Diet, the Intestinal Microbiome, and Health of Children
Gut microbes account for 90 percent of the cells and 99 percent of the genetic material in humans. The gut microbiome (bacteria and their genes) has coevolved with humans to serve a critical symbiotic role in maintaining health. However, the presence of an abnormal microbiome composition may contribute to chronic health disorders like allergic, circulatory, and inflammatory bowel diseases, functional abdominal pain disorders, and obesity. Despite its importance, little is known about the development of the child gut microbiome, the influence of diet, and how variations in the gut microbiome affect health. The long-term goal of this project is to understand the interaction between the gut microbiome and the health of children. The objectives center around gaining a better understanding of the gut microbiome, how it is affected by diet and age, its associations with gut health in the developed and developing worlds, and obesity risk. In children, we propose to:
- Determine the effects of diet/age on gut microbiome composition in relation to gut health
- Develop new methods to define and characterize the microbiome and evaluate obesity risk
- Develop noninvasive methods to assess gut disease, evaluate a dietary therapy for treatment, and determine the relationship between the gut microbiome and growth in the developing world
By addressing these questions, we anticipate an increased understanding of how diet and age influence gut microbial population composition, and in turn, alter physiological functioning and promote health. Additionally, insight will be gained into potential mechanisms as requested by the action plan by examining gut microbial genes and potential gene products (microbiome) and exploring relationships with physiologic outcomes (gut barrier function and inflammatory state) that may promote or impair health. This information will lead to improved understanding how foods and their components (e.g., dietary prebiotics) support health and reduce disease risk and can be used in formulating nutrition policies and government programs. The results will be of benefit to children and adolescents and can be used as a guide for similar investigations in adults.
Research Faculty: Rob Shulman, M.D. / Yongtao Guan, Ph.D. / Mark J. Manary, Ph.D.
Consequences of Maternal Obesity and Obesity in Young Children
The long-term objective of this project is to provide an enhanced understanding of the etiology of obesity, provide basic information about the mediators and cellular mechanisms through which it causes metabolic and cardiovascular diseases and female infertility, and to evaluate biological processes and lifestyle changes that include a targeted nutritional intervention aimed at preventing it or reversing its deleterious effects on overall health. Specific objectives are to determine:
- Negative effect of obesity-induced inflammation and oxidative stress on women’s fertility and whether it can be reversed by weight loss and supplemental nutrients with antioxidant and anti-inflammatory properties
- Whether pre-pregnant lipid supply underlies the insulin resistance and increased susceptibility to gestational diabetes in obese women and whether exercise and a modified diet will decrease the prevalence of gestational diabetes
- Whether adolescents born to obese mothers have an altered macronutrient metabolism
- Relationship of endothelial function, monocyte function and serum inflammatory markers to insulin sensitivity in youth
- Effect of hyperglycemia on endothelial function, monocyte function and inflammatory markers
- 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, ages 5 to 19 years.
Overall this project will provide new information on the cause(s) of obesity at different stages of the lifecycle, the mediators and mechanisms of obesity-induced metabolic and cardiovascular diseases and female infertility.
The Molecular Genetics of Severe Nutrient Stress in Childhood
The long-term goal of this project is to exploit current advances in genomic technologies to identify and delineate the genetic underpinnings of different responses to nutrient stress. Severe childhood undernutrition or malnutrition represents a form of nutrient stress that contributes to more than two million childhood deaths worldwide each year. SCM occurs in two clinically distinct forms -- the more lethal edematous SCM, and the milder non-edematous SCM.
Despite years of study, the reasons for this dichotomy are unclear; however, both groups have similar environmental and dietary exposures, suggesting that phenotypic differences may partly result from innate genetic differences in the response to nutritional stress. Previous studies have observed significant metabolic differences between ESCM and NESCM in the major pathway contributing to DNA methylation, suggesting that genome-wide, levels of DNA methylation may differ between the two groups, possibly as a result of genetic variation.
This research project will use genome-wide assessments to identify genomic and epigenomic differences between SCU phenotypes and integrate these differences using advanced statistical models in order to identify gene variants that causally contribute to outcome differences. The project will also evaluate the ability of methylation levels to categorize SCU phenotypes and assess the potential long-term molecular effects of nutrient stress. The study will also create a framework for evaluating methyl-group supplementation in SCU. This project thus aims to provide novel insights to the nutrient stress response and a better understanding of the impact of early nutrient stress on later-life outcomes.
Research Faculty: Neil Hanchard, M.D., Ph.D.