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Research Project: Pediatric Clinical Nutrition

Location: Children's Nutrition Research Center

2017 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 3092-51000-057-02S (Project #2), 3092-51000-057-03S (Project #3) and 3092-51000-057-04S (Project #4).

1. DNA methylation changes in severe childhood malnutrition. Research suggests that the activity of biochemical pathways involved in DNA methylation (chemical modifications of DNA) is reduced among children with the most severe form of acute childhood malnutrition. Researchers in Houston, Texas compared the level of methylation at DNA sites from children with severe- and mild- forms of malnutrition. We found hundreds of positions across the genome where methylation levels were significantly lower in the severe form of acute malnutrition. Our results suggest that nutritional supplementation that increases the activity of the methylation pathway, may be a viable way of treating the most severe form of malnutrition in the future.

2. Adverse changes in the function of small blood vessels in youth related to obesity. Endothelial dysfunction is an early marker of atherosclerosis (hardening of the arteries that can lead to heart attacks and/or strokes), and can be measured non-invasively by measuring the blood flow characteristics from an individual's fingers. Researchers in Houston, Texas utilized this method to understand whether there is evidence of early changes in endothelial function in youth with obesity and type 2 diabetes, and what drives this early abnormality. We demonstrated impairment in endothelial function in youth in relation to total body fat and abdominal fat, and evidence of greater stiffness of the blood vessels. These findings show that childhood obesity is associated with early subclinical vessel dysfunction and insulin resistance appears to explain the effect of obesity on the early vascular abnormality in youth.

3. A novel method to quantify sequencing data. For many applications of next generation sequencing, challenges remain due to unavailable or low quality reference genomes which often cause half of the samples that cannot be mapped. Researchers in Houston, Texas developed a novel method to quantify sequencing data without the need of reference genomes by reconstructing phylogenetic relationship between different bacterial species. Our method recapitulates genetic diversities in Human Microbiome Project which collects hundreds of metagenomics samples from various sites. Our analysis revealed the contribution of unmapped reads in metagenomics studies and will aid researchers for future studies.

4. Dietary fiber reduces belly pain risk in children. Belly pain is a common complaint in children and up to 20% of school age children have pain frequently. Researchers in Houston, Texas completed a study in children (7-18 years of age) that showed that adding fiber to the diet can reduce the number of episodes of belly pain. By providing extra fiber to their diet, the children had less belly pain and the fiber did not disrupt the types of bacteria found in the intestine. These findings are important and provide potential solutions to relieving pain through ones diet.

5. Bacteria in the gut influences stooling pattern. Constipation is a common problem in children. Methane is produced by bacteria in the gut and excreted in breath. Researchers in Houston, Texas measured the amount of methane gas excreted in the breath of children ages 7-17 years. They discovered that how fast food moved along the gastrointestinal tract was related to the amount of methane produced. These results suggest that the types of bacteria in the gut can affect the risk of constipation.

6. Stooling pattern of normal children defined. There is little information about the normal stooling pattern of healthy children. Researchers in Houston, Texas examined a large group of healthy children and described for the first time how often they stooled and whether they had constipation or diarrhea. By defining normal in healthy children, future studies will be able to examine how diet, bacteria, and other factors influence stooling pattern and gastrointestinal health.

7. Altered stooling habits are related to the development of long-term belly pain. Belly pain is a common complaint in children and up to 20% of school age children have pain frequently. Researchers in Houston, Texas discovered that children whose belly pain was related to their stooling habits were more likely to have long-term pain than those children who had belly pain that did not relate to their stooling habit. Bacteria in the intestine can affect stooling habit, suggesting that in some children, belly pain likely is related to the type of bacteria present in the intestine.

Review Publications
Bacha, F., Gidding, S.S., Pyle, L., Katz, L.L., Kriska, A., Nadeau, K.J., Lima, J.A. 2016. Relationship of cardiac structure and function to cardiorespiratory fitness and lean body mass in adolescents and young adults with Type 2 Diabetes. Journal of Pediatrics. 177:159-166.
Bacha, F., Arslanian, S.A. 2016. Race or vitamin D: A determinant of intima media thickness in obese adolescents? Pediatric Diabetes. doi:10.1111/pedi.12472.
Tomsa, A., Bartz, S.K., Krishnamurthy, R., Krishnamurthy, R., Bacha, F. 2016. Endothelial function in youth: A biomarker modulated by adiposity-related insulin resistance. Journal of Pediatrics. 178:171-177.
Semba, R.D., Shardell, M., Trehan, I., Moaddel, R., Maleta, K.M., Ordiz, M.I., Kraemer, K., Khadeer, M., Ferrucci, L., Manary, M.J. 2016. Metabolic alterations in children with environmental enteric dysfunction. Scientific Reports. 6:28009.
Semba, R.D., Shardell, M., Sakr Ashour, F.A., Moaddel, R., Trehan, I., Maleta, K.M., Ordiz, M.I., Kraemer, K., Khadeer, M.A., Ferrucci, L., Manary, M.J. 2016. Child stunting is associated with low circulating essential amino acids. EBioMedicine. 6:246-252.
Manary, M., Callaghan, M., Singh, L., Briend, A. 2016. Protein quality and growth in malnourished children. Food and Nutrition Bulletin. Suppl 1:S29-S36.
Stauber, J., Shaikh, N., Ordiz, M.I., Tarr, P.I., Manary, M.J. 2016. Droplet digital PCR quantifies host inflammatory transcripts in feces reliably and reproducibly. Cellular Immunology. 303:43-49.
Yu, J., Ordiz, M.I., Stauber, J., Shaikh, N., Trehan, I., Barnell, E., Head, R.D., Maleta, K., Tarr, P.I., Manary, M.J. 2015. Environmental enteric dysfunction includes a broad spectrum of inflammatory responses and epithelial repair processes. Cellular and Molecular Gastoenterology and Hepatology. 2(2):158-174.
Semba, R.D., Zhang, P., Gonzalez-Freire, M., Moaddel, R., Trehan, I., Maleta, K.M., Ordiz, M.I., Ferrucci, L., Manary, M.J. 2016. The association of serum choline with linear growth failure in young children from rural Malawi. American Journal of Clinical Nutrition. 104(1):191-197.
Ordiz, M.I., Ryan, K.N., Cimo, E.D., Stoner, M.E., Loehnig, M.E., Manary, M.J. 2015. Effect of emulsifier and viscosity on oil separation in ready-to-use therapeutic food. International Journal of Food Sciences and Nutrition. 66(6):642-648.
Motil, K.J., Fete, M., Fete, T.J. 2016. Growth, nutritional, and gastrointestinal aspects of focal dermal hypoplasia (Goltz-Gorlin syndrome). American Journal of Medical Genetics. 172C(1):29-33.
Wang, A.Z., Shulman, R.J., Crocker, A.H., Thakwalakwa, C., Maleta, K.M., Devaraj, S., Manary, M.J., Trehan, I. 2017. A combined intervention of zinc, multiple micronutrients, and albendazole does not ameliorate environmental enteric dysfunction or stunting in rural Malawian children in a double-blind randomized controlled trial . Journal of Nutrition. 147:97-103. doi:10.3945/jn.116.237735.
Hollier, J.M., Czyzewski, D.I., Self, M.M., Weidler, E.M., Smith, O.E., Shulman, R.J. 2017. Pediatric irritable bowel syndrome patient and parental characteristics differ by care management type. Journal of Pediatric Gastroenterology and Nutrition. 65(3):391-395.
Chumpitazi, B.P., Weidler, E.M., Czyzewski, D.I., Self, M.M., Heitkemper, M., Shulman, R.J. 2016. Childhood irritable bowel syndrome characteristics are related to both sex and pubertal development. Journal of Pediatrics. 180:141-147.
Semba, R.D., Trehan, I., Gonzalez-Freire, M., Kraemer, K., Moaddel, R., Ordiz, M.I., Ferrucci, L., Manary, M.J. 2016. Perspective: The potential role of essential amino acids and the mechanistic target of rapamycin complex 1 (mTORC1) pathway in the pathogenesis of child stunting. Advances in Nutrition. 7(5):853-865.
Papathakis, P.C., Singh, L.N., Manary, M.J. 2016. How maternal malnutrition affects linear growth and development in the offspring. Molecular and Cellular Endocrinology. 435:40-47.
Weber, J.M., Ryan, K.N., Tandon, R., Mathur, M., Girma, T., Steiner-Asiedu, M., Saalia, F., Zaidi, S., Soofi, S., Okos, M., Vosti, S.A., Manary, M.J. 2017. Acceptability of locally produced ready-to-use therapeutic foods in Ethiopia, Ghana, Pakistan and India. Maternal and Child Nutrition. 13(2). doi:10.1111/mcn.12250.
Freedman, D.S., Butte, N.F., Taveras, E.M., Goodman, A.B., Ogden, C.L., Blanck, H.M. 2017. The limitations of transforming very high body mass indexes into z-scores among 8.7 million 2- to 4-year-old children. Journal of Pediatrics. pii:S0022-3476(17):30451-1. doi:10.1016/j.jpeds.2017.03.039.
Martinez, S.M., Tschann, J.M., Butte, N.F., Gregorich, S.E., Penilla, C., Flores, E., Greenspan, L.C., Pasch, L.A., Deardorff, J. 2017. Short sleep duration is associated with eating more carbohydrates and less dietary fat in Mexican American Children. Sleep. 40(2). doi:10.1093/sleep/zsw057.
Freedman, D.S., Butte, N.F., Taveras, E.M., Lundeen, E.A., Blanck, H.M., Goodman, A.B., Ogden, C.L. 2017. BMI z-scores are a poor indicator of adiposity among 2- to 19-year-olds with very high BMIs, NHANES 1999-2000 to 2013-2014. Obesity. 25(4):739-746.
Chittoor, G., Haack, K., Mehta, N.R., Laston, S., Cole, S.A., Comuzzie, A.G., Butte, N.F., Voruganti, V.S. 2017. Genetic variation underlying renal uric acid excretion in Hispanic children: The Viva La Familia Study. BMC Medical Genetics. 18(1):6.
Puyau, M.R., Adolph, A.L., Liu, Y., Wilson, T.A., Zakeri, I.F., Butte, N.F. 2016. Energy cost of activities in preschool-aged children. Journal of Physical Activity and Health. 13(6 Suppl 1):S11-S16.
Shypailo, R.J. 2017. Longitudinal monitoring of whole body counter NaI(TI) detector efficiency. Applied Radiation And Isotopes. 125:74-79.
Devy, S., Mukhopadhyay, A., Dwarkanath, P., Thomas, T., Crasta, J., Thomas, A., Sheela, C., Hsu, J.W., Tang, G.J., Jahoor, F., Kurpad, A.V. 2017. Combined vitamin B-12 and balanced protein-energy supplementation affect homocysteine remethylation in the methionine cycle in pregnant south Indian women of low vitamin B-12 status. Journal of Nutrition. 147(6):1094-1103.
Sabo, A., Mishra, P., Dugan-Perez, S., Voruganti, V., Kent Jr, J.W., Kalra, D., Cole, S.A., Comuzzie, A.G., Muzny, D.M., Gibbs, R.A., Butte, N.F. 2017. Exome sequencing reveals novel genetic loci influencing obesity-related traits in Hispanic children. Obesity. doi:10.1002/oby.21869.
Lee, J.S., Zakeri, I.F., Butte, N.F. 2017. Functional data analysis of sleeping energy expenditure. PLoS One. 12(5):e0177286.
Ordiz, M.I., Shaikh, N., Trehan, I., Maleta, K., Stauber, J., Shulman, R., Devaraj, S., Tarr, P.I., Manary, M.J. 2016. Environmental enteric dysfunction is associated with poor linear growth and can be identified by host fecal mRNAs. Journal of Pediatric Gastroenterology and Nutrition. 63(5):453-459.
Chumpitazi, B.P., Weidler, E.M., Shulman, R.J. 2017. Lactulose breath test gas production in childhood IBS is associated with intestinal transit and bowel movement frequency. Journal of Pediatric Gastroenterology and Nutrition. 64(4):541-545.
Arslanian, S., El Ghormli, L., Bacha, F., Caprio, S., Goland, R., Haymond, M.W., Levitsky, L., Nadeau, K.J., White, N.H., Willi, S.M. 2016. Adiponectin, insulin sensitivity, beta-cell function, and racial/ethnic disparity in treatment failure rates in TODAY. Diabetes Care. 40(1):85-93.
Varni, J.W., Shulman, R.J., Self, M.M., Saeed, S.A., Patel, A.S., Nurko, S., Neigut, D.A., Saps, M., Zacur, G.M., Dark, C.V., Bendo, C.B., Pohl, J.F. 2017. Patient health communication mediating effects between gastrointestinal symptoms and gastrointestinal worry in pediatric inflammatory bowel disease. Inflammatory Bowel Diseases. 23(5):704-711.
Shulman, R.J., Hollister, E.B., Cain, K., Czyzewski, D.I., Self, M.M., Weidler, E.M., Devaraj, S., Luna, R., Versalovic, J., Heitkemper, M. 2017. Psyllium fiber reduces abdominal pain in children with irritable bowel syndrome in a randomized, double-blind trial. Clinical Gastroenterology and Hepatology. 15(5):712-719.
Semba, R.D., Gonzalez-Freire, M., Moaddel, R., Trehan, I., Maleta, K.M., Khadeer, M., Ordiz, M.I., Ferrucci, L., Manary, M.J. 2017. Environmental enteric dysfunction is associated with altered bile acid metabolism. Journal of Pediatric Gastroenterology and Nutrition. 64(4):536-540.
Ordiz, M.I., Stephenson, K., Agapova, S., Wylie, K.M., Maleta, K., Martin, J., Trehan, I., Tarr, P.I., Manary, M.J. 2017. Environmental enteric dysfunction and the fecal microbiota in Malawian children. American Journal of Tropical Medicine and Hygiene. 96(2):473-476.
Semba, R.D., Trehan, I., Li, X., Moaddel, R., Ordiz, M.I., Maleta, K.M., Kraemer, K., Shardell, M., Ferrucci, L., Manary, M. 2017. Environmental enteric dysfunction is associated with carnitine deficiency and altered fatty acid oxidation. EBioMedicine. 17:57-66.
Callaghan, M., Oyama, M., Manary, M. 2017. Sufficient protein quality of food aid varies with the physiologic status of recipients. Journal of Nutrition. 147(3):277-280.
Di Giovanni, V., Bourdon, C., Wang, D.X., Seshadri, S., Senga, E., Versloot, C.J., Voskuijl, W., Semba, R.D., Trehan, I., Moaddel, R., Ordiz, M.I., Zhang, L., Parkinson, J., Manary, M.J., Bandsma, R.H. 2016. Metabolomic changes in serum of children with different clinical diagnoses of malnutrition. Journal of Nutrition. 146(12):2436-2444.
Trehan, I., Kelly, P., Shaikh, N., Manary, M.J. 2016. New insights into environmental enteric dysfunction. Archives of Disease in Childhood. 101(8):741-744.
Owino, V., Ahmed, T., Freemark, M., Kelly, P., Loy, A., Manary, M., Loechl, C. 2016. Environmental enteric dysfunction and growth failure/stunting in global child health. Pediatrics. 138(6):e20160641.
El-Hattab, A.W., Jahoor, F. 2017. Assessment of nitric oxide production in mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome with the use of a stable isotope tracer infusion technique. Journal of Nutrition. doi:10.3945/jn.117.248435.
Kim, J.Y., Michaliszyn, S.F., Nasr, A., Lee, S., Tfayli, H., Hannon, T., Hughan, K.S., Bacha, F., Arslanian, S. 2016. The shape of the glucose response curve during an oral glucose tolerance test heralds biomarkers of type 2 diabetes risk in obese youth. Diabetes Care. 39(8):1431-1439.
Marcus, M.D., Wilfley, D.E., El Ghormli, L., Zeitler, P., Linder, B., Hirst, K., Levers-Landis, C.E., Van Buren, D.J., Walders-Abramson, N, The Today Study Group. 2016. Weight change in the management of youth-onset type 2 diabetes: The TODAY clinical trial experience. Pediatric Obesity. doi:10.1111/ijpo.12148.
Arslanian, S., Kim, J.Y., Nasr, A., Bacha, F., Tfayli, H., Lee, S., Toledo, F.G. 2017. Insulin sensitivity across the lifespan from obese adolescents to obese adults with impaired glucose tolerance: Who is worse off? Pediatric Diabetes. doi:10.1111/pedi.12562.
Bell, K.A., Wagner, C.L., Feldman, H.A., Shypailo, R.J., Belfort, M.B. 2017. Association of infant feeding with trajectories of body composition and growth. American Journal of Clinical Nutrition. doi:10.3945/ajcn.116.151126.
Varni, J.W., Shulman, R.J., Self, M.M., Saeed, S.A., Patel, A.S., Nurko, S., Neigut, D.A., Saps, M., Franciosi, J.P., Denham, J.M., Zacur, G.M., Dark, C.V., Bendo, C.B., Pohl, J.F. 2016. Gastrointestinal symptoms predictors of health-related quality of life in patients with inflammatory bowel disease. Journal of Pediatric Gastroenterology and Nutrition. 63(6):e186-e192.
Chumpitazi, B.P., Weidler, E.M., Lu, D.Y., Tsai, C.M., Shulman, R.J. 2016. Self-perceived food intolerances are common and associated with clinical severity in childhood irritable bowel syndrome. Journal of the Academy of Nutrition and Dietetics. 116:1458-1464.
Cao, F., Lu, L., Abrams, S.A., Hawthorne, K.M., Tam, A., Jin, W., Dawson, B., Shypailo, R., Liu, H., Lee, B., Nagamani, S.C.S., Wang, L.L. 2017. Generalized metabolic bone disease and fracture risk in Rothmund-Thomson syndrome. Human Molecular Genetics. doi:10.1093/hmg/ddx178.
Varni, J.W., Shulman, R.J., Self, M.M., Nurko, S., Saps, M., Saeed, S.A., Patel, A.S., Dark, C.V., Bendo, C.B., Pohl, J.F. 2016. Gastrointestinal symptoms predictors of health-related quality of life in pediatric patients with functional gastrointestinal disorders. Quality of Life Research. doi:10.1007/S11136-016-1430-3.
Wong, W.W., Ortiz, C.L., Stuff, J.E., Mikhail, C., Lathan, D., Moore, L.A., Alejandro, M.E., Butte, N.F., Smith, E.O. 2016. A community-based healthy living promotion program improved self-esteem among minority children. Journal of Pediatric Gastroenterology and Nutrition. 63(1):106-112.
Shi, L., Guo, Y., Dong, C., Huddleston, J., Yang, H., Han, X., Fu, A., Li, Q., Li, N., Gong, S., Lintner, K.E., Ding, Q., Wang, Z., Hu, J., Wang, D., Wang, F., Wang, L., Lyon, G.J., Guan, Y., Shen, Y., Evgrafov, O.V., Knowles, J.A., Thibaud-Nissen, F., Schneider, V., Yu, C.Y., Zhou, L., Eichler, E.E., So, K.F., Wang, K. 2016. Long-read sequencing and de novo assembly of a Chinese genome. Nature Communications. 7:12065.
Zhou, Q., Guan, Y. 2017. On the null distribution of Bayes factors in linear regression. Journal of the American Statistical Association. doi:10.1080/01621459.2017.1328361.
Mlotschwa, B.C., Mwesigwa, S., Mboowa, G., Williams, L., Retshabile, G., Kekitiinwa, A., Wayengera, M., Kyobe, S., Brown, C.W., Hanchard, N.A., Mardon, G., Joloba, M., Anabwani, G., Mpoloka, S.W. 2017. The collaborative African genomics network training program: A trainee perspective on training the next generation of African scientists. Genetics in Medicine. 19(7):826-833.