ActivitiesActivities-Scientific track-record
This section sets the key points of our work into context and serves as a map to guide you through the list of publications. The subjects are presented under two headings: 1. Iron and related problems, and 2. Nutritional behavior in less developed countries.
1. Iron and related problems
1.1 Molecular mechanisms of iron metabolism
One focus of our activities deals with the problems related to extra iron supply. Genetic approaches improved our understanding of molecular mechanisms that link iron-absorption and –distribution to the demand of the organism, of their interaction with inflammation, and of how dietetic intervention may improve the situation. We reviewed present knowledge on this field and on the consequences of new insights for recommended iron intake (R3, R5, R6, R7, R10). Development and validation of a method that determines the distribution of the iron isotope 59Fe in mice is to be mentioned here, that solves the problem how to differ between 59Fe taken up into the tissue itself, and 59Fe in erythrocytes which are in the tissue by chance when the animal is killed (I1, I2). Based on these findings a computer model was developed that permits to analyze all steps in iron-distribution that change in consequence of a knock-out or of genetic modification of proteins involved in iron metabolism (I9).
Iron supplementation programs use highly bioavailable iron compounds; if absorbed excessively they can induce negative health effects (R1). Particularly infants and small children with their immature homoeostatic mechanisms are vulnerable to excessive iron exposure which may retard growth (R8). A recent study, supported by our foundation, extended the understanding of the intestinal iron absorption mechanisms (I12). It showed that the iron-storage in mucosal ferritin is indispensible to avoid overshooting iron absorption.
1.2 Iron and inflammation
Iron-deficient diets significantly reduce the intensity of inflammation in a mouse model for colitis ulcerosa (I6) and inflammation remains low when the missing iron amounts were supplemented by parenteral injection (I13). Moreover, these experiments help to understand the molecular mechanisms of inflammation and the participation of oxidative stress and protein folding in its pathogenesis, as well as the effect of local inflammation on iron distribution (I7, I13). These results open perspectives for future therapeutic interventions.
Oxidative stress in the intestinal lumen participates in the pathogenesis of inflammatory bowel diseases and tumors in the colon. HGF supported the development of a method to determine the extent of such stress in stool samples. Oral iron supplementation at dosages recommended by WHO increases oxidative stress in the intestinal lumen significantly. This can be balanced by simultaneous consumption of antioxidative food components, such as palm oil (I8).
1.3 Optimizing iron intervention programs in children and adolescents
To mitigate the high prevalence of anemia in South-East Asia Hildegard Grunow Foundation supported, under leadership of the German Technical Cooperation (GTZ), the application of “foodlets” in Cambodia. A “foodlet” is a crushable tablet to add micronutrients to children’s dishes on the table (ready-to-eat foodlets); it has a shelf-life of 18 months under tropical conditions. When charged with 1 RDA of Fe/d its use reduced frequency and extent of anemias in infants and children significantly. Moreover, when additionally charged with 0.5 RDA of 11 essential micronutrients, it reduced the prevalence of diarrhea and upper respiratory tract infections that were increased in the iron group, to values below those in the placebo group. Even anemias related to hemoglobinopathias, which are frequent in SE-Asia, responded readily when overlapped by iron-deficiency (I5). Iron-deficiency anemias in Cambodian school children can be significantly reduced by seasoning school meals with iron-fortified fish-sauce. A new method of fortification with FeSO4 and citrate lead to identical results as with the commonly used NaFe-EDTA, at about 30% of cost for the supplement (I5).
1.4 Iron and malaria
Iron supplements aggravate the clinical course of plasmodium falciparum-induced malaria tropica, if they are not explicitly targeted to iron-deficient individuals. On the one hand, these findings prohibit untargeted iron-supplementation in malaria-endemic areas, as they lead to more severe clinical courses and increased death rates. Without iron intervention programs, on the other hand, impaired physical and mental development and increased numbers of still births and abortions are the consequence (R2). HGF supports the quest for solutions to this dilemma. A possible way-out is to develop or adapt inexpensive and robust methods for the determination of the hematological, inflammatory and iron status. These methods should be non-invasive to prevent dissemination of AIDS and hepatitis through blood sampling. HGF supports field-testing of devices for non-invasive, transcutaneous hemoglobin determination. Some of the results obtained so far are promising (I11, I20), though a break-through was not yet achieved. To differ between anemia of iron-deficiency and anemia of inflammation, and to help with the decision whether to administer iron or not, we tested non-invasive parameters, e.g. the use of urinary 25-hepcidin (I13).
An alternative solution would be to find an iron-preparation that releases its iron slowly enough to be available to the hosts’ erythropoietic system rather than to the malarial parasites. Oral iron-polymaltose supplements and NaFe-EDTA complexes for food fortification with iron both release their iron-moiety slowly and improve hemoglobin repletion successfully. After absorption both compounds increase the concentrations of plasma iron and of “non-transferrin-bound iron” (NTBI) significantly less than e.g. FeSO4, the latter being regarded the “gold-standard” among iron compounds. As NTBI is considered a key-component in the pathophysiological chain of iron-aggravated malaria courses, the foundation will continue to support studies along these lines.
1.5 Zinc-supplementation in Third World environments
In humans, zinc is an essential trace element; moreover, it showed to be of value in the treatment of diarrhea and may strengthen immunological defense. This is why the effects of zinc were tested in 2 subgroups of the Pemba-trial. During this study, plasma-zinc concentrations increased to a much lower extent than expected. Consequently, HGF funded a bioavailability assessment of the Nutriset-Zn-tablet used by WHO and found its absorption to be significantly lower than that of Zn-salts in solution (I9). This cast doubt on the bioavailability of the Nutriset-Zn preparation, not so, however, on its beneficial effects for the treatment of diarrhea, which is attributed to effects in the intestinal lumen.
1.6 Mechanism of intestinal lead absorption
Children are exposed to lead from the environment or with food. This is still a considerable problem in many regions, particularly in the developing world. Intestinal lead-absorption is markedly higher in children than in adults, though the underlying mechanisms are incompletely understood. However, lead absorption seems to be increased in iron deficiency, suggesting that lead may share the regulated absorptive pathways for iron, which is the conventional view. A study supported by HGF revealed that two independent mechanisms of lead absorption seem to be at work. One mechanism works in the duodenum and its activity is increased in iron-deficiency in line with the conventional concept. The increment, though, is much less marked than for iron itself. A second mechanism, however, is independent from iron-status and works in the considerably longer, lower sections of the small intestine. Food composition and the availability of food ligands seems to determine, to which extent lead is absorbed in the duodenum or in the more distal small intestine. Different binding to food ligands and, consequently, absorption or prevention of absorption in the duodenum may explain the contradictory findings on the impact of iron-status on lead absorption (I15).
1.7 DNA-analysis in saliva to detect mutations in nutrient metabolism
HGF also supported field testing of a new, non-invasive, saliva sampling method to provide DNA for analysis of polymorphism in epidemiological studies in Guatemalan school children. Results showed that the frequency of single nucleotide polymorphisms in β-carotene metabolism in children of Mayan origin was consistent to that found in Han Chinese and Japanese groups, but different from that in Europeans. It permits high efficient carotene cleavage consistent with an agrarian lifestyle, while the European form of vitamin A metabolism is consistent with a hunters fare (I16).
2. Nutritional behavior in less developed countries
Another main activity sponsored by Hildegard Grunow Foundation is research in dietary intake/food consumption habits, and assessment of fluid consumption and related calorie intake. The underlying goal of this analysis is to find ways for improvement of habitual fares, if necessary.
2.1 Diet and cancer
One focus is the question, to what extent particular diets are in accordance with the recommendations of the World Cancer Research Fund and of the American Institute for Cancer (N1). For this purpose we assessed the fraction of vegetarian food consumed for lunch and dinner (N2) by use of a self-developed pictorial register for normative enquiries in school children (N15). This permitted to test the concordance of diets with individual guidelines components in different socioeconomic strata (N3). When results were compared to corresponding data from Mexico, Scotland and Holland (N13), it may not come as a surprise that the level of concordance was inversely correlated to the economic situation in the different countries and economic strata. Thus, e.g. vegetarian food components were most frequent in the poorest strata and more frequent in Guatemala > Mexico > Scotland > Holland, which, on a group level, shows the highest concordance with cancer prevention goals (N13, N14). This approach looks for “positive deviance”, i.e. for examples of a fare which is actually consumed in a population and can, thus, serve as an example for a feasible dietary pattern for cancer prevention (N14).
2.2 Water consumption and nutrient intake with beverages in Guatemalan children
6-12 months old infants even in low-income communities are approximating the recommended adequate intake levels for fluids through breastfeeding and complementary feeding (N11). Using a one-day pictorial register we assessed volume and frequency of plain drinking water consumption in Guatemalan third and fourth grade school children which shows a wide range depending on the extent to which safe drinking water was freely available in the school environment (N8). Almost half of the fluid intake came with other beverages and approx. one third with food items (N7). The pictorial register showed that 21% of total dietary energy intake was consumed with such beverages, which contributes to the problem of overweight/obesity and low micronutrient quality (N9).
2.3 Nutrient intake in Guatemalan infants
In rural more than in urban areas complementary feeding in infants is based on starchy gruels. Compared to the 2004 WHO/FAO standards micronutrient intakes with such fares are near the recommended levels, though calcium, iron and zinc were identified as problem nutrients (N12). The use of modern versus traditional, processed versus non-processed, commercial versus non-commercial and fortified versus non-fortified food was investigated. It showed that infants 9-12 months of age consumed food specifically prepared for them, in urban rather than in rural areas where children share food from the family pot earlier (N4). In school children, ready-to-eat cereals are a key-source of micronutrient supply, though intake of such cereals was significantly higher among private school participants than in low-income public school attendants (N6). Macro- and micronutrient intakes could, again, be well assessed with the pictorial method (N5). This was also true for the assessment of meals and snacks in daycare centers in Guatemala City, in which quality and quantity of the provided food varied widely (N16). Corresponding research in third and fourth grade school children (8-10y) revealed low intakes of fat and fatty acids which could be improved by higher fish and seafood consumption (N10).
