Nutritional and Health-Related Environmental Studies (NAHRES)

Stable isotope techniques to design effective food fortification strategies in settings with high Helicobacter pylori infection.

Background

The infection H. pylori infection is the most common bacterial infection in humans and its prevalence is much higher in developing countries (around 80-90% among adults) than in developed countries (<40%). Transmission occurs in the family setting and acquisition takes place in early childhood and persists life-long in most infected subjects (2). Studies have shown that high H. pylori prevalence is associated with a variety of risk factors including low socio-economic status, low education level, poor sanitation, rural residence, and birth in a developing country (3). For example, in a study in Bangladesh, 60% of children under 5 years of age were infected (4).

H. pylori is a cofactor in three upper gastrointestinal diseases: duodenal or gastric ulcers, gastric cancer, and gastric mucosa-associated lymphoid-tissue (5). In 1994, the bacterium was classified as a group 1 carcinogen for humans by the International Agency for Research on Cancer because of its association with gastric cancer (6). However, most individuals with a chronic gastric infection of H. pylori are asymptomatic and do not present any clinically significant complications (5).

The presence of H. pylori infection will be diagnosed using the [13C] Urea Breath Test (UBT), which is based on the collection of breath samples that are analyzed for the ratio of 13CO2/12CO2 using isotope ratio mass spectrometry (IRMS) or non-dispersive infrared spectrometry (NDIRS). The [13C] UBT is a non-invasive and safe diagnostic test to detect the presence of H. pylori in the stomach and to confirm eradication after treatment. This technique is considered the best method for the diagnosis of H. pylori infection in the community setting (7). However, it does not allow classifying or ranking the severity of the infection.

Effect on gastric acid
An important consequence of chronic H. pylori infection is the impact on gastric acid secretion related to the length of exposure to the infection and the location of the bacterium in the stomach. A reduction of gastric acid output as a result of infection with H. pylori has been demonstrated in children and adults (5, 8, 9, 10). Gastric acid is a key factor for the digestion and absorption of micronutrients, i.e., for releasing the micronutrients from the food matrix and to solubilise them. In addition, low gastric acid output facilitates the acquisition of other enteropathogens because of the removal of the gastric acid barrier, which is associated with increased susceptibility to diarrheal disease, a major public health concern linked to malnutrition and growth failure in children in developing countries (11). However, to date the conventionally used and very invasive intubation technique for measuring gastric acid secretion has limited the collection of data in community studies in developing countries.

The link to micronutrients
H. pylori infection is most prevalent in resource-poor areas, where micronutrient deficiencies are common and vulnerable population groups are often caught in a vicious cycle of poor nutrition and infectious disease. Micronutrient deficiencies lead to more frequent infections, reduce the ability to fight and survive disease, and impair mental capacity in children. Iron deficiency is the most common nutrient deficiency and is thought to account for about 50% of the cases of anaemia. About two billion people are affected by iron deficiency (12). Globally, about half of the preschool-age children (under 5 years old) and 42% of pregnant women are anaemic; in Africa, 68% of preschool children and 57% of pregnant women are anaemic (13).

The epidemiological evidence regarding the relation between H. pylori infection and indicators of micronutrient status is not conclusive. Studies have shown controversial results about the association between H. pylori infection and iron deficiency or iron deficiency anaemia (IDA) and the effectiveness of the eradication of H. pylori in the treatment of IDA (14, 15). For example, the meta-analysis of 15 observational studies and 5 randomized controlled trials suggested that IDA is associated with H. pylori, although some studies reported only a slight association, and that eradication of H. pylori can improve haemoglobin and serum ferritin concentrations, but not significantly (15). Very little evidence exits to date on the impact of H. pylori infection on zinc. It seems plausible that the absorption of zinc is affected when gastric acid output decreases as a result of H. pylori infection. As iron, zinc is only absorbed if it is in a soluble form, which is achieved in acid media (16). In conclusion, the great variability in study design (sampling procedures, sample size, detection of H. pylori infection, control group and outcome variables) and analyses (adjustment for confounders) makes it difficult to compare results (17). In addition, most studies have not assessed to which extent gastric acid output was affected and have not screened for the severity of the infection. Another challenge is to interpret iron and zinc status in the presence of infection. Even subclinical inflammation alters indicators of iron and zinc status (e.g., ferritin, haemoglobin, plasma zinc) and increases the concentration of hepcidin, a small peptide hormone that regulates intestinal iron absorption (18, 19, 20).

Food fortification as a strategy to combat micronutrient deficiencies In many developing countries food fortification has become an important strategy to combat iron and zinc deficiency, because of high benefit: cost ratios. Fortification with iron and zinc has demonstrated to provide significant economic benefits at low unit cost (22). One of the key factors in designing a successful program is the choice of the iron or zinc compounds to be used. An important selection criterion is the bioavailability of the compound. Water-soluble compounds such as ferrous sulphate are highly bioavailable, but are also highly reactive and modify the sensory characteristics of food. Therefore, compounds that are insoluble in water such as ferrous fumarate are often used. However, these compounds are soluble in diluted acid solutions and require normal secretion of hydrochloric acid by the stomach. Extensive guidelines on food fortification with micronutrients have been compiled under the aegis of WHO and FAO (23) to assist countries in the design and implementation of appropriate food fortification programmes. They include technical information on various chemical forms of micronutrients that can be used to fortify foods and key steps in determining the amount of nutrients to be added to foods. However, these guidelines are primarily based on data from Western adult populations and do not differ for settings with high H. pylori infection. Data from Bangladesh indicate that extrapolation to a different context does not necessarily work: the mean iron absorption from ferrous fumarate relative to ferrous sulphate was only 27-35% in Bangladeshi children compared with 100% in Western adults (9). Thus, food fortification programmes based on current guidelines might not be effective in countries where iron and zinc deficiency is combined with high rates of H. pylori infection and consequently impaired gastric acid output (9, 16, 21).

In summary, the high prevalence of H. pylori infection adds to the existing burden of infectious diseases and micronutrient malnutrition of vulnerable population groups in developing countries and might compromise the benefits of food fortification, but studies to date on the association between H. pylori infection and micronutrient malnutrition have generated contradictory results. Therefore, more research is needed in developing countries to provide data on the effect of H. pylori infection on gastric acid output and the absorption of iron and zinc from fortification compounds with different physical and chemical properties in asymptomatic individuals. The research results will be disseminated widely to different stakeholders, including public health policy makers, and thus contributes to the evidence base for the formulation of effective food fortification programs.

This CRP will use stable isotope methods to (a) diagnose H. pylori infection and (b) measure absorption of iron and zinc. The research studies conducted in this CRP will be approved by national ethical review boards and subjects will participate in studies for a limited period of time (2-4 weeks), which is required for diagnosing the infection and measuring absorption of iron and zinc from administered fortification compounds. The participating subjects with diagnosed H. pylori infection will be treated thereafter. To date, no country with high H. pylori infection rates has adopted treatment of the infection on large scale as a public health strategy because of high costs of the treatment scheme and likely re-infection if living conditions do not change.

Objective

Overall objective
  • The overall objective is to contribute new information on the effect of H. pylori infection on iron and zinc absorption from different food fortification compounds in asymptomatic individuals in developing countries.
Specific objectives
  • Generate new data on the link between H. pylori infection and iron and zinc absorption from fortification compounds in asymptomatic individuals
  • Explore possibilities to develop a non-invasive test using stable isotopes to measure gastric acid secretion.
Expected research outputs
  • New information on how H. pylori infection affects iron and zinc absorption from fortification compounds as a result of impaired gastric acid secretion in different vulnerable population groups (e.g., young children, women of reproductive age).
  • New information on the feasibility of a non-invasive test to measure gastric acid secretion using stable isotopes.
  • Publications in the form of scientific reports and peer reviewed papers.
Expected Research Outcomes
  • To contribute new knowledge to inform the design of effective food fortification strategies to address micronutrient deficiencies in developing countries.
Proposal submission forms

Research institutions in Member States interested in participating in this CRP are invited to submit proposals directly to the Research Contracts Administration Section (NACA) of the International Atomic Energy Agency: Official.Mail@iaea.org or to Ms Cornelia Loechl: c.loechl@iaea.org. The forms can be downloaded from http://www-crp.iaea.org/html/forms.html. For more information about research contracts and research agreements, please visit the following web-site: http://www-crp.iaea.org/html/faqs.html.

Deadline for submission of proposals

Proposals must be received no later than 25 February 2011.
Transmission via Email is acceptable if all required signatures are scanned.

For additional information, please contact:
Cornelia Loechl, Nutrition Scientist
Nutritional and Health-Related Environmental Studies Section
Division of Human Health
International Atomic Energy Agency (IAEA)
Wagramer Strasse 5
A-1400 Vienna, Austria
Phone: +43-1-2600-21635 or 21674
Fax: +43-1-2600-7
c.loechl@iaea.org


References
  1. PEREZ-PEREZ, G.I., ROTHENBACHER, D., BRENNER, H., Epidemiology of Helicobacter pylori Infection, Helicobacter 9 (Suppl. 1) (2004) 1-6.
  2. EVERHART, J.E., Recent developments in the epidemiology of Helicobacter pylori, Gastroenterol. Clin. North Am. 29(3) (2000) 559-578.
  3. BRUCE, M.G., MAAROOS, H.I., Epidemiology of Helicobacter pylori Infection, Helicobacter 13 (Suppl. 1) (2008) 1-6.
  4. MAHALANABIS, D., RAHMAN, M.M., SARKER, S.A., ET AL., Helicobacter pylori Infection in the Young in Bangladesh: Prevalence, Socioeconomic and Nutritional Aspects, Intern. J. Epidem. 25(4) (1996) 894-898. [5] KENNETH, E.L., MCCOLL, M.D., Helicobacter pylori infection, N. Engl. J. Med. 362(17) (2010) 1597-1604.
  5. WORLD HEALTH ORGANIZATION, INTERNATIONAL AGENCY FOR RESEARCH ON CANCER, Schistosomes, liver flukes and Helicobacter pylori, IARC Monographs on the evaluation of carcinogenic risks to humans 61 (1994).
  6. BARRADO, A., PRESTON, T., SLATER, C., ET AL., The usefulness of stable isotopes in nutrition and human health: the application of mass spectrometry and [13C] breath tests to detect Helicobacter pylori infection, Archivos Latinoamericanos de Nutricion 54, Supl N° 2 (2004) 27-43.
  7. EL-OMAR, E.M., OIEN, K., EL-NUJUMI, A., ET AL., Helicobacter pylori infection and chronic gastric acid hyposecretion, Gastroenterol. 113(1) (1997) 15-24.
  8. SARKER, S.A., DAVIDSSON, L., MAHMUD, H., ET AL., Helicobacter pylori infection, iron absorption, and gastric acid secretion in Bangladeshi children, Am. J. Clin. Nutr. 80 (2004) 149-153.
  9. ANNIBALE, B., CAPURSO, G., LAHNER, E. ET AL., Concomitant alterations in intragastric pH and ascorbic acid concentration in patients with Helicobacter pylori gastritis and associated iron deficiency anaemia, Gut 52 (2003) 496-501.
  10. WINDLE, H.J., KELLEHER, D., CRABTREE, J.E., Childhood Helicobacter pylori Infection and Growth Impairment in Developing Countries: A Vicious Cycle? Pediatrics 119 (2007) e754-e759.
  11. BLACK, R., Micronutrient deficiency - an underlying cause of morbidity and mortality, Bulletin of the WHO 81(2) (2003) 79.
  12. WHO (World Health Organization), Worldwide prevalence of anaemia 1993-2005: WHO global database on anaemia, edited by B. de Benoist, E. McLean, I. Egli and M. Cogswell, Geneva (2008).
  13. AKCAM, M., Helicobacter pylori and Micronutrients, Ind. Pediatrics 47 (2010) 119-126.
  14. QU, X.-H., HUANG, X.-L. XIONG, P., ET AL., Does Helicobacter pylori infection play a role in iron deficiency anaemia? A meta-analysis, World J. Gastroenterol. 16(7) (2010) 886-896.
  15. SALGUEIRO, J., ZUBILLAGA, M., GOLDMAN, C., ET AL., Review article: is there a link between micronutrient malnutrition and Helicobacter pylori infection? Aliment. Pharmacol. Ther. 20 (2004) 1029-1034.
  16. MUHSEN, K., COHEN, D., Helicobacter pylori Infection and Iron Stores: A Systematic Review and Meta-analysis, Helicobacter 13 (2008) 323-340.
  17. MBURU, A.S.W., THURNHAM, D.I., MWANIKI, D.L., ET AL., The influence and benefits of controlling for inflammation on plasma ferritin and haemoglobin responses following a multi-micronutrient supplement in apparently healthy, HIV+ Kenyan adults, J. Nutr. 138 (2008) 613-619.
  18. COLLINS, J.F., WESSLING-RESNICK, M., KNUTSON, M.D., Hepcidin Regulation of Iron Transport, J. Nutr. 138(11) (2008) 2284-2288.
  19. BROWN, K., Effect of infections on plasma zinc concentration and implications for zinc status assessment in low-income countries, Am. J. Clin. Nutr. 68 (1998) 425S-429S.
  20. SALGUEIRO, M.J., ZUBILLAGA, M., LYSIONEK, A., ET AL., Fortification strategies to combat zinc and iron deficiency, Nutrition Reviews 60(2) (2002) 52-58.
  21. HORTON, S., The Economics of Food Fortification, J. Nutr. 136(4) (2006) 1068-1071.
  22. WHO AND FAO, Guidelines on food fortification with micronutrients, edited by L. Allen, B. de Benoist, O. Dary and R. Hurrell, Geneva (2006).