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Journal of Pediatric Gastroenterology & Nutrition:
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Research Agenda for Pediatric Gastroenterology, Hepatology and Nutrition: Nutrition and Obesity: Report of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the Children's Digestive Health and Nutrition Foundation

Baker, Susan S.; Motil, Kathleen J.; Heyman, Melvin B.

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Buffalo

Houston

San Francisco

Address requests for reprints to: Executive Director, Children's Digestive Health and Nutrition Foundation, PO Box 6, Flourtown, PA, 19031, U.S.A. (e-mail: NASPGHAN@naspghan.org).

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RATIONALE

Nutrition is a determinant of health and illness. The nutrition children receive can ensure health, prevent disease, have a positive effect on chronic disease and influence brain development. Nutrition may play an important role in gene regulation. However, suboptimal nutrition can lead to illness, worsen chronic disease, and place children at risk for developing disease in adulthood. There may also be critical times when the nutrition children receive has an important effect later in life. These critical times may vary with the specific nutrient or nutrients and the child's developmental status. The impact of changes in nutrition at these potentially critical times may not become evident for years.

Because nutrition is vital to so many aspects of child health, a comprehensive nutrition research agenda can be overwhelming. Therefore, this discussion focuses on areas in which an advance in knowledge can have an impact on the health of a population and prevent the later development of disease. In addition, research is discussed that may lead to new substances that can ease the lives of, and improve outcome in, children with chronic diseases and that may alter the outcome of disease through the regulation of specific genes.

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AREAS OF EMPHASIS

Study the Pathogenesis of Obesity and Potential Interventions to Prevent or Treat Comorbidities

The prevalence rate of obesity is increasing so rapidly that it has been called an epidemic by the Centers for Disease Control and Prevention (1). The National Health and Nutrition Examination Survey (NHANES) III (1988–1994) reported that approximately 14% of children aged 6 to 11 years and 12% of adolescents aged 12 to 17 are overweight. The prevalence of overweight during NHANES II (1976–1980) was 7.6% for children aged 6 to 11 years and 10.9% for 12- to 17-year-old adolescents. Similarly, the Bogalusa Heart Study showed an almost doubling of the prevalence of overweight from 1973–1974 to 1992–1994 independent of changes in height and other covariates. The trend for overweight appeared to be accelerating because larger increases in prevalence were seen during the latter part of the study.

These studies make clear that obesity is one of the most prevalent diseases among children and adolescents in the US. The trend toward an increase in body weight beginning at age 6 years is believed to be related to environmental factors and is neither biologically nor medically desirable. Overweight in adolescents is associated with changes in blood pressure, lipoproteins, and plasma insulin levels. Half of obese children in grade school remained obese as adults and that the risk of obesity in adulthood was at least twice as high for obese children as for nonobese children. Parental obesity has a profound effect on the likelihood that a child will become an obese adult. Obesity in adulthood is associated with increased morbidity and mortality. No reliable method exists to treat obesity, and long-term intervention studies have shown that 80% to 90% of those who achieve weight reduction return to their previous weight. Childhood obesity is associated with other diseases, including type 2 diabetes mellitus, liver and renal disease, and hypertension.

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Research Goals

While intuitively appropriate, weight reduction efforts to date have failed to successfully prevent obesity or sustain weight reduction over the long term. While efforts to reduce weight should continue, other approaches may be beneficial. The pathogenesis of comorbid factors needs to be understood and interventions identified to prevent or treat comorbidities, specifically liver, renal and cardiovascular disease, as well as type 2 diabetes.

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Research Strategies

Studies of basic pathogenesis as well as of pharmacological intervention are needed. Animal models can be used initially, with the most promising therapies evaluated in children in carefully designed randomized controlled studies. A combination of environmental modulation and population-based intervention studies is required, as well as studies of substrate regulation in subsets of obese children.

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Projected Timetable and Funding Requirements

These different strategies can best be accomplished by investigator-initiated grants. Because the proportion of the population that is obese is increasing dramatically, immediate attention is desirable.

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Determine Harmful Effects or Benefits of Dietary Supplements

An understanding of the beneficial and harmful actions of dietary supplements is critical in light of a $21.2 billion industry that targets children (2). Dietary supplements can be considered a form of complementary alternative medicine. These products are “intended to supplement the diet to enhance health” and include vitamins, minerals, amino acids, herbal products or other botanicals, and substances such as enzymes, organ tissues, glandular products and metabolites. Further, a dietary supplement is “not represented as a conventional food or a sole item of a meal or the diet” and is intended for ingestion in the form of a capsule, powder, soft gel, or gelcap. A nutraceutical is a “diet supplement that delivers a concentrated form of a biologically active component of food in a non-food matrix in order to enhance health” (3). An example of a nutraceutical is genistein, which is purified from soybeans and delivered in a pill in dosages greater than can be consumed in soy. Dietary supplements and nutraceuticals are different from functional foods, which are considered to deliver an active ingredient within a food matrix. An example of a functional food is bread or breakfast cereal with added high-dose folic acid. Food additives are substances that enhance flavor or aroma, but not the nutritional value of a food.

Dietary supplements, nutraceuticals and functional foods are designed to supplement the human diet by increasing the intake of bioactive agents that are thought to enhance health and fitness (3). Although some of these products have been used through the ages, their safety and efficaciousness cannot be guaranteed. It should be noted that many important medications (aspirin, atropine and digitalis, to name a few) share a common history with herbs.

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Research Goals

A key priority is to identify currently marketed products that are harmful. In addition, it is important to identify substances in marketed supplements, herbs and nutraceuticals that may have previously undescribed beneficial effects. Potentially beneficial substances should be purified and studied in randomized blinded trials to rigorously evaluate effective.

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Research Strategies

The evaluation of currently marketed products that are potentially harmful is best performed by a governmental agency. The urgency of this need has been demonstrated repeatedly by published accounts of toxicity (4). The identification of substances in marketed products with possible therapeutic benefit can best be achieved by investigator-initiated studies in conjunction with the industries that produce, package and market these products. It is to the industry's advantage to demonstrate the efficacy of these products, and industry can supply the substances in pure form for study.

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Projected Timetable and Funding Requirements

There is a real urgency to evaluate products that may have harmful effects. Activities to identify such products must begin immediately. The evaluation of novel substances in herbs and dietary supplements that may provide therapeutic benefit, if commenced within 1 to 2 years, would likely prove fruitful within 3 to 5 years.

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Evaluate Whether Childhood Nutrition Influences Adult-Onset Disease

Whether early childhood nutrition influences adult health and adult-onset disease is a critical public health question as well as a biological question. Data suggest that the nutritional support provided to premature infants likely has consequences for cognitive development, cardiovascular health, atopic disease, bone formation, blood pressure, low-density lipoprotein cholesterol and proinsulin at 13–16 years. Children and adolescents with high cholesterol levels are more likely than the general population to have high levels as adults. Adequate calcium intake during childhood is necessary for the development of maximal peak bone mass. Increasing peak bone mass may be an important way to reduce the risk of osteoporosis in later adulthood. The risk of an obese child becoming an obese adult is twice as high as for a nonobese child.

Thus, what infants, children and adolescents eat has not only immediate consequences, but likely long-term consequences as well. It is probable that a clearly articulated nutrition policy implemented in childhood would have a positive impact on adult health. However, this type of intervention, while seemingly obvious, is not supported by robust data, and many unanswered questions remain. For example, a substantial number of children with high cholesterol levels become adults with desirable cholesterol levels without intervention. About half of obese adolescents do not become obese adults (5). Calcium requirements may be affected substantially by other factors, including genetic variability and other dietary constituents.

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Research Goals

The hypothesis that early nutrition could have lifetime effects must be tested in tightly designed nutritional intervention studies. These studies needed to be performed in premature infants with special reference to cognitive development. Studies in neonates would permit the development of standardized infant feeding protocols in neonatal intensive care units (NICUs), which will result in positive health outcomes long-term. Similar studies in older children and adolescents will serve to prove or disprove the importance of child health throughout life.

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Research Strategies

An evaluation of feeding practices in NICUs is needed immediately. Current practices are highly individualized and variable among physicians and units in different parts of the country. A nationwide study is recommended, during which protocols can be put in place to test the hypothesis that feeding practices have long-term consequences. Randomized controlled interventional studies of both single nutrients (e.g., calcium or iron) and combinations of nutrients (e.g., calcium plus low levels of sodium) are needed to evaluate the effect of nutrient intake during childhood on adult health.

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Projected Timetable and Funding Requirements

Because of the public health implications of these studies and the long study periods (years) required, it is important that the work commence immediately. Large numbers of study subjects are likely needed to prove causality; therefore, the work could best be performed by a consortium of geographically diverse centers. Depending on the nutrient to be studied and the specific disease, different foundations will be interested in providing support. However, because of the immensity of the probable public health impact, federal funding through grants or contracts administered to the consortium is highly desirable.

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Identify Nutrient-Gene Interactions that Have Therapeutic Potential for Specific Single-Gene and/or Polygenic Disorders

Alteration of gene expression has become a rapidly developing area of research in medicine, particularly in the context of novel therapeutic options. Although current research has focused on the therapeutic benefit of altering gene expression by insertion of genetic material into cells, gene expression can be changed by altering the molecular environment of gene-responsive intracellular elements. Nutrition (food consumption) dynamically alters the cellular environment and serves as a potential stimulus for the alteration of gene expression (6). Thus, the future of nutrition as a therapeutic tool may lie in its potential for influencing gene regulation (7).

The human organism adapts to nutrient perturbations by means of physiological and metabolic responses that are under the influence of genetic control. The mechanisms underlying these responses to nutritional perturbations are poorly understood in humans. Progress in our understanding of nutrient-gene interactions has been slow because the molecular mechanisms controlling gene expression are complex and the direct functional consequence may, in fact, be the effect of nutrient metabolites rather than the nutrient itself.

The physiological importance of the nutritional regulation of gene expression resides in the variety of functional consequences underlying specific clinical considerations. For example, genes may be regulated to better utilize nutrients during periods of scarcity, including up-regulation of nutrient transporters or enzymes that metabolize nutrients. Gene expression may be altered in the context of nutrient abundance and, hence, nutrient storage (8). Nutrients regulate the secretion of hormones to achieve metabolic homeostasis and, therefore, indirectly affect genetic mechanisms responsible for the endocrine control of cellular metabolism. Nutrients within the gut lumen may directly alter epithelial cell gene expression or change primarily luminal flora with secondary effects on tissue gene expression. Finally, nutrients may serve as regulatory factors for gene expression during critical windows of cellular development, resulting in a cascade of differential effects (9).

The fundamental regulation of gene expression by nutrients involves two mechanisms:

A) Molecules, either receptors or enzymes within the cell, must sense or recognize the presence of the nutrient;

B) Once nutrient sensing occurs, this interaction initiates a sequence of molecular events, i.e., signal transduction, which ultimately alters gene transcription or translation.

For example, glucose deficiency leads to the up-regulation of specific glucose transporter proteins. Transporter protein synthesis usually is the consequence of increased transporter messenger ribonucleic acid (mRNA) owing to increased transcription, although other mechanisms have been observed.

The clinical and therapeutic implications of nutrient-gene interactions have been difficult to ascertain in children. An example is total parenteral nutrition, which has profound alterations on the gut. Although much emphasis has been placed on individual nutrients that may be responsible for the maintenance of normal bowel morphology and function, no clear answer has emerged. Indeed, the luminal contents of the gut may prove to dominate the molecular control of gene expression. The more important aspect is the role of nutrients as they affect the luminal contents of the gut. How these mechanisms affect the intestinal cell is not clearly understood.

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Research Goals

It is important to identify the genes that are altered in single-gene or polygenic disorders for which nutritional interventions are likely to have an impact. These disorders include inflammatory bowel disease, diabetes mellitus, cancer, Rett syndrome, and obesity. It is also important to identify the molecular mechanisms of individual gene functions. Studies are needed to determine the susceptibility of specific gene targets to single or multiple nutrient perturbations, e.g., glucose, folate and vitamin A.

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Research Strategies

These goals require a combination of approaches to achieve gene identification and an understanding of gene function. Recommended approaches include basic cell biology research, the development of specific animal (transgenic) models that reflect comparable human abnormalities, and ultimately large-scale multicenter collaborative registries and therapeutic trials that provide the basis for the assessment of favorable clinical and biochemical outcomes in response to individual or multiple nutrient therapies.

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Projected Timetable and Funding Requirements

These initiatives should be started immediately. These research questions should be addressed via multiple funding approaches, including investigator-initiated grants, center grants, industry support, and inter-institutional consortium arrangements.

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Investigate Antecedents, Mechanisms and Long-Term Outcomes of Nutrition in Chronic Disease

Nutritional comorbidities frequently complicate the clinical course of chronic diseases of childhood. The prevalence of nutritional deficiencies and excesses such as growth failure, osteopenia, vitamin or mineral deficiencies or toxicities, and obesity is estimated to range from 30% to 40% in specific intestinal, hepatic, and pancreatic diseases of childhood. The potential scope of nutritional comorbidities is broad; most, if not all, major pediatric disorders are potentially affected. The future of nutrition as a therapeutic tool in chronic childhood illnesses may be in reversing the cellular dysregulation associated with individual chronic diseases and replacing or removing nutrients, or their metabolites, essential to normal cellular function.

Before a healthy nutritional status can be restored and nutritional comorbidities reversed, the mechanisms that precipitate nutritional comorbidities in individual chronic diseases must be identified. These mechanisms may be associated with:

Decreased dietary intake, particularly in conjunction with altered appetite regulation

Perturbations in nutrient metabolism, particularly in relation to the hormonal milieu and substrate utilization

Increased nutrient losses, particularly from the gastrointestinal tract

Increased nutrient requirements in conjunction with cellular dysfunction underlying the disease entity, inflammation, or growth

The pathophysiological factors contributing to these mechanisms have not been elucidated fully. Progress in our understanding of nutritional comorbidities in chronic diseases has been slow because of difficulties in achieving homogeneity of study populations, the possibility of unrecognized nutrient interactions, and the presence of confounding variables associated with various therapeutic regimens.

A greater understanding of nutritional comorbidities in children afflicted with chronic diseases, it is hoped, will enable interruption of the cascade of associated adverse physiological events and improvement in functional clinical outcome. For example, in conditions such as childhood cancer, inflammatory bowel disease, cystic fibrosis, and chronic liver disease requiring transplantation, the presence of nutritional comorbidities may be associated with metabolic, physiological and hormonal perturbations; increased occurrence of infections; and reduced tolerance to pharmacological treatment or surgical intervention (10). Conversely, in some conditions, including cystic fibrosis and inflammatory bowel disease, aggressive nutritional intervention and reversal of nutritional comorbidities may alter the clinical course of disease, reduce pharmacological toxicities, and improve quality of life (11). Thus, a focus on basic, clinical and epidemiologic research is needed to broaden our understanding of the antecedents, mechanisms, and long-term outcomes of nutritional comorbidities associated with chronic diseases of childhood.

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Research Goals

Research goals include:

Identification of the risk factors, such as genetic polymorphisms and critical windows of development, that predispose children to nutritional comorbidities and lend themselves to preventive or delay-of-onset strategies;

Exploration of mechanisms that account for nutritional comorbidities—e.g., appetite regulation in the context of altered dietary intake; the endocrine-metabolic control of nutrient disposal in the context of the underlying cellular dysregulation associated with the chronic disorder; quantitative and qualitative differences in nutrient requirements in the context of impaired cellular metabolism, inflammation, increased nutrient losses and growth; and

Assessment of short- and long-term outcomes based on novel nutritional intervention strategies, e.g., prebiotics and probiotics (12).

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Research Strategies

These research goals require prioritization of chronic diseases of interest, based on frequency of occurrence or the robustness with which potential mechanisms of cellular dysfunction contribute to nutritional comorbidities. Subsequently, studies in this area will require a combination of approaches, including basic cell biology research, the development of specific animal models that reflect comparable human disorders, and ultimately large-scale multicenter collaborative registries and clinical trials.

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Projected Timetable and Funding Requirements

These initiatives should be started immediately. These research questions should be addressed via multiple funding approaches, including investigator-initiated grants, center grants, industry support, and inter-institutional consortium arrangements.

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REFERENCES


2. Metzl JD, Small E, Levine SR, Gershel JC. Creatine use among young athletes. Pediatrics 2001; 108:421–5.

3. Zeisel SH. Regulation of “neutraceuticals.” Science 1999; 285:1853–5.

4. Koutkia P, Chen TC, Holick MF. Vitamin D intoxication associated with an over-the-counter supplement. N Engl J Med 2001; 345: 66–7.

5. Serdula MK, Ivery D, Coates RJ, Freedman DS, Williamson DF, Byers T. Do obese children become obese adults? A review of the literature. Prev Med 1993; 22:167–77.

6. Abumrad NA. The gene-nutrient-gene loop. Curr Opin Clin Nutr Metab Care 2001; 4:407–10.

7. Kim YI. Methylenetetrahydrofolate reductase polymorphisms, folate, and cancer risk: a paradigm of gene-nutrient interactions in carcinogenesis. Nutr Rev 2000; 58:205–9.

8. Perusse L, Bouchard C. Gene-diet interactions in obesity. Am J Clin Nutr 2000; 72(5 suppl):1285–90S.

9. Go VL, Wong DA, Butrum R. Diet, nutrition and cancer prevention: where are we going from here? J Nutr 2001; 131:3121–6S.

10. Shepherd RW, Greer RM, McNaughton SA, Wotton M, Cleghorn GJ. Energy expenditure and the body cell mass in cystic fibrosis. Nutrition 2001; 17:22–5.

11. Phylactos AC, Fasoula IN, Arnaud-Battandier F, Walker-Smith JA, Fell JM. Effect of enteral nutrition on antioxidant enzyme systems and inflammation in paediatric Crohn's disease. Acta Paediatr 2001; 90:883–8.

12. Gupta P, Andrew H, Kirschner BS, Guandalini S. Is lactobacillus GG helpful in children with Crohn's disease? Results of a preliminary, open-label study. J Pediatr Gastroenterol Nutr 2000; 31: 453–7.

© 2002 Lippincott Williams & Wilkins, Inc.

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