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Research Project: Pediatric Clinical Nutrition

Location: Children's Nutrition Research Center

2018 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; 12) no longer applies; and 13) identify genomic and epigenomic markers associated with clinically relevant manifestations in severe childhood malnutrition.

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, and test whether micronutrient and/or fish oil supplements can reduce environmental enteropathy. Scientists will determine by using genome-wide technologies, whether epigenetic markers can be used as surrogate biomarkers of sever childhood malnutrition phenotypes.

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. New test for children's gut health. Rural African children often are stunted because of gut inflammation. Children's Nutrition Research Center researchers based in rural Malawi, Africa worked closely with 300 young children to compare their gut health measured by two different tests. Traditionally, gut health is measured by a sugar absorption test and this test was compared to a panel of small molecules that indicate cellular function in the gut. The comparison found that either test can be used to identify poor gut health. With this test we can more easily identify children who need interventions to improve their gut health in a less expensive way.

2. Molecular changes in severe childhood malnutrition affect genes important to over-nutrition. Previous studies from researchers in Houston, Texas demonstrated a lower level of DNA methylation (chemical modifications of DNA) in samples from children with more severe- rather than the mild- forms of malnutrition. In recent studies, we show that these methylation changes alter the amount of the gene that is present, and the genes affected by this methylation change are in diseases where there is over-nutrition, such as diabetes and obesity. Further, the relationship between methylation at different sites was also affected by the severe undernutrition, and these changes occurred at sites where methylation is disturbed in cancer. These results suggest that the molecular changes occurring in under-nutrition are also highly relevant to studies of cancer and common nutritional diseases.

3. Immune system activation may identify children who may respond to dietary treatment for abdominal pain. Activation of the immune system and gut nerves account for pain related to certain meals. Up to 15% of children worldwide experience chronic abdominal pain and in a large percent of these cases the pain is related to diet. Researchers in Houston, Texas have discovered that in many of these children there is activation of the immune system and nerves within the gut that appear to be responsible for the pain. Using tests to detect this activation, we can begin to identify children for whom specific changes in diet will relieve their pain. These findings are important as it provides a nutritional change that may relieve chronic abdominal pain in this young population worldwide.

4. Adverse effect on small blood vessels related to fat deposition in the liver. 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 in the small vessels of the fingers. Researchers in Houston, Texas, utilized this method to investigate the influence of increased fat in the liver on endothelial function in obese youth suffering from prediabetes and type 2 diabetes. We demonstrated a direct relationship between liver fat accumulation and impairment in vessel function in these youth. These findings indicate that increased fat in the liver is associated with an added risk for cardiovascular disease in obese youth. This has important implications for childhood health and supports the need for surveillance for liver disease in obese youth with prediabetes and type 2 diabetes and intensifying prevention efforts in these children.

Review Publications
Bacha, F., Cheng, P., Gal, R.L., Kollman, C., Tamborlane, W.V., Klingensmith, G.J., Manseau, K., Wood, J., Beck, R.W. 2017. Initial presentation of type 2 diabetes in adolescents predicts durability of successful treatment with metformin monotherapy: Insights from the pediatric diabetes consortium T2D registry. Hormone Research in Paediatrics.
Gidding, S.S., Bacha, F., Bjornstad, P., Levitt Katz, L.E., Levitsky, L.L., Lynch, J., Tryggestad, J.B., Weinstock, R.S., El Ghormli, L., Lima, J.C. 2018. Cardiac biomarkers in youth with type 2 diabetes mellitus: Results from the Today Study. Journal of Pediatrics. 192:86-92. https://doi.org10.1016/j.jpeds.2017.09.012.
Semba, R.D., Trehan, I., Li, X., Salem, N.J., Moaddel, R., Ordiz, M.I., Maleta, K.M., Kraemer, K., Manary, M.J. 2017. Low serum omega-3 and omega-6 polyunsaturated fatty acids and other metabolites are associated with poor linear growth in young children from rural Malawi. American Journal of Clinical Nutrition. 106(6):1490-1499.
Friebert, A., Callaghan-Gillespie, M., Papathakis, P.C., Manary, M.J. 2018. Adolescent pregnancy and nutrition: A subgroup analysis from the Mamachiponde study in Malawi. Annals of the New York Academy of Sciences. 1416(1):140-146.
Cheng, W.D., Wold, K.J., Benzoni, N.S., Thakwalakwa, C., Maleta, K.M., Manary, M.J., Trehan, I. 2017. Lactoferrin and lysozyme to reduce environmental enteric dysfunction and stunting in Malawian children: Study protocol for a randomized controlled trial. Trials. 18(1):523.
Stephenson, K.B., Agapova, S.E., Divala, O., Kaimila, Y., Maleta, K.M., Thakwalakwa, C., Ordiz, M.I., Trehan, I., Manary, M.J. 2017. Complementary feeding with cowpea reduces growth faltering in rural Malawian infants: A blind, randomized controlled clinical trial. American Journal of Clinical Nutrition. 106(6):1500-1507.
Agapova, S.E., Stephenson, K.B., Divala, O., Kaimila, Y., Maleta, K.M., Thakwalakwa, C., Ordiz, M.I., Trehan, I., Manary, M.J. 2018. Additional common bean in the diet of Malawian children does not affect linear growth, but reduces intestinal permeability. Journal of Nutrition. 148(2):267-274.
Mulukutla, S.N., Hsu, J.W., Gaba, R., Bohren, K.M., Guthikonda, A., Iyer, D., Ajami, N.J., Petrosino, J.F., Hampe, C.S., Ram, N., Jahoor, F., Balasubramanyam, A. 2018. Arginine metabolism is altered in adults with A-B + ketosis-prone diabetes. Journal of Nutrition. 148(2):185-193.
Bjornstad, P., Nehus, E., El Ghormli, L., Bacha, F., Libman, I.M., McKay, S., Willi, S.M., Laffel, L., Arslanian, S., Nadeau, K.J. 2017. Insulin sensitivity and diabetic kidney disease in children and adolescents with type 2 diabetes: an observational analysis of data from the today clinical trial. American Journal of Kidney Diseases. 71(1):65-74.
Levitt Katz, L.E., Bacha, F., Gidding, S.S., Weinstock, R.S., El Ghormi, L., Libman, I., Nadeau, K.J., Porter, K., Marcovina, S. 2018. Lipid profiles, inflammatory markers, and insulin therapy in youth with type 2 diabetes. Journal of Pediatrics. 196:208-216.
Stobaugh, H.C., Bollinger, L.B., Adams, S.E., Crocker, A.H., Grise, J.B., Kennedy, J.A., Thakwalakwa, C., Maleta, K.M., Dietzen, D.J., Manary, M.J., Trehan, I. 2017. Effect of a package of health and nutrition services on sustained recovery in children after moderate acute malnutrition and factors related to sustaining recovery: A cluster-randomized trial. American Journal of Clinical Nutrition. 106(2):657-666.
Callaghan-Gillespie, M., Schaffner, A.A., Garcia, P., Fry, J., Eckert, R., Malek, S., Trehan, I., Thakwalakwa, C., Maleta, K.M., Manary, M.J., Papathakis, P.C. 2017. Trial of ready-to-use supplemental food and corn-soy blend in pregnant Malawian women with moderate malnutrition: A randomized controlled clinical trial. American Journal of Clinical Nutrition. 106(4):1062-1069.
Blanton, L.V., Charbonneau, M.R., Salih, T., Barratt, M.J., Venkatesh, S., Ilkaveya, O., Subramanian, S., Manary, M.J., Trehan, I., Jorgensen, J.M., Fan, Y., Henrissat, B., Leyn, S.A., Rodionov, D.A., Osterman, A.L., Maleta, K.M., Newgard, C.B., Ashorn, P., Dewey, K.G., Gordon, J.I. 2016. Gut bacteria that prevent growth impairments transmitted by microbiota from malnourished children. Science. 351(6275):aad3311.
Varni, J.W., Shulman, R.J., Self, M.M., Saeed, S.A., Zacur, G.M., Patel, A.S., Nurko, S., Neigut, D.A., Franciosi, J.P., Saps, M., Denham, J.M., Dark, C.V., Bendo, C.B., Pohl, J.F. 2017. Perceived medication adherence barriers mediating effects between gastrointestinal symptoms and health-related quality of life in pediatric inflammatory bowel disease. Quality of Life Research.
Kim, J.Y., Nasr, A., Tfayli, H., Bacha, F., Michaliszyn, S.F., Arslanian, S. 2017. Increased lipolysis, diminished adipose tissue insulin sensitivity and impaired B-cell function relative to adipose tissue insulin sensitivity in obese youth with impaired glucose tolerance (IGT). Diabetes.
Bacha, F., Tomsa, A., Bartz, S.K., Barlow, S.E., Chu, Z., Krishnamurthy, R., Krishnamurthy, R., Smith, E. 2017. Nonalcoholic fatty Liver disease in Hispanic youth with dysglycemia: Risk for subclinical atherosclerosis? Endocrine Journal. 1(8):1029-1040.
Shulman, R.J. 2018. Starch malabsorption in infants. Journal of Pediatric Gastroenterology and Nutrition. 66:s65-s67.
Chumpitazi, B.P., Kearns, G.L., Shulman, R.J. 2018. Review article: The physiological effects and safety of peppermint oil and its efficacy in irritable bowel syndrome and other functional disorders. Alimentary Pharmacology & Therapeutics. 47(6):738-752.
Chumpitazi, B.P., Lim, J., McMeans, A.R., Shulman, R.J., Hamaker, B.R. 2018. Evaluation of FODMAP carbohydrates content in selected foods in the United States. Journal of Pediatrics.
Robin, S.G., Keller, C., Zwiener, R., Hyman, P.E., Nurko, S., Saps, M., Di Lorenzo, C., Shulman, R.J., Hyams, J.S., Palsson, O., Van Tilburg, M.A. 2018. Prevalence of pediatric functional gastrointestinal disorders utilizing the rome IV criteria. Journal of Pediatrics. 195:134-139.
Chumpitazi, B.P., McMeans, A.R., Vaughan, A., Ali, A., Orlando, S., Elsaadi, A., Shulman, R.J. 2018. Fructans exacerbate symptoms in a subset of children with irritable bowel syndrome. Clinical Gastroenterology and Hepatology. 16:219-225.
Li, A.H., Hanchard, N.A., Furthner, D., Fernbach, S., Azamian, M., Nicosia, A., Rosenfeld, J., Muzny, D., D'Alessandro, L.C., Morris, S., Jhangiani, S., Parekh, D.R., Franklin, W.J., Lewin, M., Towbin, J.A., Penny, D.J., Fraser, C.D., Martin, J.F., Eng, C., Lupski, J.R., Gibbs, R.A., Boerwinkle, E., Belmont, J.W. 2017. Whole exome sequencing in 342 congenital cardiac left sided lesion cases reveals extensive genetic heterogeneity and complex inheritance patterns. Genome Medicine. 9(1):95.
Penilla, C., Tschann, J.M., Deardoff, J., Flores, E., Pasch, L.A., Butte, N.F., Geregorich, S.E., Greenspan, L.C., Martinez, S.M., Ozer, E. 2017. Fathers' feeding practices and children's weight status in Mexican American families. Appetite. 117:109-116.
Hanchard, N.A., Swaminathan, S., Bucasas, K., Furthner, D., Fernbach, S., Azamian, M.S., Wang, X., Lewin, M., Towbin, J.A., D'Alessandro, L.C., Morris, S.A., Dreyer, W., Denfield, S., Ayres, N.A., Franklin, W.J., Justino, H., Lantin-Hermoso, M.R., Ocampo, E.C., Santos, A.B., Parekh, D., Moodie, D., Jeewa, A., Lawrence, E., Allen, H.D., Penny, D.J., Fraser, C.D., Lupski, J.R., Popoola, M., Wadhwa, L., Brook, J.D., Bu'Lock, F.A., Bhattacharya, S., Lalani, S.R., Zender, G.A., Fitzgerald-Butt, S.M., Bowman, J., Corsmeier, D., White, P., Lecerf, K., Zapata, G., Hernandez, P., Goodship, J.A., Garg, V., Keavney, B.D., Leal, S.M., Cordell, H.J., Belmont, J.W., McBride, K.L. 2016. A genome-wide association study of congenital cardiovascular left-sided lesions shows association with a locus on chromosome 20. Human Molecular Genetics. 25(11):2331-2341.
Hanchard, N.A., Umana, L.A., D'Alessandro, L., Azamian, M., Poopola, M., Morris, S.A., Fernbach, S., Lalani, S.R., Towbin, J.A., Zender, G., Fitzgerald-Butt, S., Garg, V., Bowman, J.A., Zapata, G., Hernandez, P., Arrington, C.B., Furthner, D., Prakash, S.K., Bowles, N., McBride, K.L., Belmont, J.W. 2017. Assessment of large copy number variants in patients with apparently isolated congenital left-sided cardiac lesions reveals clinically relevant genomic events. American Journal of Medical Genetics. 173(8):2176-2188.
Barlow, S.E., Butte, N.F., Hoelscher, D.M., Salahuddin, M., Pont, S.J. 2017. Strategies to recruit a diverse low-income population to child weight management programs from primary care practices. Preventing Chronic Disease. 14:E138.
He, D., Zhu, Q., Zhou, Q., Qi, Q., Sun, H., Zachariah, L.M., Wang, G., Reveille, J.D., Guan, Y., Zhou, X. 2017. Correlation of serum MMP3 and other biomarkers with clinical outcomes in patients with ankylosing spondylitis: A pilot study. Clinical Rheumatology. doi:10.1007/s10067-017-3624-7.
Xu, H., Wang, S., Ma, L.L., Huang, S., Liang, L., Liu, Q., Liu, Y.Y., Liu, K.D., Tan, Z.M., Ban, H., Guan, Y., Lu, Z. 2017. Informative priors on fetal fraction increase power of the noninvasive prenatal screen. Genetics in Medicine.
Salahunddin, M., Perez, A., Ranjit, N., Kelder, S.H., Barlow, S.E., Pont, S.J., Butte, N.F., Hoelscher, D.M. 2017. Predictors of severe obesity in low-income, predominantly hispanic/latino children: The Texas Childhood Obesity Research Demonstration study. Preventing Chronic Disease. 14:1-11.
Butte, N.F., Watson, K.B., Ridley, K., Zakeri, I.F., McMurray, R.G., Pfeiffer, K.A., Crouter, S.E., Herrmann, S.D., Bassett, D.R., Long, A., Berhane, Z., Trost, S.G., Ainsworth, D.E., Berrigan, D., Fulton, J.E. 2017. A youth compendium of physical ctivities: Activity codes and metabolic Intensities. Epidemiology. 50(2):246-256.
Butte, N.F., Hoelscher, D.M., Barlow, S.E., Pont, S., Durand, C., Vandewater, E.A., Liu, Y., Adolph, A.L., Perez, A., Wilson, T.A., Gonzalez, A., Puyau, M.R., Sharma, S.V., Byrd-Williams, C., Oluyomi, A., Huang, T., Finkelstein, E.A., Sacher, P.M., Kelder, S.H. 2017. Efficacy of a community-versus primary care–centered Program for childhood obesity: TX CORD RCT. Obesity. 25(9):1584-1596.
Freedman, D.S., Butte, N.F., Taveras, E.M., Goodman, A.B., Blanck, H.M. 2017. Longitudinal changes in BMI z-scores among 45,414 2–4-year olds with severe obesity. Annals of Human Biology.
May, T., Klatt, K.C., Smith, J., Castro, E., Manary, M., Caudill, M.A., Jahoor, F., Fiorotto, M.L., 2018. Choline supplementation prevents a hallmark disturbance of kwashiorkor in weanling mice fed a maize vegetable diet: Hepatic steatosis of undernutrition. Nutrients. 10:653.
Duerrschmid, C., He, Y., Wang, C., Li, C., Bournat, J., Romere, C., Saha, P., Lee, M., Phillips, K., Jia, P., Zhao, Z., Farias, M., Wu, Q., Milewicz, D., Sutton, R., Moore, D., Butte, N., Krashes, M., Xu, Y., Chopra, A. 2017. Asprosin is a centrally acting orexigenic hormone. Nature Medicine.
Hollier, J.M., Vaughan, A.O., Liu, Y., Van Tilburg, M.A., Shulman, R.J., Thompson, D.J. 2018. Maternal and child acceptability of a proposed guided imagery therapy mobile app designed to treat functional abdominal pain disorders in children: Mixed-methods predevelopment formative research. JMIR Pediatrics and Parenting. 1(1):e6.
Byrd-Williams, C., Dooley, E.E., Sharma, S.V., Chuang, R., Butte, N., Hoelscher, D.M. 2017. Best practices and barriers to obesity prevention in head start: Differences between director and teacher perceptions. Preventing Chronic Disease. 14:170294.
Lutchmansingh, F.K., Hsu, J.W., Bennett, F.I., Badaloo, A.V., McFarlane-Anderson, N., Gordon-Strachan, G.M., Wright-Pascoe, R.A., Jahoor, F., Boyne, M.S. 2018. Glutathione metabolism in type 2 diabetes and its relationship with microvascular complications and glycemia. PLoS One. 13(6):e0198626.
Borresen, E.C., Zhang, L., Trehan, I.J., Nealon, N., Maleta, K.M., Manary, M.J., Ryan, E.P. 2017. The nutrient and metabolite profile of 3 complementary legume foods with potential to improve gut health in rural Malawian children. Current Developments in Nutrition. 1:e001610. https://doi:10.3945/cdn.117.001610.
Stobaugh, H.C., Rogers, B.L., Rosenberg, I.H., Webb, P., Maleta, K.M., Manary, M.J., Trehan, I. 2018. Children with poor linear growth are at risk for repeated relapse to wasting after recovery from moderate acute malnutrition. American Society for Nutrition. 148:974-979.
Janssen, S., McDonald, D., Gonzalez, A., Navas-Molina, J.A., Jiang, L., Xu, Z., Winker, K., Kado, D., Orwoll, E., Manary, M., Mirarab, S., Knight, R. 2018. Phylogenetic placement of exact amplicon sequences improves associations with clinical information. American Society for Microbiology. 3(3):1-18.
Stobaugh, H.C., Rogers, B.L., Webb, P., Rosenberg, I.H., Thakwalakwa, C., Maleta, K.M., Trehan, I., Manary, M.J. 2018. Household-level factors associated with relapse following discharge from treatment for moderate acute malnutrition. British Journal of Nutrition. 119:1039-1046.
Pipaon, M.S., Dorronsoro, I., Alvarez-Cuervo, L., Butte, N.F., Madero, R., Barrios, V., Coya, J., Martínez-Biarge, M., Martos-Moreno, G.A., Fewtrell, M.S., Argente, J., Quero, J. 2017. The impact of intrauterine and extrauterine weight gain in premature infants on later body composition. Pediatric Research. 82:658-664.
Glosz, C.M., Schaffner, A.A., Reaves, S.K., Manary, M.J., Papathakis, P.C. 2018. Effect of nutritional interventions on micronutrient status in pregnant Malawian women with moderate malnutrition: A randomized, controlled trial Nutrients. 10:879.
Ngoma, T.N., Chimimba, U.K., Mwangwela, A.M., Thakwalakwa, C., Maleta, K.M., Manary, M.J., Trehan, I. 2018. Effect of cowpea flour processing on the chemical properties and acceptability of a novel cowpea blended maize porridge. PLoS One. 13(7):e0200418.
Lee, R., Singh, L., Van Liefde, D., Callaghan-Gillespie, M., Steiner-Asiedu, M., Saalia, K., Edwards, C., Serena, A., Hershey, T., Manary, M.J. 2018. Milk powder added to a school meal increases cognitive test scores in Ghanaian children. Journal of Nutrition. 148(7):1177-1184.
Ordiz, M.I., Wold, K., Kaimila, Y., Divala, O., Gilstrap, M., Zu, H.Z., Manary, M.J. 2018. Detection and interpretation of fecal host mRNA in rural Malawian infants aged 6-12 months at risk for environmental enteric dysfunction. Experimental Biology and Medicine.
Ordiz, I.M., Davitt, C., Stephenson, K., Agapova, S., Divala, O., Shaikh, N., Manary, M.J. 2018. Interpretation of the lactulose:mannitol test in rural Malawian children at risk for perturbations in intestinal permeability. Experimental Biology and Medicine. 243:667-683.