2011 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.
In obj. 1, DHA was assigned to all subjects and psychological testing has begun. In obj. 2 we are studying underweight pregnant women to determine the effect of dietary supplementation with extra energy and protein on protein synthesis and production of serine and glycine. We have now completed 18 measurements after 12 weeks and 9 after 30 weeks of pregnancy. The rest of the women will be studied when they reach 30 weeks of pregnancy. In obj. 3, 320 twin pairs and 3 sets of triplets were enrolled in Malawi to explore relationships between intestinal bacteria and the growth rate/nutritional status of children. 100 twin families are enrolled in the study, and 143 pairs of children graduated at 3 yr. 15,235 patient visits were conducted; 8,211 stool samples were collected from the children, 519 from their mothers, and 250 from their siblings. 382 children were diagnosed with moderate malnutrition and 166 with severe malnutrition. Sample analyses are completed, and data is being interpreted. For Obj. 4-6, we completed genetic testing on 104 children with severe malnutrition. We showed that children from Jamaica had the expected African-European genetic heritage and are similar to children from West Africa. Our genetic tests did not show a single strong gene responsible for kwashiorkor, but several genetic variants may be involved. In obj. 7-9, infants on different diets were assessed for the composition differences of GI tract bacteria. Samples from children were compared to adult samples. This study will provide information as to when to collect stool samples, how to store the samples, and optimal methods to analyze the stool samples to tell us what bacteria and how many of each type of bacteria we might find. Stool samples from the children were analyzed, and the main types of bacteria present were identified. The amount of bacteria did not differ between children and adults. Since bacteria are classified by their degree of relatedness, we compared those from children with those from adults along a scale that provided information as to whether the bacteria were broadly related (phylum) down to closely related (genus). At the phylum level, a greater proportion of bacteria were Firmicutes in children compared with adults. In contrast, children had a smaller proportion of Bacteroidetes and Proteobacteria. In obj. 10, we created a massive computing cluster and storage array to fulfill the need of large-scale computation for the proposed statistical methods development. We received funding to develop statistical methods to analyze next-gen sequencing data in unison with this project. Grants have been submitted since this will lead to data access, which is important in order to test the methods developed. A manuscript was submitted describing the statistical framework used to study population structure, local ancestry inference for admixed individuals, and haplotype-phenotype association mapping. A companion software package was developed and is being tested.
Including antibiotics to address severe acute malnutrition reduces mortality rate by half. Severe acute malnutrition (SAM) contributes to 1 million child deaths annually. It is unclear if providing empiric antibiotics, in which an antibiotic is selected based upon clinical history as opposed to a specific diagnosis, decreases mortality and failure rates for children. Children's Nutrition Research Center scientists tested the effect of empiric oral antibiotics on mortality and recovery rates of children treated for SAM. Among 2775 children the overall recovery rate for children who received antibiotics was significantly better than those who received no antibiotics. The mortality rate was also significantly less among children receiving antibiotics. These findings are important as they show that SAM should not be addressed solely with nutritional supplementation, the addition of an empiric oral antibiotic to the outpatient therapy improves the recovery and the mortality rate by approximately half.
Genetic factors in the response to severe childhood malnutrition. A longstanding problem in human nutrition is to understand why some children develop edema (kwashiorkor) when they suffer severe nutritional deprivation. Researchers at the Children's Nutrition Research Center in Houston, TX, conducted a study that uses genetic methods to identify pathways that affect the physiological response to malnutrition. Early results indicate that there is not a major single gene that determines the edema response; thus a larger sample size is required to find multiple genes that may influence the response. This is the first study to use state-of-the art genetic mapping methods to understand the physiological response to severe childhood malnutrition. Ongoing work is expected to establish whether edema is influenced by a few genes with relatively large effect or whether there are many weakly acting genetic factors involved.
Phylochip versus gene sequencing for identifying bacteria in the human GI tract. The normal bacteria flora of humans are complex and consist of several hundred species that impact overal health and nutrition of the individual. It is not known which method, phylochip (a fast DNA microarray) or gene sequencing, is better to determine the bacterial composition of the gastrointestinal tract. Children's Nutrition Research Center scientists in Houston, TX, compared these two common methods for evaluating bacterial composition, and our results indicated that scientists can use either method, but gene sequencing provides a more complete picture of the types of bacteria present in the GI tract. These results will enhance scientists' ability to investigate the role of GI bacteria in human health and nutrition.
Does the bacterial composition of the GI tract differ between children and adults. It is not known if the types of bacteria in the gastrointestinal tract differ between children and adults and what influences the development of the normal gastrointestinal population during human life. Scientists at the Children's Nutrition Research Center, Houston, TX, are the first to describe in detail differences between children and adults in the composition of the gastrointestinal bacteria. The results of these studies can be used to move forward with other important investigations that will provide information regarding the development of the bacterial population in the gastrointestinal tract. This information is important since abnormalities in the bacterial population have been associated with such problems as inflammatory conditions of the intestine, obesity, changes in mood and activity level as some examples.
Developing software to improve nutritional health in populations. It has been shown that certain nutrition related diseases are more prevalent in certain populations (individual groups from different continents, i.e., European, Asian, African) and races than in others. Children's Nutrition Research Center researchers in Houston, TX, have developed a software package that is able to use a small amount of genetic data to accurately infer population structure with high resolution, which will be important for controlling for (local) population stratification for disease association studies. The software can infer the local ancestry for multi-way admixed individuals, which is likely to have an impact for disease association mapping for African Americans and Hispanics in America. This tool can detect if there are certain types of DNA associated with certain phenotypes and may serve as an important impact in disease mapping for the prevention of chronic diseases in the US.
A novel fortified blended flour for treating moderate acute malnutrition. Children with moderate acute malnutrition are often treated with low-cost, fortified corn/soy blended (CSB) flour, but the recovery rates are approximately 75% lower than that achieved with costly peanut paste-based ready-to-use supplementary foods (RUSF); thus an effective but reasonably price solution is needed. Children's Nutrition Research Center researchers have bridged the gap between affordable but ineffective CSB, and costly but effective RUSF, by developing a novel fortified CSB recipe, "CSB++". We found that the children's recovery rate for CSB++ was similar to soy RUSF; however, the children receiving CSB++ required on average 2 days longer to recover. The recovery rate observed for CSB++ was higher than for any other fortified blended flour tested previously. These findings are internationally important as a new nutritional supplement will benefit children suffering from moderate acute malnutrition.
Badaloo, A., Hsu, J.W., Taylor-Bryan, C., Reid, M., Forrester, T., Jahoor, F. 2010. Tyrosine requirement during the rapid catch-up growth phase of recovery from severe childhood undernutrition. British Journal of Nutrition. 104(8):1174-1180.
Sekhar, R.V., Mckay, S.V., Patel, S.G., Guthikonda, A.P., Reddy, V.T., Balasubramanyam, A., Jahoor, F. 2011. Glutathione synthesis is diminished in patients with uncontrolled diabetes and restored by dietary supplementation with cysteine and glycine. Diabetes Care. 34(1):162-167.
Chumpitazi, B.P., Lane, M.M., Czyewski, D.I., Weidler, E.M., Swank, P.R., Shulman, R.J. 2010. Creation and initial evaluation of a stool form scale for children. Journal of Pediatrics. 157(4):594-597.
Jensen, C.L., Voigt, R.G., Llorente, A.M., Peters, S.U., Prager, T.C., Zou, Y.L., Rozelle, J.C., Turcich, M.R., Fraley, J.K., Anderson, R.E., Heird, W.C. 2010. Effect of early maternal docosahexaenoic acid intake on neuropsychological status and visual acuity at five years of age of breast-fed infants. Journal of Pediatrics. 157(6):900-905.
Whitfield, K.L., Shulman, R.J. 2009. Treatment options for functional gastrointestinal disorders: From empiric to complementary approaches. Pediatric Annals. 38(5):288-294.
Motil, K.J., Morrissey, M., Caeg, E., Barrish, J.O., Glaze, D.G. 2009. Gastrostomy placement improves height and weight gain in girls with Rett syndrome. Journal of Pediatric Gastroenterology and Nutrition. 49(2):237-242.
Thame, M.M., Fletcher, H.M., Baker, T.M., Jahoor, F. 2010. Comparing the glucose kinetics of adolescent girls and adult women during pregnancy. American Journal of Clinical Nutrition. 91(3):604-609.
Kao, C.C., Bandi, V., Guntupalli, K.K., Wu, M., Castillo, L., Jahoor, F. 2009. Arginine, citrulline and nitric oxide metabolism in sepsis. Clinical Science. 117(1):23-30.
Kurpad, A.V., Dwarkanath, P., Thomas, T., Mhaskar, A., Thomas, A., Mhaskar, R., Jahoor, F. 2010. Comparison of leucine and dispensable amino acid kinetics between Indian women with low or normal body mass indexes during pregnancy. American Journal of Clinical Nutrition. 92(2):320-329.
Thame, M., Fletcher, H., Baker, T., Jahoor, F. 2010. Comparing the in vivo glycine fluxes of adolescent girls and adult women during early and late pregnancy. British Journal of Nutrition. 104(4):498-502.
Hopkinson, J., Heird, W.C. 2009. Maternal response to two electric breast pumps. Breastfeeding Medicine. 4(1):17-23.
Heird, W.C. 2010. Influences of timing and duration of formula feeding on infant growth. In: Symonds, M.E., Ramsay, M.M., editors. Maternal-Fetal Nutrition during Pregnancy and Lactation. New York: Cambridge University Press. p. 92-105.
Heird, W.C. 2010. Do you need a supplement of docosahexaenoic acid or an n-3 long-chain polyunsaturated fatty acid? American Journal of Clinical Nutrition. 91:827-828.
Shulman, R.J., Ou, C., Smith, E.O. 2010. Evaluation of potential factors predicting attainment of full gavage feedings in preterm infants. Neonatology. 99:38-44.
Tsai, J., Kienesberger, P.C., Pulinilkunnil, T., Sailors, M.H., Durgan, D.J., Villegas-Montoya, C., Jahoor, A., Gonzalez, R., Garvey, M.E., Boland, B., Blasier, Z., Mcelfresh, T.A., Nannegari, V., Chow, C., Heird, W.C., Chandler, M.P., Dyck, J.R., Bray, M.S., Young, M.E. 2010. Direct regulation of myocardial triglyceride metabolism by the cardiomyocyte circadian clock. Journal of Biological Chemistry. 285(5):2918-2929.
Mao, J., Yang, T., Gu, Z., Heird, W.C., Finegold, M.J., Lee, B., Wakil, S.J. 2009. aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues. Proceedings of the National Academy of Sciences. 106(41):17576-17581.
Ellis, K.L. 2010. Body composition in infancy: impact on health later in life. In: Lucas, A., Makrides, M., Ziegler, EE., editors. Nestle Nutrition Workshop Series Pediatric Program. Basel, Switzerland: Nestle Ltd. p 213-224.
O'Connor, D.P., Bray, M.S., Mcfarlin, B.K., Sailors, M.H., Ellis, K.J., Jackson, A.S. 2010. Generalized equations for estimating DXA percent fat of diverse young women and men: The Tiger Study. American College of Sports Medicine. 42(10):1959-1965.
Amthor, R.E., Cole, S.M., Manary, M.J. 2009. The use of home-based therapy with ready-to-use therapeutic food to treat malnutrition in a rural area during a food crisis. Journal of The American Dietetic Association. 109(3):464-467.
Hsu, J.W., Jahoor, F., Butte, N.F., Heird, W.C. 2011. Rate of phenylalanine hydroxylation in healthy school-aged children. Pediatric Research. 69(4):341-346.
Czyzewski, D.I., Lane, M.M., Weidler, E.M., Williams, A.E., Swank, P.R., Shulman, R.J. 2011. The interpretation of Rome II criteria and method of assessment affect the irritable bowel syndrome classification of children. Alimentary Pharmacology & Therapeutics. 33(3):403-411.
Mcomber, M.E., Ou, C., Shulman, R.J. 2010. Effects of timing, sex, and age on site-specific gastrointestinal permeability testing in children and adults. Journal of Pediatric Gastroenterology and Nutrition. 50(3): 269-275.
Sailors, M.H., Jackson, A.S., Mcfarlin, B.K., Turpin, I., Ellis, K.J., Foreyt, J.P., Hoelscher, D.M., Bray, M.S. 2010. Exposing college students to exercise: the training interventions and genetics of exercise response (TIGER) study. Journal of American College Health. 59(1):13-20.
Weisz, A., Meuli, G., Thakwalakwa, C., Trehan, I., Maleta, K., Manary, M. 2011. The duration of diarrhea and fever is associated with growth faltering in rural Malawian children aged 6-18 months. Nutrition Journal. 10(25): 1-4.
Oakley, E., Reinking, J., Sandige, H., Trehan, I., Kennedy, G., Maleta, K., Manary, M. 2010. A ready-to-use therapeutic food containing 10% milk is less effective than one with 25% milk in the treatment of severely malnourished children. Journal of Nutrition. 140(12):2248-2252.
Shypailo, R.J., Ellis, K.J. 2011. Whole body counter calibration using Monte Carlo modeling with an array of phantom sizes based on national anthropometric reference data. Physics in Medicine and Biology (London). 56:2979-2997.
Kennedy, G., Hambidge, K.M., Manary, M. 2010. A reduced phytate diet does not reduce endogenous fecal zinc in children on a habitual high-phytate diet. Journal of Pediatric Gastroenterology and Nutrition. 51(5):678-679.
Mehta, S., Shulman, R.J. 2010. Carbohydrates: changes with development. In: Corkins, M.R., editor. The A.S.P.N. Pediatric Nutrition Support Core Curriculum. Silver Spring, MD: American Society for Parenteral and Enteral Nutrition (ASPEN). p 17-21.
Motil, K.J., Phillips, S.M., Conkin, C. 2011. Nutritional Assessment. In: Wyllie, R., Hyams, J.S., Kay, M., editors. Pediatric Gastrointestinal and Liver Disease. 4th edition. Philadelphia, PA: Elsevier Saunders. p. 948-956.
Lane, M.M., Weidler, E.M., Czyzewski, D.I., Shulman, R.J. 2009. Pain symptoms and stooling patterns do not drive diagnostic costs for children with functional abdominal pain and irritable bowel syndrome in primary or tertiary care. Pediatrics. 123(3):758-764.
Shypailo, R.J., Ellis, K.J. 2009. Longitudinal DXA Studies: Minimum scanning interval for pediatric assessment of body fat. International Journal of Body Composition Research. 7(3):117-122.
Bier, D.M. 2010. Promoting innovation in pediatric nutrition. In: Koletzko, B., Koletzko, S., Ruemmele, F., editors. Drivers of Innovation in Pediatric Nutrition: Nestle Nutrition Institute Workshop Series Pediatric Program. Volume 66. Switzerland: Reinhardt Druck. pp. 205-215.
Gabbay, K.H., Bohren, K.M., Morello, R., Bertin, T., Liu, J., Vogel, P. 2010. Ascorbate synthesis pathway, dual role of ascorbate in bone homeostatis. Journal of Biological Chemistry. 285(25):19510-19520.