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Research Project: Microbiota and Nutritional Health

Location: Children's Nutrition Research Center

2023 Annual Report

A number of pressing nutritional issues face mankind. In the US and other developed countries strategies are needed to address the ever-increasing epidemic of obesity and related chronic diseases and in impoverished countries severe acute malnutrition directly contributes to deaths of more than a million children under the age of 5 each year globally. To address these concerns researchers will conduct the following objectives: 1) compare the effects of inulin and fructo-oligosaccharides against a maltodextrin placebo in obese children, using a double-blind randomized controlled trial, to study weight loss, fecal microbiota and their functions; 2) removed due to scientists departure; and 3) conduct a clinical trial adding black-eyed peas to diets of young children at risk for stunting. Determine efficacy in reducing stunting and analyze fecal sample to understand potential mechanisms by which the food supplement ameliorates stunting. Assess dietary compliance in a novel, quantitative manner using a urinary biomarker for black eyed peas. Currently quercetin and ferulic acid are candidates for this biomarker. Additionally, breastfeeding has enormous health benefits to both infant and mother and continued efforts to understand the biology of mammary development and lactation are important to improving both infant and maternal health. Thus we will undertake this objective to further our knowledge: 4) select inbred mouse strains with phenotypic extremes in milk production will be used to: a) identify genomic variants along with intestinal and mammary-expressed genes that differentiate low and high milk production, and b) determine the extent to which genome-driven differences in milk production and mammary gene expression are directly mediated through host-dependent differences in the intestinal and/or mammary tissue microbiome.

A multi-discipline approach will be undertaken to address these nutritional concerns. Hispanic children ages 7-18 years of age will be enrolled in the study, anthropometric measurements and blood draws will be taken and analyzed. Urine and stool samples will be collected and analysis will be performed to account for inulin and B-defensin. Researchers will also assess the pre- and post-treatment serum samples from a recently concluded study of 1-carbon metabolites. We will perform laboratory procedures to assess DNA methylation from the samples collected. Scientists will conduct a randomized, double blind, clinical controlled trial in south central Mali among healthy 6-12 month old children by adding black-eyed peas to diets of young children at risk for stunting. Scientists will analyze urinary and fecal samples to understand potential mechanisms by which the food supplement reduces stunting. And finally, researchers will use genome-wide pathway association study approaches in conjunction with bioinformatics tools to predict the functional consequences of the private alleles within the lactation phenome strains to better understand the phenotypic expression of increased lactation.

Progress Report
To review the progress made during the year, please refer to the following projects: 3092-51000-062-01S (Project #1), 3092-51000-062-03S (Project #2), and 3092-51000-062-04S (Project #3).

1. A novel role of estrogen in inhibiting prolactin production. It is well known that estrogen can directly promote prolactin production which is important for female health. However, the indirect impacts of estrogen are not well studied. Researchers at the Children's Nutrition Research Center in Houston, Texas, discovered that estrogen can inhibit prolactin levels indirectly during lactation through the brain, which may contribute to the remodeling of the energy balance in mothers. Additional studies are necessary to fully explore the detailed mechanism for brain estrogen effect on prolactin and study the impact of this mechanism on maternal health.

2. Maternal metabolic adaptation during lactation. During pregnancy, the energy needs of the mother are maintained despite an increased need to support the growing fetus. Yet after birth, a dramatic shift to a negative energy balance (energy expenditure exceeds energy intake) occurs during the lactation period. A limited body of knowledge exists that addresses how breastfeeding metabolism changes during lactation. Researchers at the Children’s Nutrition Research Center in Houston, Texas, studied key metabolic regulators in the liver and intestine of lactating and non-lactating mice. We found several regulatory factors in lipid metabolism were increased during lactation, indicating metabolic adaptations occur and potential long-term metabolic consequences from lactation were also identified. This lactation study provides valuable insights in the body’s adaptation to changes in metabolic needs, sustaining healthy nutrition for the mother and offspring, and the potential long-term metabolic benefits for the mother.

3. Boys and girls respond differently to dietary fiber (carbohydrate). Fiber in the diet is beneficial yet Americans eat much less than the recommended amount. Whether fiber is beneficial to specific individuals is less clear. To investigate whether boys and girls respond differently to fiber in the diet, researchers at the Children’s Nutrition Research Center in Houston, Texas, studied the relationship between fiber intake and the development of belly pain. They discovered that increasing fiber intake led to less pain in school-age boys but not girls. Fiber intake in boys increased the presence of a gut bacteria associated with less inflammation but did not in girls. These results shed light on how fiber can be beneficial in boys with belly pain and also highlight the great importance of examining potential differences between the sexes when studying the relationships between diet, the gut bacteria, and health.

Review Publications
Woeltje, M.M., Evanoff, A.B., Helmink, B.A., Culbertson, D.L., Maleta, K.M., Manary, M.J., Trehan, I. 2021. Community-based management of acute malnutrition for infants under 6 months of age is safe and effective: Analysis of operational data. Public Health Nutrition. 26:246-255.
Yang, P., Kamp, K.J., Burr, R.L., Tang, H., Dobra, A., Shulman, R.J., Heitkemper, M.M. 2023. Age differences in core symptoms and symptom relationships in patients with irritable bowel syndrome: A network analysis. American Journal of Gastroenterology.
Deblais, L., Ojeda, A., Brhane, M., Mummed, B., Hassen, K.A., Ahmedo, B.U., Weldesenbet, Y.D., Amin, J.K., Ahmed, I.A., Usmane, I.A., Yusuf, E.A., Seran, A.J., Abrahim, F.I., Game, H.T., Mummed, B.A., Usmail, M.M., Umer, K.A., Dawid, M.M., Gebreyes, W., French, N., Hassen, J.Y., Roba, K.T., Mohammed, A., Yimer, G., Saleem, C., Chen, D., Singh, N., Manary, M.J., McKune, S.L., Havelaar, A., Rajashekara, G. 2023. Prevalence and load of the campylobacter genus in infants and associated household contacts in rural eastern Ethiopia: A longitudinal study from the Campylobacter Genomics and Environmental Enteric Dysfunction (CAGED) project. Applied and Environmental Microbiology.
Parkman, H.P., Blackford, A.L., Murray, H., Yates, K.P., Grover, M., Malik, Z., Schey, R., Bulat, R.S., Koch, K.L., Sarosiek, I., Kuo, B., Shulman, R.J., Chumpitazi, B.P., Farrugia, G., Miriel, L., Tonascia, J., Hamilton, F., Pasricha, P.J., McCallum, R.W., Abell, T.L. 2023. Characteristics and outcomes of patients with gastroparesis using enteral and/or exclusive parenteral nutrition. Journal of Parenteral and Enteral Nutrition. 47(4):541-549.
Varni, J.W., Chumpitazi, B.P., Febo-Rodriguez, L., Shulman, R.J. 2023. Gastrointestinal symptoms profile in gastroparesis compared to other functional and organic gastrointestinal diseases. Journal of Pediatric Gastroenterology and Nutrition. 77(1):e1-e7.
Hendrixson, D., Naskidashvili, N., Stephenson, K.B., Laury, M.L., Koroma, A.S., Manary, M.J. 2022. An alternative oat-containing, ready-to-use, therapeutic food does not alter intestinal permeability or the 16S ribosomal RNA fecal microbiome configuration among children with severe malnutrition in Sierra Leone: A Randomized Controlled Trial. Journal of Nutrition. 152:2744-2753.
Gauglitz, J.M., West, K.A., Bittremieux, W., Williams, C.L., Weldon, K.C., Panitchpakdi, M., Di Ottavio, F., Aceves, C.M., Brown, E., Sikora, N.C., Jarmusch, A.K., Martino, C., Tripathi, A., Meehan, M.J., Dorrestein, K., Shaffer, J.P., Coras, R., Vargas, F., Deright Goldasich, L., Schwartz, T., Bryant, M., Humphrey, G., Johnson, A.J., Spengler, K., Belda-Ferre, P., Diaz, E., McDonald, D., Zhu, Q., Elijah, E., Wang, M., Marotz, C., Sprecher, K.E., Vargas-Robles, D., Withrow, D., Ackerman, G., Herrera, L., Bradford, B., Mauriz Marques, L., Geraldo Amaral, J., Moreira Silva, R., Protasio Veras, F., Mattar Cunha, T., Donizeti Ribiero Ol, R., Louzada-Junior, P., Mills, R.H., Piotrowski, P.K., Servetas, S.L., Da Silva, S.M., Jones, C.M., Lin, N.J., Lippa, K.A., Jackson, S.A., Kaddurah Daouk, R., Galasko, D., Dulai, P.S., Kalashnikova, T., Wittenberg, C., Terkeltaub, R., Doty, M.M., Kim, J.H., Rhee, K.E., Beauchamp-Walters, J., Wright, K.P., Dominguez-Bello, M.G., Manary, M., Oliveira, M.F., Boland, B.S., Peporine Lopes, N., Guma, M., Swafford, A.D., Dutton, R.J., Knight, R., Dorreistein, P.C. 2022. Enhancing untargeted metabolomics using metadata-based source annotation. Nature Biotechnology. 40.1774–1779.
Zhu, Q., Zhu, Y., Hepler, C., Zhang, Q., Park, J., Gliniak, C., Henry, G.H., Crewe, C., Bu, D., Zhang, Z., Zhao, S., Morley, T., Li, N., Kim, D., Strand, D., Deng, Y., Robino, J.J., Varlamov, O., Gordillo, R., Kolonin, M.G., Kusminski, C.M., Gupta, R.K., Scherer, P.E. 2022. Adipocyte mesenchymal transition contributes to mammary tumor progression. Cell Reports. 40(11). Article 111362.
Eseonu, D., Dongarwar, D., Salihu, H., Chumpitazi, B.P., Shulman, R.J. 2023. Many pediatric patients with gastroparesis do not receive dietary education. BioMed Central (BMC) Gastroenterology. 23. Article 240.
Shulman, R.J., Chichlowwski, M., Gutierrez Orozco, F., Harris, C.L., Wampler, J.L., Bokulich, N.A., Berseth, C.L. 2022. Infant behavioral state and stool microbiome in infants receiving Lactocaseibacillus rhamnosus GG in formula: Randomized controlled trial. BMC Pediatrics. 22. Article 580.
Plantinga, A.M., Kamp, K.J., Wu, Q., Chen, L., Yoo, L., Burr, R.L., Cain, K.C., Raftery, D., Neto, F.C., Badu, S., So, S., Savidge, T., Shulman, R.J., Heitkemper, M.M. 2023. Exploration of associations among dietary tryptophan, microbiome composition and function, and symptom severity in irritable bowel syndrome. Neurogastroenterology & Motility. 35. Article e14545.
James, J., Stephenson, K., Callaghan-Gillespie, M., Kamara, M.T., Park, H.G., Brenna, J.T., Manary, M.J. 2023. Docosahexaenoic acid stability in ready-to-use therapeutic food. Foods. 12(2). Article 308.
Havelaar, A.H., Brhane, M., Ahmed, I.A., Kedir, J., Chen, D., Deblais, L., French, N., Gebreyes, W.A., Hassen, J.Y., Li, X., Manary, M.J., Mekuria, Z., Ibrahim, A.M., Mummed, B., Ojeda, A., Rajashekara, G., Roba, K.T., Saleem, C., Singh, N., Usmane, I.A., Yang, Y., Yimer, G., McKune, S. 2022. Unravelling the reservoirs for colonisation of infants with Campylobacter spp. in rural Ethiopia: Protocol for longitudinal study during a global pandemic and political tensions. BMJ Open. 12(10). Article e061311.
Koroma, A.S., Ellie, M., Bangura, K., Iversen, P.O., Hendrixson, D.T., Stephenson, K., Manary, M.J. 2022. Supplementary feeding and infection control in pregnant adolescents - A secondary analysis of a randomized trial among malnourished women in Sierra Leone. Maternal and Child Nutrition. 19(1). Article e13456.
Hendrixson, D.T., Lasowski, P.N., Koroma, A.S., Manary, M.J. 2022. Newborn mid–upper arm circumference identifies low–birth weight and vulnerable infants: A secondary analysis. Current Developments in Nutrition. 6(10). Article nzac138.
Magalhaes, M., Ojeda, A., Mechlowitz, K., Brittain, K., Daniel, J., Roba, K.T., Hassen, J.Y., Manary, M.J., Gebreyes, W.A., Havelaar, A.H., McKune, S.L. 2022. Socioecological predictors of breastfeeding practices in rural eastern Ethiopia. International Breastfeeding Journal. 17. Article 93.
Miller, V., Webb, P., Cudhea, F., Shi, P., Zhang, J., Reedy, J., Erndt-Marino, J., Coates, J., Mozaffarian, D., Global Dietary Database. 2022. Global dietary quality in 185 countries from 1990 to 2018 show wide differences by nation, age, education, and urbanicity. Nature Food. 3:694–702.
Miller, V., Webb, P., Cudhea, F., Zhang, J., Reedy, J., Shi, P., Erndt-Marino, J., Coates, J., Micha, R., Mozaffarian, D., & Global Dietary Database. 2023. Children's and adolescents' rising animal-source food intakes in 1990–2018 were impacted by age, region, parental education and urbanicity. Nature Food. 4:305-319.
Hollier, J.M., Strickland, T.A., Fordis, C.M., Van Tilburg, M.A., Shulman, R.J., Thompson, D.J. 2023. Children's and caregivers' review of a guided imagery therapy mobile app designed to treat children with functional abdominal pain disorders: Leveraging a mixed methods approach with user-centered design. JMIR Formative Research. 7. Article e41321.
Tenenbaum, R.B., Czyzewski, D., McMeans, A., Narayana, V., Chumpitazi, B.P., Levy, R.L., Shulman, R.J., Musaad, S., Mirabile, Y.Z., Self, M. 2023. Factors associated with adherence to a low fermentable carbohydrate diet in children with functional gastrointestinal disorders. Journal of the Academy of Nutrition and Dietetics.