U.S. Department of Health and Human Services

Connecting Food, Genes, and Rare Metabolic Diseases

​Researchers have mapped out an intricate network of genes that connect metabolism, responses to different foods, and rare metabolic diseases in a study of tiny worms. Seeking to understand the effects of different diets on gene activity, the research team selected a model organism that would enable them to carry out experiments not possible in humans. With a miniature digestive system, a transparent body, and a genome readily amenable to manipulation, the small (one millimeter) worm, C. elegans, affords numerous advantages for discovering genes that can then be analyzed in people. Worms will also eat different types of food in the laboratory, allowing examination of responses to different diets. As a starting point for their study, the researchers found a gene with activity that ramped up or diminished depending upon what the worms ate; this gene appears to be involved in breaking down certain amino acids, which are components of proteins. They attached this gene to a luorescent marker that, relecting the gene’s activity, would glow to a greater or lesser extent based on the type of food eaten. Using luorescence as a dietary sensor (visible through the transparent worms), along with other experimental techniques, the researchers were able to identify over 180 other genes that worked with the irst one in a vast network to respond to dietary nutrients and other aspects of metabolism. Some of these genes encode enzymes important in breaking down various components of food, and some of the genes appear regulatory in nature, modulating the extent to which other genes are activated or shut down. Applying their new knowledge to gain insight into human metabolism, the researchers found that many of the worm genes had counterparts in humans. This network may thus mirror similar interconnections among human genes, elucidating pathways by which the body senses different dietary nutrients or other metabolic signals, and modulates gene activity to be able to digest and process the nutrients or respond in other ways as needed. Moreover, several of these human genes are known to be associated with rare diseases. Collectively referred to as inborn diseases of amino acid metabolism, these diseases are caused by mutations in the genes and are marked by incomplete breakdown of certain amino acids; treatments involve speciic dietary modiications. Thus, in addition to advancing understanding of metabolism and response to diet, this study may also lead to new avenues for therapeutic development to improve the health of people with inborn metabolic diseases.

Watson E, MacNeil LT, Arda HE, Zhu LJ, and Walhout AJM.
Integration of metabolic and gene regulatory networks
modulates the C. elegans dietary response. Cell 153:253­
266, 2013.