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Location: Children's Nutrition Research Center

2012 Annual Report

1a. Objectives (from AD-416):
There is an ongoing need to enhance our understanding of the role of various nutrients on fetal, postnatal, and childhood growth and development. This is becoming increasingly important as studies continue to show an association between the patterns of growth during these early time periods and health later in life. At present, little is known about the functional need for different amino acids in support of these changes, and the variability in normal growth. The research objectives include: 1) define the nutritional and functional requirements of methionine, cysteine, and arginine for healthy children; 2) investigate the impact of docosahexaenoic acid (DHA) intake from food and supplemental sources on blood levels, cognitive performance, and neurophysiological function, heart rate and blood pressure, as well as a lower incidence of allergies and upper respiratory infection in children; 3) investigate the pathways and nutritional modulation of methyl group production in underweight and normal weight pregnant women; 4) investigate differences in bowel flora, antioxidant capacity, and mitochondrial integrity between severely malnourished and well-nourished children; 5) conduct a pilot study of genetic susceptibility to edematous severe child malnutrition (ESCM); 6) conduct exploratory analyses of the relationship between risk of ESCM and individual genetic variation; 7) critically evaluate population-specific genetic variation in samples; 8) determine how obesity, ethnicity, and obesity-related liver disease contribute to low serum 25-hydroxyvitamin D levels; 9) understand the relationship between serum 25-hydroxyvitamin D levels and serum inflammatory cytokines, gastronintestinal permeability, and elevated liver transaminases; 10) characterize glucose and insulin tolerance, serum and liver lipids, and liver histology and gene expression; and 11) explore the molecular mechanisms for the lipotropic and anti-diabetic effects. This project will provide novel and new information directly useful to nutritional scientists, pediatricians, industry, and governmental agencies responsible for establishing pediatric dietary guidelines. These data will have global application and provide a strong basis for evidence-based development of nutritional recommendations for children and pregnant mothers.

1b. Approach (from AD-416):
The goal of our research is to obtain better data on amino acid nutritional and functional requirements for growth. Our researchers aim to determine if an intake of methionine and cysteine is more efficient to support glutathione synthesis rates in healthy children, than an equimolar intake of methionine alone. We will evaluate whether arginine supplementation in obese children improves insulin sensitivity and protein synthesis, and explore gluconeogenesis under these conditions. We will investigate the impact of docosahexaenoic acid (DHA) intake from food and supplemental sources on blood levels, cognitive performance, and neurophysiological function of 4- to 12-year-old children. We will advance our understanding of the genetic determinants of risk of ESCM which will provide new insights into the causes of ESCM. Through our studies of Vitamin Din different ethnic groups of obese children, we will contribute to new insights into the actions of vitamin D and the pathogenesis of obesity related liver disease in children. Additionally we will identify novel dietary supplement strategies to prevent or treat obesity related chronic diseases by evaluating the lipotropic effect.

3. Progress Report:
Significant research progress was accomplished during the year. To review the progress, please refer to project 6250-51000-052-20S (Project 2).

4. Accomplishments
1. Increasing methyl production to meet the requirements of pregnancy? During pregnancy compounds called methyl groups are needed to make new tissues, especially in late pregnancy when the fetus is rapidly growing. Because Indian women give birth to a lot of low birth weight babies Children's Nutrition Research Center researchers in Houston, Texas, measured the amount of methyl group that was being made and utilized by underweight and normal weight pregnant Indian women. We learned that both groups of women were unable to increase the amount of methyl groups they were making in late pregnancy. This finding suggests that the inability to increase methyl groups may be contributing to the high numbers of low birth weight babies born among Indian women. If true, nutritional therapies aimed at increasing methyl group production by Indian women may increase the birth weights of their babies.

2. Understanding intestinal bacteria. Additional knowledge is needed to further understand why the numbers and type of bacteria in the intestine change with a child's age and nutritional status. Children's Nutrition Research Center researchers successfully identified and characterized the populations of bacteria and their metabolic capacity in Malawian children aged 0-3 years, and saw how both changed with the child's diet and nutritional status. Our studies showed that there are populations of bacteria that represent older and younger children, and before a child becomes malnourished, the bacteria change to resemble the bacterial population of younger children, with its limited metabolic capacity. As a result of this study researchers now know that these bacteria are one of many contributing factors to childhood malnutrition.

3. Genome-wide studies of severe under-nutrition. We are using genetic approaches to understand why some children develop acute swelling and multi-organ involvement in the face of severe under-nutrition, while others have only chronic wasting. There are significant differences in morbidity and mortality between these two groups, which contribute to millions of childhood deaths around the world each year. Researchers at the Children's Nutrition Research Center in Houston, Texas, performed preliminary genome-wide studies of common DNA variation and DNA methylation in samples from individuals with edematous and non-edematous severe childhood malnutrition. These early studies implicate genes and genetic pathways (involving carbohydrate metabolism and phosphate metabolism) that may play a significant role in determining differences between the two groups. If substantiated, this research could provide new insights as to why the two groups respond differently to similar nutrient deprivation and thus inform new avenues for treatment and management.

4. Using technology to discover disease-causing genes. Human Leukocyte Antigen (HLA) genes play a central role in the immune response and disease (such as Type I diabetes) susceptibility, and developing a computational method to infer HLA allele type (the classification of individual specific combination of HLA genes) would be valuable to researchers since traditional methods of HLA allele typing is expensive and also not very reliable. Children's Nutrition Research Center researchers in Houston, Texas, have developed a software program to infer HLA allele type, and relatedness among different HLA genes. The computerized method can predict HLA type with high accuracy and is only a fraction of the cost when compared to traditional methods. This software has the potential to make significant contributions to find disease-causing genes and to assess different nutritional approaches to addresses these concerns.

5. How bacteria in the gut influence each other. There are trillions of bacteria in the human gut that play a role in keeping us healthy or sometimes, making it more likely we will become ill. It is critical to understand how these bacteria influence each other – either enhance or inhibit the growth of other bacteria like themselves. Researchers at the Children's Nutrition Research Center in Houston, Texas, have shown previously that the bacterial population of the gut is different in adults, young children, and young children who frequently experience stomachaches, often related to diet; but through using a new technique called network analysis we have learned that in healthy children the presence of one type of good bacteria predicts the presence of other good bacteria. In contrast, for example, in children who have constipation and stomachaches, the presence of some good bacteria is not as extensively linked to other good bacteria; it is as if their group of "friends" is much smaller. By understanding the factors that govern these relationships we potentially could enhance the populations of bacteria we know to be beneficial, which would significantly reduce healthcare costs by minimizing the risk from bacteria thought to play a role in a multitude of common disorders: obesity, inflammatory bowel disease (which includes Crohn’s), and autoimmune disease.

6. Identifying the products of gut bacteria by identifying the genes in the bacteria. It is one thing to identify the bacteria present in health and disease, but the next vital step is to determine what products these bacteria are capable of making. Knowing what products (hormones) specific bacteria can produce will help us understand how bacteria cause, contribute to, or help prevent disease, and it will also potentially tells us how we can influence the composition of the bacteria in the gut (for example, through diet). This can be accomplished through a technique called whole genome shotgun (WGS) sequencing, which is not easy and is relatively expensive; however, given the unique capabilities present at the Children's Nutrition Research Center, the Texas Children's Hospital, Microbiome Center, and Baylor College of Medicine, researchers have been able to establish WGS sequencing lab for analyses of the gut bacteria in healthy adults, children, and children with diet-related stomach disorders. Using this technique, CNRC researchers will open a new world of opportunity to understand how gut bacteria interact with each other, with us, the foods we eat, and the medications we take, to influence our state of health. Such information will create critical opportunities for us to improve the health of the global population.

Review Publications
Connor, N.E., Manary, M.J. 2011. Monitoring the adequacy of catch-up growth among moderately malnourished children receiving home-based therapy using mid-upper arm circumference in Southern Malawi. Maternal and Child Health Journal. 15(7):980-984.

Phuka, J., Ashorn, U., Ashorn, P., Zeilani, M., Cheung, Y., Dewey, K.G., Manary, M., Maleta, K. 2011. Acceptability of three novel lipid-based nutrient supplements among Malawian infants and their caregivers. Maternal and Child Nutrition. 7(4):368-377.

Motil, K.J., Barrish, J.O., Lane, J.B., Geerts, S.P., Annese, F., Mcnair, L., Percy, A.K., Skinner, S.A., Neul, J.L., Glaze, D.G. 2011. Vitamin D deficiency is prevalent in girls and women with rett syndrome. Journal of Pediatric Gastroenterology and Nutrition. 53(5):569-574.

Trehan, I., Amthor, R.E., Maleta, K., Manary, M.J. 2010. Evaluation of the routine use of amoxicillin as part of the home-based treatment of severe acute malnutrition. Tropical Medicine and International Health. 15(9):1022-1028.

Phuka, J.C., Gladstone, M., Maleta, K., Thakwalakwa, C., Cheung, Y.B., Briend, A., Manary, M.J., Ashorn, P. 2012. Developmental outcomes among 18-month-old Malawians after a year of complementary feeding with lipid-based nutrient supplements or corn-soy flour. Maternal and Child Nutrition. 8(2):239-248.

Sayre, R., Beeching, J.R., Cahoon, E.B., Egesi, C., Fauquet, C., Fellman, J., Fregene, M., Gruissem, W., Mallowa, S., Manary, M., Maziya-Dixon, B., Mbanaso, A., Schachtman, D.P., Siritunga, D., Taylor, N., Vanderschuren, H., Zhang, P. 2011. The BioCassava Plus program: Biofortification of cassava for sub-Saharan Africa. Annual Reviews of Plant Biology. 62:251-272.