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Research Project: Pediatric Clinical Nutrition

Location: Children's Nutrition Research Center

2015 Annual Report

There is an ongoing need to enhance our understanding of the influences and role of various nutrients on fetal, postnatal, and childhood health, growth, and development as well as the etiology of obesity. A goal of this project is to provide evidence-based nutrient bioavailability data for the development of nutritional guidelines in children 6-24 months of age by: 1) using stable isotopes to assess the absorption of calcium, zinc, and magnesium over a range of usual dietary intakes in groups of children at 6-12, 12-18, and 18-24 months of age; 2) relate mineral absorption values to dietary mineral intake and body composition as determined by DXA; 3) evaluate mineral absorption and body composition in a group of preterm infants. We plan to increase understanding of how diet and age influence gut microbial population composition and promote health; we will: 4) determine effects of diet/age on gut microbial composition and relate these to gut barrier function and inflammation in children 7-18 years of age; 5) develop de novo method to assemble short sequence reads into contigs; apply method to assemble gut microbiome sequence reads; develop statistical method to cluster contigs and quantify abundance of these clusters; perform genetic association testing for haplotype-microbiome interactions that affect risk of childhood obesity; and 6) identify panel of human mRNAs indicative of environmental enteropathy (EE); evaluate as biomarker for EE in other populations; test whether micronutrient and/or fish oil supplements can reduce EE; explore microbiome of children with and without EE; correlate mRNA panel markers with child growth parameters. Additionally we will determine: 7) negative effect of obesity-induced inflammation and oxidative stress on women's fertility and if it can be reversed by weight loss and supplemental nutrients with antioxidant and anti-inflammatory properties; 8) if pre-pregnant lipid supply underlies the insulin resistance and increased susceptibility to gestational diabetes in obese women and if exercise and modified diet will decrease the prevalence of gestational diabetes; 9) whether children born to obese and/or gestational diabetic mothers have an altered macronutrient metabolism; 10) the relationship of vascular function to insulin resistance in youth; and relationship of monocyte function and serum inflammatory markers and vascular reactivity to insulin sensitivity; 11) the effect of hyperglycemia on endothelial function, monocyte function and inflammatory markers; and 12) individual variability, metabolic pathways, and genetic variants underlying differences in obligatory and adaptive components of energy expenditure and macronutrient utilization in non-obese and obese children.

A multi-discipline approach will be undertaken to improve our understanding of how foods support health, meet dietary requirements, and reduce disease risk such as cardiovascular disease and obesity. Our studies will utilize stable isotope techniques to provide accurate, practically applicable information that may be obtained from the study populations in a safe manner. Comparison will be made of intake and absorption of calcium and magnesium with total body bone mineral as determined by Dual Energy X-ray Absorptiometry. For magnesium and zinc, comparisons will be made of estimated retained minerals with expected tissue accretion rates in early childhood. We will also evaluate these values in a group of preterm infants who may have greater nutrient requirements due to the need to have catch-up growth. For other studies, obese and normal weight infertile women will be recruited, measured, and assigned a calorie-specific diet. Numerous biological measurements will be taken and correlations between body fat and other outcomes will be made. Additionally, we will conduct a cross-sectional study to evaluate endothelial dysfunction in obese youth with and without Type 2 diabetes compared with normal weight controls with the primary aim to explore the effect of insulin resistance vs. hyperglycemia on endothelial function. A cross-sectional study design will also take place comparing non-obese/obese adolescents wherein plasma samples will be collected and DNA will be sequenced and analyzed. Furthermore we will determine the effects of diet and age on gut microbial composition, ascertain the metagenomic profile of the gut microbes, and relate these to gut barrier function and inflammation in children 7-18 years of age; and develop a new de novo assembly method to assemble short sequence reads into long contiguous reads and apply this method to assemble gut microbiome sequence reads. Development of a statistical method to cluster contigs and quantify abundance of these clusters will occur, and we will perform genetic association testing for haplotype-microbiome interactions that affect the risk of childhood obesity. Researchers will identify a panel of human mRNAs in fecal samples indicative of environmental enteropathy, evaluate this panel as a biomarker for environmental enteropathy in other populations, test whether micronutrient and/or fish oil supplements can reduce environmental enteropathy.

Progress Report
Significant research progress was accomplished during the year. To review the progress, please refer to project 3092-51000-057-01S (Project #1), 3092-51000-057-02S (Project #2), and 3092-51000-057-03S (Project #3). This is the final report for 3092-51000-057-01S.


Review Publications
Abrams, S.A., Tiosano, D. 2015. Disorders of calcium, phosphorus, and magnesium metabolism in the neonate. In: Martin, R.J., Fanaroff, A.A., Walsh, M.C., editors. Fanaroff & Martin's Neonatal-Perinatal Medicine: Diseases of the Fetus and Infant. 10th edition. Philadelphia, PA: Elsevier Saunders. p. 1460-1489.
Vaisman, N., Shaltiel, G., Daniely, M., Meiron, O.E., Shechter, A., Abrams, S.A., Niv, E., Shapira, Y., Sagi, A. 2014. Increased calcium absorption from synthetic stable amorphous calcium carbonate: Double-blind randomized crossover clinical trial in post-menopausal women. Journal of Bone and Mineral Research. 29(10):2203-2209.
Hair, A.B., Blanco, C.L., Moreira, A.G., Hawthorne, K.M., Lee, M.L., Rechtman, D.J., Abrams, S.A. 2014. Randomized trial of human milk cream as a supplement to standard fortification of an exclusive human milk-based diet in infants 750-1250 g birth weight. Journal of Pediatrics. 165(5):915-920.
Roth, D.E., Pezzack, B., Mahmud, A., Abrams, S.A., Islam, M., Aimone Phillips, A., Baxter, J.B., Dimitris, M.C., Hawthorne, K.M., Ahmed, T., Zlotkin, S.H. 2014. Bioavailability of enteric-coated microencapsulated calcium during pregnancy: A randomized crossover trial in Bangladesh. American Journal of Clinical Nutrition. 100(6):1587-1595.
Garcia, O.P., Martinez, M., Romano, D., Camacho, M., De Moura, F.F., Abrams, S.A., Khanna, H.K., Dale, J.L., Rosado, J.L. 2015. Iron absorption in raw and cooked bananas: A field study using stable isotopes in women. Food and Nutrition Research. 59:25976.
Abrams, S.A., Hawthorne, K.M., Pammi, M. 2015. A systematic review of controlled trials of lower-protein or energy-containing infant formulas for use by healthy full-term infants. Advances in Nutrition. 6(2):178-188.
Martinez, S.M., Tschann, J.M., Greenspan, L.C., Deardorff, J., Penilla, C., Flores, E., Pasch, L.A., Gregorich, S.E., Butte, N.F. 2014. Is it time for bed? Short sleep duration increases risk of obesity in Mexican American children. Sleep Medicine. 15:1484-1489.
Lee, B., Lin, A., Nichols, B.L., Jones, K., Rose, D.R., Quezada-Calvillo, R., Hamaker, B.R. 2014. Mucosal C-terminal maltase-glucoamylase hydrolyzes large size starch digestion products that may contribute to rapid postprandial glucose generation. Molecular Nutrition and Food Research. 58(5):1111-1121.
Lin, A., Ao, Z., Quezada-Calvillo, R., Nichols, B.L., Lin, C., Hamaker, B.R. 2014. Branch pattern of starch internal structure influences the glucogenesis by mucosal Nt-maltase-glucoamylase. Carbohydrate Polymers. 111:33-40.
Simsek, M., Quezada-Calvillo, R., Ferruzzi, M.G., Nichols, B.L., Hamaker, B.R. 2015. Dietary phenolic compounds selectively inhibit the individual subunits of maltase-glucoamylase and sucrase-isomaltase with the potential of modulating glucose release. Journal of Agricultural and Food Chemistry. 63(15):3873-3879.
Levitt Katz, L., Gidding, S.S., Bacha, F., Hirst, K., Mckay, S., Pyle, L., Lima, J.A. 2015. Alterations in left ventricular, left atrial, and right ventricular structure and function to cardiovascular risk factors in adolescents with type 2 diabetes participating in the TODAY clinical trial. Pediatric Diabetes. 16(1):39-47.
Kao, C.C., Hsu, J.W., Dwarkanath, P., Karnes, J.M., Baker, T.M., Bohren, K.M., Badaloo, A., Thame, M.M., Kurpad, A.V., Jahoor, F. 2015. Indian women of childbearing age do not metabolically conserve arginine as do American and Jamaican women. Journal of Nutrition. 145(5):884-892.
Michaliszyn, S.F., Mari, A., Lee, S., Bacha, F., Tfayli, H., Farchoukh, L., Ferrannini, E., Arslanian, S. 2014. Beta-cell function, incretin effect, and incretin hormones in obese youth along the span of glucose tolerance from normal to prediabetes to Type 2 diabetes. Diabetes. 63(11):3846-3855.
Burns, S.F., Lee, S., Bacha, F., Tfayli, H., Hannon, T.S., Arslanian, S.A. 2014. Pre-diabetes in overweight youth and early atherogenic risk. Metabolism. 63(12):1528-1535.
Hsieh, J., Liu, L., Zeilani, M., Ickes, S., Trehan, I., Maleta, K., Craig, C., Thakwalakwa, C., Singh, L., Brenna, T., Manary, M.J. 2015. High-oleic ready-to-use therapeutic food maintains docosahexaenoic acid status in severe malnutrition. Journal of Pediatric Gastroenterology and Nutrition. 61(1):138-143.
Kau, A.L., Planer, J.D., Liu, J., Rao, S., Yatsunenko, T., Trehan, I., Manary, M.J., Liu, T., Stappenbeck, T.S., Maleta, K.M., Ashorn, P., Dewey, K.G., Houpt, E.R., Hsieh, C., Gordon, J.I. 2015. Functional characterization of IgA-targeted bacterial taxa from undernourished Malawian children that produce diet-dependent enteropathy. Science Translational Medicine. 7(276):276ra24.
Ryan, K.N., Adams, K.P., Vosti, S.A., Ordiz, M., Cimo, E.D., Manary, M.J. 2014. A comprehensive linear programming tool to optimize formulations of ready-to-use therapeutic foods: An application to Ethiopia. American Journal of Clinical Nutrition. 100(6):1551-1558.
Mangani, C., Ashorn, P., Maleta, K., Phuka, J., Thakwalakwa, C., Dewey, K., Manary, M.J., Puumalainen, T., Cheung, Y. 2014. Lipid-based nutrient supplements do not affect the risk of malaria or respiratory morbidity in 6- to 18-month-old Malawian children in a randomized controlled trial. Journal of Nutrition. 144(11):1835-1842.
Briend, A., Akomo, P., Bahwere, P., De Pee, S., Dibari, F., Golden, M.H., Manary, M., Ryan, K. 2015. Developing food supplements for moderately malnourished children: Lessons learned from ready-to-use therapeutic foods. Food and Nutrition Bulletin. 36(1 Suppl):S53-S58.
Young, G.P., Mortimer, E.K., Gopalsamy, G.L., Alpers, D.H., Binder, H.J., Manary, M.J., Ramakrishna, B.S., Brown, I.L., Brewer, T.G. 2014. Zinc deficiency in children with environmental enteropathy - development of new strategies: Report from an expert workshop. American Journal of Clinical Nutrition. 100(4):1198-1207.
Gopalsamy, G.L., Alpers, D.H., Binder, H.J., Tran, C.D., Ramakrishna, B.S., Brown, I., Manary, M.J., Mortimer, E., Young, G.P. 2015. The relevance of the colon to zinc nutrition. Nutrients. 7(1):572-583.
Iannotti, L.L., Trehan, I., Clitheroe, K.L., Manary, M.J. 2015. Diagnosis and treatment of severely malnourished children with diarrhea. Journal of Paediatrics and Child Health. 51(4):387-395.
Murray, E., Manary, M. 2015. Possible role of the microbiome in the development of acute malnutrition and implications for food-based strategies to prevent and treat acute malnutrition. Food and Nutrition Bulletin. 36(1 Suppl):S72-S75.
Trehan, I., Manary, M.J. 2015. Management of severe acute malnutrition in low-income and middle-income countries. Archives of Disease in Childhood. 100(3):283-287.
May, T., Westcott, C., Thakwalakwa, C., Ordiz, M.I., Maleta, K., Westcott, J., Ryan, K., Hambidge, K.M., Miller, L.V., Young, G., Mortimer, E., Manary, M.J., Krebs, N.F. 2015. Resistant starch does not affect zinc homeostasis in rural Malawian children. Journal of Trace Elements in Medicine and Biology. 30:43-48.
Trehan, I., Banerjee, S., Murray, E., Ryan, K.N., Thakwalakwa, C., Maleta, K.M., Manary, M.J. 2015. Extending supplementary feeding for children younger than 5 years with moderate acute malnutrition leads to lower relapse rates. Journal of Pediatric Gastroenterology and Nutrition. 60(4):544-549.
Hall, K.D., Butte, N.F., Swinburn, B.A., Chow, C.C. 2013. Dynamics of childhood growth and obesity development and validation of a quantitative mathematical model. Lancet Diabetes Endocrinology. 1(2):97-105.
Beck, A.L., Tschann, J., Butte, N.F., Penilla, C., Greenspan, L.C. 2013. Association of beverage consumption with obesity in Mexican American children. Public Health Nutrition. 17(2):338-344.
Butte, N.F., Gregorich, S.E., Penilla, C., Pasch, L.A., De Groat, C.L., Flores, E., Deardorff, J., Greenspan, L.C., Martinez, S.M. 2014. Longitudinal effects of parental child and neighborhood factors on moderate vigorous physical activity and sedentary time in Latino children. International Journal of Behavioral Nutrition and Physical Activity. 11:108.
Di Nardo, G., Barbara, G., Cucchiara, S., Cremon, C., Shulman, R.J., Isoldi, S., Zecchi, L., Oliva, S., Saulle, R., Barbaro, M.R. 2013. Neuroimmune interactions at different intestinal sites are related to abdominal pain symptoms in children with IBS. Neurogastroenterology & Motility. 26:196-204.
Yang, Y., Adolph, A.L., Puyau, M.R., Vohra, F.A., Butte, N.F., Zakeri, I.F. 2013. Modeling energy expenditure in children and adolescents using quantile regression. Journal of Applied Physiology. 115: 251-259.
Self, M.M., Czyzewski, D.I., Chumpitazi, B.P., Weidler, E.M., Shulman, R.J. 2014. Subtypes of irritable bowel syndrome in children and adolescents. Clinical Gastroenterology and Hepatology. 12:1468-1473.
Varni, J.W., Denham, J., Shulman, R.J., Self, M.M., Neigut, D.A., Nurko, S., Patel, A.S., Franciosi, J.P., Saps, M., Smith, A., Yeckes, A., Heinz, N., Saeed, S., Zacur, G.M., Pohl, J.F. 2014. PedsQL gastrointestinal symptoms module feasibility reliability and validity. Journal of Pediatric Gastroenterology and Nutrition. 59:347-355.
Ryan, K.N., Stephenson, K.B., Trehan, I., Shulman, R.J., Thakwalakwa, C., Murray, E., Maleta, K., Manary, M.J. 2014. Zinc or albendazole attenuates the progression of environmental enteropathy a randomized controlled trial. Clinical Gastroenterology and Hepatology. 12:1507-1513.
Chumpitazi, B.P., Hollister, E.B., Qezguen, N., Tsai, C.M., Mcmeans, A.R., Luna, R.A., Savidge, T.C., Versalovic, J., Shulman, R.J. 2014. Gut microbiota influences low fermentable substrate diet efficacy in children with irritable bowel syndrome. Gut Microbes. 5(2):1-11.
Wong, G.K., Shulman, R.J., Chiou, E.H., Chumpitazi, B.P. 2014. Decreased relative diagnostic yield of esophagogastroduodenoscopy in children with gastroparesis. Clinical Gastroenterology and Hepatology. 48:231-235.
Mayer, E.A., Savidge, T., Shulman, R.J. 2014. Brain gut microbiome interactions and functional bowel disorders. Gastroenterology. 146(6):1500-1512.
Jarrett, M.E., Shulman, R.J., Cain, K.C., Deechakawan, W., Smith, L.T., Richebe, P., Eugenio, M., Heitkemper, M.M. 2014. Conditioned pain modulation in women with irritable bowel syndrome. Biological Research for Nursing. 16(4):368-377.
Thame, M.M., Hsu, J.W., Gibson, R., Baker, T.M., Tang, G.J., Badaloo, A.V., Fletcher, H.M., Jackson, A.A., Jahoor, F. 2014. Adaptation of in vivo amino acid kinetics facilitates increased amino acid availability for fetal growth in adolescent and adult pregnancies alike. British Journal of Nutrition. 112(11):1779-1786.
Ubelmann, F., Chamaillard, M., El-Marjou, F., Simon, A., Netter, J., Vignjevic, D., Nichols, B.L., Quezada-Calvillo, R., Grandjean, T., Louvard, D., Revenu, C. 2013. Enterocyte loss of polarity and gut wound healing rely upon the F-actin-severing function of villin. Proceedings of the National Academy of Sciences. 110(15):E1380-E1389.
Bacha, F., Edmundowicz, D., Sutton-Tyrell, K., Lee, S., Tfayli, H., Arslanian, S.A. 2014. Coronary artery calcification in obese youth: What are the phenotypic and metabolic determinants? Diabetes Care. 37(9):2632-2639.
Weyand, P.G., Smith, B.R., Schultz, N.S., Ludlow, L.W., Puyau, M.R., Butte, N.F. 2013. Predicting metabolic rate across walking speed: One fit for all body sizes? Journal of Applied Physiology. 115:1332-1342.
Smith, S.M., Castaneda-Sceppa, C., O'Brien, K.O., Abrams, S.A., Gillman, P., Brooks, N.E., Cloutier, G.J., Heer, M., Zwart, S.R., Wastney, M.E. 2014. Calcium kinetics during bed rest with artificial gravity and exercise countermeasures. Osteoporosis International. 25(9):2237-2244.
Murray, E., Manary, M. 2014. Home-based therapy for severe acute malnutrition with ready-to-use food. Paediatrics and International Child Health. 34(4):266-270.
Osendarp, S., Rogers, B., Ryan, K., Manary, M., Akomo, P., Bahwere, P., Belete, H., Zeilani, M., Islam, M., Dibari, F., De Pee, S. 2015. Ready-to-use foods for management of moderate acute malnutrition: Considerations for scaling up production and use in programs. Food and Nutrition Bulletin. 36(1 Suppl):S59-S64.
Oluyomi, A.O., Byars, A., Byrd-Williams, C., Sharma, S.V., Durand, C., Hoelscher, D.M., Butte, N.F., Kelder, S.H. 2015. The utility of Geographical Information Systems (GIS) in systems-oriented obesity intervention projects: The selection of comparable study sites for a quasi-experimental intervention design--TX CORD. Childhood Obesity. 11(1):58-70.
Hoelscher, D.M., Butte, N.F., Barlow, S., Vandewater, E.A., Sharma, S.V., Huang, T., Finkelstein, E., Pont, S., Sacher, P., Byrd-Williams, C., Oluyomi, A.O., Durand, C., Li, L., Kelder, S.H. 2015. Incorporating primary and secondary prevention approaches to address childhood obesity prevention and treatment in a low-income, ethnically diverse population. Childhood Obesity. 11(1):71-91.
Butte, N.F., Brandt, M.L., Wong, W.W., Liu, Y., Mehta, N.R., Wilson, T.A., Adolph, A.L., Puyau, M.R., Vohra, F.A., Shypailo, R.J., Zakeri, I.F. 2015. Energetic adaptations persist after bariatric surgery in severely obese adolescents. Obesity. 23:591-601.
Tschann, J.M., Martinez, S.M., Penilla, C., Gregorich, S.E., Pasch, L.A., De Groat, C.L., Flores, E., Deardorff, J., Greenspan, L.C., Butte, N.F. 2015. Parental feeding practices and child weight status in Mexican American families: a longitudinal analysis. International Journal of Behavioral Nutrition and Physical Activity. 12:66.
Mcmurray, R.G., Butte, N.F., Crouter, S.E., Trost, S.G., Pfeiffer, K.A., Bassett, D.R., Puyau, M.R., Berrigan, D., Watson, K.B., Fulton, J.E. 2015. Exploring metrics to express energy expenditure of physical activity in youth. PLoS One. 10(6):e130869.
Voruganti, V.S., Laston, S., Haack, K., Mehta, N.R., Cole, S.A., Butte, N.F., Comuzzie, A.G. 2015. Serum uric acid concentrations and SLC2A9 genetic variation in Hispanic children: The Viva La Familia Study. American Journal of Clinical Nutrition. 101:725-732.
Chumpitazi, B.P., Cope, J.L., Hollister, E.B., Tsai, C.M., Mcmeans, A.R., Luna, R.A., Versalovic, J., Shulman, R.J. 2015. Randomised clinical trial: Gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome. Alimentary Pharmacology & Therapeutics. 42:418-427.
Varni, J.W., Bendo, C.B., Shulman, R.J., Self, M.M., Nurko, S., Franciosi, J.P., Saps, M., Saeed, S., Zacur, G.M., Dark, C.V., Pohl, J.F. 2015. Interpretability of the PedsQL gastrointestinal symptoms scales and gastrointestinal worry scales in pediatric patients with functional and organic gastrointestinal diseases. Journal of Pediatric Psychology. 40(60):591-601.
Butte, N.F., Liu, Y., Zakeri, I.F., Mohney, R.P., Mehta, N., Voruganti, V.S., Goring, H., Cole, S.A., Comuzzie, A.G. 2015. Global metabolomic profiling targeting childhood obesity in the Hispanic population. American Journal of Clinical Nutrition. 10.3945.
Cheng, M., Chegeni, M., Kim, K., Zhang, G., Benmoussa, M., Quezada-Calvillo, R., Nichols Jr, B.L., Hamaker, B.R. 2014. Different sucrose—isomaltase response of Caco-2 cells to glucose and maltose suggests dietary maltose sensing. Journal of Clinical Biochemistry and Nutrition. 54(1):55-60.