populations studied, but there are considerable differences between developed and developing countries, particularly in early life (TAYLOR & BLASER, 1991; WEAVER & THOMAS, 1994). Countries of West and North Africa have the highest prevalence of infection (Fig. l), and in Peru, Thailand, Chile and Mexico infection from an early age is also common. In Europe, the

-‘.“j: 0

10

20

30

Age (years) Fig. 1. Age-related prevalence of Helicobacterpylwi infection in different populations diagnosed by IgCi serology or (in Zaire) the [%]urea breath test. 1, The Gambia; 2, Algeria; 3, Zaire; 4, Ivory coast; 5, Peru; 6, Thailand; 7, France; 8, England; 9, Australia. (Reproduced by permission from WEAVER& THOMAS,1994.)

USA and Australia prevalence rates are significantly lower during childhood. Becausethe precise mode of transmission of the organism is unknown, it has been very difficult to describe the natural history of acute infection. In 2 reports describing a total of 3 children with severeacute infection, IgG sero-

34%

conversion occurred about 50 d after infection (THOMAS et al., 1990; MITCHELL et al., 1992). In adults, when gastric acid output has been monitored following primary infection, hypochlorhydria has been seen to accompany acute gastritis. This may persist for weeks or months, before normal acid output resumes (MORRIS & NICHOLSON,1987). The recognition that H. pylori is very common in Africa (HOLCOMBE, 1991) prompted my colleagues and me* to mount a major study of the interrelation of this microorganism with hypochlorhydria, childhood diarrhoea, malnutrition and growth faltering. It was basedon the earlier finding that the prevalence of H. pylori infection in children with persistent diarrhoea and malnutrition was double that in ‘healthy’ controls (SULLIVAN et al., 1990). When the nutritional status of a group of children at the time of seroconversion was compared with age and sex matched controls, it was found that malnutrition did not predispose to H. pyZoti infection, but rather the converse: H. pylti infection was the primary event, which was followed by diarrhoea and growth faltering. Moreover, the increasing age-related prevalence of infection with H. pylori coincided with the increasing incidence of diarrhoea and malnutrition in early life (WEAVER, 1994). Using the [13C]urea breath test as a non-invasive means of detecting acute H. pylori infection? 248 Gambian children aged 3 to 45 months were studied at intervals of 3 months for 2 years. Changes in urine acid output (UAO) in response to a feed were used as an indirect measure of gastric acidity (THOMAS et al., 1993a), specific IgM and IgG were measured to follow the systemic immune response to infection (THOMAS, et al., 1990), and regular anthropometery was performed. The age-relatedpoint prevalence, calculated from urea breath tests, increased from around 20% at 3 months to over 80% at 30 months (Fig. 2). Many newborn babies had high circulating titres of specific IgG, acquired transplacentally from the mother, which declined neonatally. Specific IgM seroconversion occurred within 3 months of

weight gains during the first 18months (P
no.

ELBA

0,126 8::;: ;:g 0.152 8%

01705

pylon’

DFgnosis ofgH. pyIo$infection’ 12

months monthsmonthsmonths ND + -+ + 1 i+D + + 0~08-0~191) + +

result?

0.069-0.12 0.075-0.13 c 0~074-0~15 0~093-0~15 i 0.092-0.224) 0~13-0~17) 0.087-0.216)

0.122-0.207)’ 0~14-0~198) 0.161-0.218 0.501-0.939i


-

ND

+ +

N’D

aMean optical density (standard deviation and range in parentheses); bdetennined 3-&months after birth except where shown. Diagnosis by [ C]urea breath testing; ND=not done. ‘Determined 7-8 months after birth.

9 ‘12’15’18’21 ‘24’27.30. AGE (months) Fig. 2. Age-related point-prevalence of Helicobacter pylon’ infection in Gambian infantsandchildren. a positive urea breath test in most children, and preceded the reappearanceof circulating IgG. During the first 6 months of life there was a highly significant relation (P
The mothers exhibited anti-H. pylon’ IgA reactivity in their breast milk, with optical densities in the ELISA ranging from 0.1 to 0.7. Five of the 7 infants of mothers whose mean specific breast milk IgA optical densities were less than 0.15 developed H. pylori within the first 9 months of life. None of the 5 infants whose mothers had mean specific breast milk IgA optical densities greater than 0.15 had developed H. pylon’ infection by 9 months of age (P
349 Western blotting has demonstrated the presenceof secretory IgA directed against 3 major antigens in the milk of all mothers. The band associated most strongly with protection against H. pylori infection has been shown, using H. pylori urease as antigen, to correspond to the 66 kDa subunit of H. pylori urease. Similar antibodies have been shown to confer passiveimmunity in animal models (CZINN et al., 1993), but our studies were the first to demonstrate this effect in man. Prevention of H. pylori infection may reduce childhood diarrhoea, malnutrition and growth faltering If it is true that acute H. pylon’ infection, by depressing the gastric acid barrier, opens the way to enteric infections, leading to diarrhoea, malnutrition and growth failure in childhood, then prevention or eradication of H. pylori may significantly reduce the incidence of a syndrome that is a maior cause of childhood morbiditv_I and mortality (WEAVER, 1993). The importance of H. pylon’ in early life is that it occurs at a critical period of childhood growth and development. Weaning foods may be contaminated with H. pylori, and the immature stomach and intestine may lack the defence mechanisms to cope with overwhelming infection so early in life. In a community where over 90% of children are infected by 5 years of age, and many of whom are probably excreting-the organism (THOMAS et al.. 1992). it is no surmise that infants become infected retieatedly, and so young. There are 3 possible approaches to the eradication of H. pylon’ infection: antimicrobial therapy, public health interventions, and immunization. At present there is no medication, suitable for widespread use in children, that specifically and effectively eradicatesH. pylori. Improvements in water supply and hygiene, designed to prevent interpersonal transmission, are at present beyond the capacity of most developing countries. Immunization offers the most hope of preventing H. pylori infection in early life. Immunization strategies The major problem in the development of a vaccine against H. pylon’ is the apparent lack of natural immunity to the infection. Recently, however, using a mouse model, oral immunization with a crude lysate of H. felis has been shown to induce protection against H. pylori infection through induction of high levels of IgA antibodies (CHEN et al., 1993; CZINN et al., 1993). The antibody was directed against the B subunit of the ureaseenzyme. All primary isolates of H. py2ori produce a urease and oral immunization with H. pylori urease, or its A or B subunits, also protects mice against H. felis infection (MICHETTI et al., 1994). Urease represents an attractive candidate antigen for vaccine development and carriers are & now being considered for its deliverv_ (MICHETTI ~ HAAS, 199).

IgA antibodies against H. pylon’ in human milk appear to protect infants from early acquisition of infection (THOMAS et al.. 1993b). and this finding raises the oossibility of a vaccination strategy based on’ enhancement of maternal milk antibody secretion. We are now trying to identify the functional properties of human milk IgA, and working towards an intervention study aimed at preventing, delaying or eradicating H. pylori infection, using a vaccine given to mothers before or during lactation. The concept of preventing neonatal infections by immunizing pregnant women has been used extensively to protect against diphtheria, tetanus, and pertussis, and recently maternal immunization to prevent Haemophilus injluertzae, group B streptococcal, and meningococcal disease has been under evaluation. Although parenteral immunization with protein antigens does not generally induce an IgA immune response in mucosal secretions, both pregnancy and prior exposure to the antigen by the mucosal route appear to result in exceptions to this rule. Via the enteromammary circulation, high levels of anti-

bodies to microorganisms that colonize or infect respiratory and intestinal mucosal surfaces are secreted in breast milk. Parenteral immunization during pregnancy, therefore, has the potential to increase antibody titres not only in serum but also in colostrum and milk, particularly in the mother who has experienced earlier ‘mucosal priming’ (INSEL et al., 1994). Conclusions It has becomeincreasingly evident that H. pyluri infection is not only widespread in industrialized nations, but even more prevalent in the developing world, where populations are infected first in childhood. The importance of H. pylori infection in early life is that it occurs during a critical period of growth and development. Loss of gastric defences, with hypochlorhydria, may permit passageto the small intestine of enteropathogens ingested in contaminated weaning foods. However, augmentation of maternal breast milk antibodies may lead to a shift in incidence of infection from early infancy to later childhood, beyond the critical weaning period when diarrhoea, malnutrition and growth faltering are so common. There is a pressing need for further studies aimed at elucidating the natural history of childhood H. pyZori infection and the factors that regulate it (SACK & GYR, 1993). BecauseH. pylori infection is a risk factor for gastric carcinoma, as well as gastroduodenal disease,vaccine development is now well under way (MICHETTI & HAAS, 1994). Acknowledgements The work describedwasthe co-operativeeffort of Mr S. Austin, Dr W. A. Coward, Dr A. Dale, Mr M. Darboe, Mrs M. Harding, Dr I’. G. Sullivan, Dr J. E. Thomas and Dr L. T. Weaver of the MRC Dunn Nutrition Unit, Keneba, The Gambia, and Cambridge, UK. We thank the Thrasher Research Fund for its generoussupport. References Chen, M. H., Lee, A., Hazel& S., Hu, P. J. & Li, Y. Y. (1993). Immunization against gastric infection with Helicobacter species-first step in the prophylaxis of gastric cancer. ZnternationalJournal of Microbiology, Virology, Parasitology and Infectious Disease, 280, 155-165. Czinn, S. J., Cai, A. & Nedrud, J. G. (1993). Protection of germ-free mice from infection bv Helicobacter felis after oral or passive I A immunization. Vaccine, 11,634-842. Dale, A., f homas, J. E., Harding, M., Darboe, M. K., Coward, W. A. & Weaver, L. T. (1993). Acute Helicobacterpylori infection and impaired gastric acid secretion in children. Acta Gastroenterologica Belgica, 56, 60 [abstract]. Gilman, R. H., Partanen, R. & Brown, K. H. (1988). Decreasedgastric acid secretion and bacterial colonization of the stomach in severely malnourished Bangaldeshi children. Gastroenterology, 94,1308-1314. Holcombe, C. (1992). Helicobacter pylon’: the African enigma. Gut, 33,429-431.

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