Skip to main content
ARS Home » Plains Area » Houston, Texas » Children's Nutrition Research Center » Research » Research Project #426343

Research Project: Pediatric Clinical Nutrition

Location: Children's Nutrition Research Center

2019 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
To review the progress made during the year, please refer to the following projects: 3092-51000-062-20S (Project #1), 3092-51000-062-30S (Project #2), and 3092-51000-062-40S (Project #3).

1. Genetic differences in body metabolism are associated with the risk for different types of undernutrition. Severe undernutrition in children, commonly found in impoverished countries, is known to occur as one of two forms – a severe form known as ESAM that is associated with body swelling and widespread organ dysfunction, and a less severe form associated with the rapid loss of weight and muscle bulk. The reasons why some children get one form over the other has remained a mystery despite decades of study. By assessing the human genome in the first molecular study of severe undernutrition, researchers in Houston, Texas, have demonstrated that changes in DNA that affect how the body breaks down and uses specific amino acids and vitamins (one-carbon metabolism) are associated with an increased risk of developing the severe form of undernutrition (ESAM). Previously we showed that one-carbon metabolism is abnormal in those with ESAM and that there is also decreased levels and abnormal patterns of DNA methylation. These results suggest that nutritional supplementation of one-carbon metabolism substrates (choline, vitamin B12, and methionine) could be important in improving the outcomes for those suffering from ESAM.

2. Impaired integrity of the intestinal lining and inflammation in the intestine are related to diet. Between 10-15% of school age children and adults worldwide suffer from intermittent chronic abdominal pain. This pain is sometimes associated with constipation and/or diarrhea and the economic cost of this condition in the United States (for adults) has been calculated to be $30 billion per year. Scientists in Houston, Texas, conducted research that showed that impaired integrity of the intestinal lining and/or inflammation in the intestine are associated with abdominal pain conditions and that carbohydrate ingested is linked to both. This relationship between dietary carbohydrate and impaired integrity of the intestinal lining and inflammation in the intestine is not associated with obesity. Studies by other researchers have shown that, in addition to abdominal pain, impaired integrity of the intestinal lining and/or inflammation in the intestine have been associated with a number of health problems such as liver disease, depression, and pancreatic disease; thus, our results have relevance to other disorders associated with impaired integrity of the intestinal lining. These results add to the understanding of how diet can affect the intestinal lining and contribute to poor health.

3. Vitamin D deficiency in overweight children is associated with higher risks for early forms of diabetes, heart and blood vessel disease. Low vitamin D levels (Vitamin D deficiency) are present in overweight children and in minorities, and these low levels appear to contribute to an increased risk of cardiovascular disease later as an adult. Researchers in Houston, Texas, evaluated the relationship of vitamin D (that is more readily available in the blood) and the risk for heart and blood vessel disease in overweight and obese youth. We found that children with lower vitamin D levels in their blood had higher body fat, worse blood vessel function, lower insulin sensitivity (how well the body responds to insulin), and higher markers of inflammation (a measure of risk for heart disease). These findings have important implications for future studies evaluating vitamin D status in obese and overweight children as we can now derive more accurate guidelines for these children. In addition, we can now evaluate if resolving this vitamin D deficiency in these children will restore their heart and blood vessel health over time.

Review Publications
Bliss, J., Lelijveld, N., Briend, A., Kerac, M., Manary, M., McGrath, M., Weise Prinzo, Z., Shepherd, S., Marie Zagre, N., Woodhead, S., Guerrero, S., Mayberry, A. 2018. Use of mid-upper arm circumference by novel community platforms to detect, diagnose, and treat severe acute malnutrition in children: A systematic review. Global Health: Science and Practice. 6(3):552-564.
Thaxton, G.E., Melby, P.C., Manary, M.J., Preidis, G.A. 2018. New insights into the pathogenesis and treatment of malnutrition. Gastroenterology Clinics of North America. 47(4):813-827.
Stobaugh, H.C., Mayberry, A., McGrath, M., Bahwere, P., Zagre, N.M., Manary, M.J., Black, R., Lelijveld, N. 2019. Relapse after severe acute malnutrition: A systematic literature review and secondary data analysis. Maternal and Child Nutrition. 15(2):e12702.
Shivakumar, N., Kashyap, S., Kishore, S., Thomas, T., Varkey, A., Devi, S., Preston, T., Jahoor, F., Sheshshayee, M.S., Kurpad, A.V. 2019. Protein-quality evaluation of complementary foods in Indian children. American Journal of Clinical Nutrition. 109(5):1319-1327.
Tan, H.C., Hsu, J.W., Khoo, C.M., Tai, E.S., Yu, S., Chacko, S., Lai, O.F., Jahoor, F. 2018. Alterations in branched-chain amino acid kinetics in nonobese but insulin-resistant Asian men. American Journal of Clinical Nutrition. 108(6):1220-1228.
Bailey, J., Lelijveld, N., Marron, B., Onyoo, P., Ho, L.S., Manary, M., Briend, A., Opondo, C., Kerac, M. 2018. Combined Protocol for Acute Malnutrition Study (ComPAS) in rural South Sudan and urban Kenya: A study protocol for a randomized controlled trial. Trials. 19(1):251.
Kaimila, Y., Pitman, R.T., Divala, O., Hendrixson, D.T., Stephenson, K.B., Agapova, S., Trehan, I., Maleta, K., Manary, M.J. 2019. Development of acute malnutrition despite nutritional supplementation in Malawi. Journal of Pediatric Gastroenterology and Nutrition. 68(5):734-737.
Kaimila, Y., Divala, O., Agapova, S.E., Stephenson, K.B., Thakwalakwa, C., Trehan, I., Manary, M.J., Maleta, K.M. 2019. Consumption of animal-source protein is associated with improved height-for-age z scores in rural Malawian children aged 12-36 months. Nutrients. 11(2):480.
Chegeni, M., Amiri, M., Nichols, B.L., Naim, H.Y., Hamaker, B.R. 2018. Dietary starch breakdown product sensing mobilizes and apically activates alpha-glucosidases in small intestinal enterocytes. Journal of Federation of American Societies for Experimental Biology. 32(7):3903-3911.
Robayo-Torres, C.C., Diaz-Sotomayor, M.M., Hamaker, B.R., Baker, S.S., Chumpitazi, B.P., Opekun, A.R., Nichols, B.L. 2018. 13C-labeled-starch breath test in congenital sucrase-isomaltase deficiency. Journal of Pediatric Gastroenterology and Nutrition. 66:S61-S64.
Chumpitazi, B.P., Robayo-Torres, C.C., Tsai, C.M., Opekun, A.R., Baker, S.S., Nichols, B.L., Gilger, M.A. 2018. Demographic and clinical correlates of mucosal disaccharidase deficiencies in children with functional dyspepsia. Journal of Pediatric Gastroenterology and Nutrition. 66:S52-S55.
Nichols, B.L., Baker, S.S., Quezada-Calvillo, R. 2018. Metabolic impacts of maltase deficiencies. Journal of Pediatric Gastroenterology and Nutrition. 66:S24-S29.
Cisse, F., Erickson, D.P., Hayes, A.M., Opekun, A.R., Nichols, B.L., Hamaker, B.R. 2018. Traditional malian solid foods made from sorghum and millet have markedly slower gastric emptying than rice, potato, or pasta. Nutrients. 10(2):E124.
Simsek, M., Quezada-Calvillo, R., Nichols, B.L., Hamaker, B.R. 2017. Phenolic compounds increase the transcription of mouse intestinal maltase-glucoamylase and sucrase-isomaltase. Food and Function. 8(5):1915-1924.
Shulman, R.J., Ohman, L., Stridsberg, M., Cain, K., Simren, M., Heitkemper, M. 2019. Evidence of increased fecal granins in children with irritable bowel syndrome and correlates with symptoms. Neurogastroenterology & Motility. 31:e13486.
Calarge, C.A., Devaraj, S., Shulman, R.J. 2019. Gut permeability and depressive symptom severity in unmedicated adolescents. Journal of Affective Disorders. 246:586-594.
Schulze, K.V., Bhatt, A., Azamian, M.S., Sundgren, N.C., Zapata, G.E., Hernandez, P., Fox, K., Kaiser, J.R., Belmont, J.W., Hanchard, N.A. 2019. Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy. Genetics in Medicine.
Hollier, J.M., Van Tilburg, M.A., Liu, Y., Czyzewski, D.I., Self, M.M., Weidler, E.M., Heitkemper, M., Shulman, R.J. 2018. Multiple psychological factors predict abdominal pain severity in children with irritable bowel syndrome. Neurogastroenterology & Motility. 31:e13509.
Cheng, W.D., Wold, K.J., Bollinger, L.B., Ordiz, M.I., Shulman, R.J., Maleta, K.M., Manary, M.J., Trehan, I. 2019. Supplementation with lactoferrin and lysozyme ameliorates environmental enteric dysfunction: A double-blind, randomized, placebo-controlled trial. American Journal of Gastroenterology. 114:671-678.
Hollister, E.B., Oezguen, N., Chumpitazi, B.P., Luna, R., Weidler, E.M., Rubio-Gonzales, M., Dahdouli, M., Cope, J.L., Mistretta, T., Raza, S., Metcalf, G.A., Muzny, D.M., Gibbs, R.A., Petrosino, J.F., Heitkemper, M., Savidge, T.C., Shulman, R.J., Versalovic, J. 2019. Leveraging human microbiome features to diagnose and stratify children with irritable bowel syndrome. Molecular Diagnosis. 21(3):449-461.
Grover, M., Gibbons, S.J., Nair, A.A., Bernard, C.E., Zubair, A.S., Eisenman, S.T., Wilson, L.A., Miriel, L., Pasricha, P.J., Parkman, H.P., Sarosiek, I., McCallum, R.W., Koch, K.L., Abell, T.L., Snape, W.J., Kuo, B., Shulman, R.J., McKenzie, T.J., Kellogg, T.A., Kendrick, M.L., Tonascia, J., Hamilton, F.A., Farrugia, G. 2018. Transcriptomic signatures reveal immune dysregulation in human diabetic and idiopathic gastroparesis. BMC Genomics. 11:62.
Heitkemper, M.M., Cain, K.C., Shulman, R.J., Burr, R.L., Ko, C., Hollister, E.B., Callen, N., Zia, J., Han, C.J., Jarrett, M.E. 2018. Stool and urine trefoil factor 3 levels: Associations with symptoms, intestinal permeability, and microbial diversity in irritable bowel syndrome. Beneficial Microbes. 9(3):345-355.
Bhatt, R.R., Gupta, A., Labus, J.S., Zeltzer, L.K., Tsao, J.C., Shulman, R.J., Tillisch, K. 2019. Altered brain structure and functional connectivity and its relation to pain perception in girls with irritable bowel syndrome. Psychosomatic Medicine. 81(2):146-154.
Duryea, T., Motil, K.J. 2018. Poor weight gain. In Kline, M.W., Blaney, S.M., Giardino, A.P., Orange, J.S., Penny, D. J., Schutze, G.E., Shekerdemian, L.S., editors. Rudolph's Pediatrics. 23rd edition. Volume 1. New York, NY: McGraw-Hill Education. p. 98-101.
Shah, A.S., Ghormli, L.E., Gidding, S.S., Bacha, F., Nadeau, K.J., Levitt Katz, L.E., Tryggestad, J.B., Leibel, N., Hale, D.E., Urbina, E.M. 2018. Prevalence of arterial stiffness in adolescents with type 2 diabetes in the TODAY cohort: Relationships to glycemic control and other risk factors. Journal of Diabetes. 32(8):740-745.
Hollister, E.B., Cain, K.C., Shulman, R.J., Jarrett, M.E., Burr, R.L., Ko, C., Zia, J., Han, C.J., Heitkemper, M.M. 2018. Relationships of microbiome markers with extraintestinal, psychological distress and gastrointestinal symptoms, and quality of life in women with irritable bowel syndrome. Journal of Clinical Gastroenterology.
Arslanian, S., El Ghormli, L., Kim, J.Y., Bacha, F., Chan, C., Ismail, H.M., Levitt Katz, L., Levitsky, L., Tryggestad, J., White, N.H. 2019. The shape of glucose response curve during an oral glucose tolerance test: Forerunner of heightened glycemic failure rates and accelerated decline in B-Cell function in TODAY. Diabetes Care. 42(1):164-172.
Kim, J.Y., Bacha, F., Tfayli, H., Michaliszyn, S.F., Yousuf, S., Arslanian, S. 2019. Adipose tissue insulin resistance in youth on the spectrum from normal weight to obese and from normal glucose tolerance to impaired glucose tolerance to type 2 diabetes. Diabetes Care. 42(2):265-272.
Schutt, A.K., Blesson, C.S., Hsu, J.W., Valdes, C.T., Gibbons, W.E., Jahoor, F., Yallampalli, C. 2019. Preovulatory exposure to a protein-restricted diet disrupts amino acid kinetics and alters mitochondrial structure and function in the rat oocyte and is partially rescued by folic acid. Reproductive Biology and Endocrinology. 17(1):12.
Redondo, M.J., Libman, I., Cheng, P., Kollman, C., Tosur, M., Gal, R.L., Bacha, F., Klingensmith, G.J., Clements, M. 2018. Racial/ethnic minority youth with recent onset type 1 diabetes have poor prognostic factors. Diabetes Care. 41(5):1017-1024.
O'Connor, T., Sisley, S., Bacha, F. 2018. The overweight or obese child. In: Kline, M.W., Blaney, S.M., Giardino, A.P., Orange, J.S., Penny, D.J., Schutze, G.E., Shekerdemian, L.S., editors. Rudolph's Pediatrics. 23rd edition, Volume 1. Sykesville, MD: McGraw-Hill Medical. p. 1-7.
Baranowski, T., Motil, K.J., Moreno, J.P. 2019. Multi-etiological perspective on child obesity prevention. Current Nutrition Reports.
Gandhi, M., Gandhi, R., Mack, L.M., Shypailo, R., Adolph, A.L., Puyau, M.R., Wong, W.W., Deter, R.L., Sangi-Haghpeykar, H., Lee, W., Butte, N.F. 2018. Estimated energy requirements increase across pregnancy in healthy women with dichorionic twins. American Journal of Clinical Nutrition. 108(4):775-783.
Gandhi, M., Gandhi, R., Mack, L.M., Shypailo, R., Adolph, A.L., Puyau, M.R., Wong, W.W., Deter, R.L., Sangi-Haghpeykar, H., Lee, W., Butte, N.F. 2018. Impact of changes in maternal body composition on birth weight and neonatal fat mass in dichorionic twin pregnancies. American Journal of Clinical Nutrition. 108(4):716-721.
Shaw, P.A., McMurray, R., Butte, N., Sotres-Alvarez, D., Sun, H., Stoutenberg, M., Evenson, K.R., Wong, W.W., Moncrieft, A.E., Sanchez-Johnsen, L.A., Carnethon, M.R., Arredondo, E., Kaplan, R.C., Matthews, C.E., Mossavar-Rahmani, Y. 2019. Calibration of activity-related energy expenditure in the Hispanic community health study/study of Latinos (HCHS/SOL). Journal of Science and Medicine in Sports. 22(3):300-306.
Molina, T.L., Stoll, B., Mohammad, M., Mohila, C.A., Call, L., Cui, L., Guthrie, G., Kunichoff, D., Lin, S., Welch-Jernigan, R., Nielsen, J., Premkumar, M., Robinson, J., Smith, V., Teets, H., Obelitz-Ryom, K., Hagan, J., Cruz, S., Lau, P., Puyau, M., Fang, Z., Shypailo, R., Manjarin, R., Butte, N., Burrin, D.G., Olutoye, O., Thymann, T., Sangild, P. 2019. New generation lipid emulsions increase brain DHA and improve body composition, but not short-term neurodevelopment in parenterally-fed preterm piglets. Brain Behavior and Immunity.
Bacha, F., Bartz, S.K., Tomsa, A., Sharma, S. 2019. Free vitamin D: Relationship to insulin sensitivity and vascular health in youth. Journal of Pediatrics.
Johnston, B.C., Seivenpiper, J.L., Vernooij, R.W., De Souza, R.J., Jenkins, D.J., Zeraatkar, D., Bier, D.M., Guyatt, G.H. 2019. The philosophy of evidence-based principles and practice in nutrition. Mayo Clinic Proceedings. 3(2):189-199.
Kohlmann, K., Callaghan-Gillespie, M., Gauglitz, J.M., Steiner-Asiedu, M., Saalia, K., Edwards, C., Manary, M.J. 2019. Alternative ready-to-use therapeutic food yields less recovery than the standard for treating acute malnutrition in children from Ghana. Global Health: Science and Practice. 7(2):203-214.
Thomas, D.M., Oken, E., Rifas-Shiman, S.L., Tellez-Rojo, M., Just, A., Svensson, K., Deierlein, A.L., Chandler-Laney, P.C., Miller, R.C., McNamara, C., Phelan, S., Yoshitani, S., Butte, N.F., Redman, L.M. 2019. Do women know their prepregnancy weight? Obesity. 27:1161-1167.