Nutrition and Gene Expression

Altering the expression of genes has become a rapidly evolving area of research in medicine. The realization that gene expression is important in a wide range of diseases, and not just in inherited disease, has resulted in recognition of the whole fi eld of gene expression as one that may bring new therapeutic options. Although more recent attention has focused on the benefi ts of altering gene expression by inserting new genetic material into cells by a variety of vectors, the expression of genes can also be altered by other means, most notably by changing the molecular environment that cells inhabit. Utilizing the natural responses of a cell to changes in its surroundings offers a new and amenable way to alter the expression of its genes. Many ways of altering these surroundings can be proposed, but no single act alters the environment of the cells of the body more than the ingestion of food. Thus, the future of nutrition as a therapeutic tool may lie in its potential for infl uencing gene regulation. This chapter will examine this emerging fi eld and will lay down some concepts that may prove useful in establishing the scientifi c basis from which future treatments may develop. The survival of a child to reproductive age and beyond requires an ability to respond to external demands. Every organ in the body is attuned to this need. Many organ systems have two levels of response to external changes. There is a rapid response, often occurring within seconds of a new stimulus, for example, contraction of muscle fi bers following a neuronal impulse or the breakdown of glycogen by the liver during hypoglycemia. Such responses do not involve changes in gene expression. The cells maintain themselves in a state of readiness, responding rapidly to external stimuli by altering protein/ion activity. Behind this immediate response, there lie other slower, but more lasting, responses that require genetic control. For example, exercise on a regular basis not only leads to muscle mass increase, but change in activity of the attendant enzymes that serve the increased metabolic need also occurs. Similarly, regular exposure of the liver to drugs induces the expression of enzymes that catalyze their breakdown. There are few external stimuli on a child more important than his or her nutritional environment. The metabolic processes underlying the rapid response of cells to nutritional variations have long been documented in humans and other mammals. However, the mechanisms whereby gene expression changes in response to nutritional stimuli is still poorly understood in humans or indeed in any multiorgan animal. This is, at fi rst, surprising because in bacteria, the study of nutritional changes led to our understanding of some of the most fundamental mechanisms of gene expression. The elucidation of the induction of proteins that transport and hydrolyze lactose (the lac operon) after adding lactose to bacterial culture media was the fi rst examination of any form of gene regulation. These observations spawned an explosion of research in other regulatory genes in bacteria and in unicellular, eukaryotic organisms such as yeast. The upregulation of the bacterial genes that handle tryptophan when this amino acid is scarce (the trp operon) has become another well-understood example of nutrient–gene interaction. Progress in the study of nutrient–gene interaction in eukaryotic cells has been slower for two main reasons. First, the molecular mechanisms controlling gene expression are more complex than in bacteria, and second, it is more diffi cult to identify the metabolites of nutrients that may be responsible for inducing such changes. This review will therefore cover some of the major advances in the study of nutrition and gene expression in the human and, where necessary, in other mammals. Nutritional changes ultimately impinge on most cells in the body; however, it is the epithelium of the gastrointestinal (GI) tract that fi rst encounters any variation in nutrient intake. Much of this chapter will therefore concentrate on how nutritional factors can alter the expression of genes in intestinal epithelial cells. The relevance of nutrient–gene interactions to human physiology will also be stressed. Finally, because manipulating nutritional intake may be a way of treating disease in children, the review will discuss nutritional therapy in childhood in the light of its effects on gene expression.