HOW CAN THE METABOLOME BE USEFUL?
One very important area is the metabolome, which is the collection of all metabolites. These are both synthesized by our bodies and obtained from our food or other sources (e.g., our microbiome, discussed later). Although clearly very important for virtually all human diseases, the metabolome is the least studied of the various ‘omes, because, as of yet, no technology has been devised to capture the totality of its complexity in one single assay. Moreover, for the metabolite signatures captured using current methods, only less than half of them can be precisely matched to the existing databases. We do not even know how large a person’s metabolome is, though estimates have ranged from a few thousand to a few tens of thousands of molecules.
The metabolome is closely linked to many diseases. In cancer, for instance, the metabolism of solid tumors differs from that of normal tissues in that there is a much higher reliance on glycolysis, which produces lactate, instead of aerobic respiration for energy generation. Indeed, many cancer mutations fall into metabolic enzymes, which affect energy metabolism. For example, the Krebs cycle genes fumarate hydratase (FH) and succinate dehydrogenase (SDH) are mutated in a several cancers as are the IDH1 and IDH2 genes, which affect both metabolism and DNA methylation status and are mutated in many different cancers.
Thus far, the study of metabolomics in disease is in its infancy and of the disease associations that have been made, most involve only individual metabolites. For example, high iron is associated with hemochromatosis and HHR mutations. Similarly, low levels of folic acid have been associated with birth defects (neural tube malformations); consequently, it is recommended that women take folic acid supplements to reduce the chances of having children with these defects. One exception to the study of individual metabolites is type 2 diabetes, in which both elevated levels of several branched chain amino acids and amino acyl carnitines have been reported. These changes often happen gradually from a low-grade insulin-resistance state to the severe case of diabetes ketoacidosis. Thus, it is likely that identification of metabolites as biomarkers, especially a panel of compounds, could significantly assist early diagnosis and prevention of both congenital and age-related chronic diseases.
Our understanding of metabolomics, personal differences, and human disease will likely evolve as the study of metabolomics becomes more widespread. In particular, it is well known that people metabolize different molecules differently. For example, processing of folic acid can vary up to fivefold among different people, suggesting that women may need very different levels of folic acid supplementation during pregnancy. Furthermore, because many of the enzymes that metabolize drugs and other environmental compounds normally process metabolites, it is likely that our metabolites and requirements will vary greatly among different people. This is already well known for alcohol metabolism, in which genetic variants in key genes (e.g., ADH genes involved in alcohol breakdown) affect differences in alcohol metabolism and its effects on people. As our understanding of what constitutes a healthy metabolism materializes, it is easy to envision a future in which people will have their food intake “personalized” through food recommendations and supplements to enhance their health. Furthermore, a better understanding and application of the drug metabolism in individuals will help improve clinical outcome and optimal drug dosing.