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Tools to understand nutrition

12.07.2007

Traditionally, nutritional science has focused largely on nutritional deficiencies and their impact on health and disease. Over the past few decades, research emphasis has gradually shifted to the relationship between (over)-nutrition and chronic diseases, including cancer, obesity, cardiovascular disease, and diabetes. Alongside, there has been growing interest in the molecular mechanisms underlying the beneficial or adverse effects of foods and food components. More recently, driven by the exciting progress in genomics-related technologies, unique possibilities have emerged to investigate the genome-wide effects of nutrients at the molecular level. This research field, which combines molecular nutrition with genomics, is called nutrigenomics. It is widely recognised that nutrigenomics has the potential to increase our understanding of how nutrition influences metabolic pathways and homeostasis, how this regulation is disturbed in a diet-related disease and to what extent individual genotypes contribute to such diseases.

A search for “Nutrigenomics” on the Internet will bring up results such as “personalised nutrition” and “give me your genotype and I will give you your personalised dietary advice”. These outcomes have no connection with academic research and are mainly run by small companies that hope to sell their expensive kits. Many researchers have become more realistic in their promises. A similar search on Pubmed brings up greater numbers of research papers, with a balance between review and opinion papers, illustrating overall that nutrigenomics research has become more mature and successful through the use of new tools that help us to more thoroughly understand nutrition. However, the challenges are not minor. Nutritional research, including nutrigenomics, needs to take into account specific problems inherent to nutritional interventions. The rather small deviations from homeostasis that characterise the early phase of nutrition-related diseases, and the complexity and variability of foods in general, are examples for this. The body has to handle a variety of nutrients at the same time, each of which can have numerous targets with different affinities and specificities. This contrasts starkly with pharmacology, where single agents are used at low concentrations and act with relatively high affinity and selectivity for a limited number of biological targets. Furthermore, nutritional research dealing with healthy human volunteers is limited by being less invasive then medical research in collecting biological samples. With rare exceptions, this mainly allows for the collection of urine, blood and maybe muscle and adipose tissue biopsies.
Because of these limitations and complexity and the differing robustness of genomics tools (genotyping >> transcriptomics >> proteomics > metabolomics) it is of outmost importance in nutrigenomics to separate the important but complex research problems into small and feasible projects.

Model systems

This requires simplification of model systems in order to obtain accurate and clear answers to the research questions that are being addressed. A fruitful strategy is to borrow methods that are well established in medical or pharmacological research but are rather new in the field of nutritional research. For example, in analogy to pharmacology, nutrients such as fatty acids can be considered as signaling molecules that are recognised by specific cellular sensing mechanisms such as certain transcription factors belonging to the nuclear hormone receptor superfamily. Since the property that allows nutrients to activate specific signaling pathways is carried in their molecular structure, small changes in structure can have a profound influence on exactly which sensor pathways are activated.
Nutrigenomics is research that cannot be performed by individual researchers. Instead, it is currently performed in larger national or international research consortia such as the Dutch Nutrigenomics Consortium (www.nutrigenomicsconsortium.nl) or the EU Network of Excellence NUGO (www.nugo.com). A single nutrigenomics experiment can generate an enormous amount of data, in particular if whole genome microarrays are used – available from a number of commercial suppliers. Nutrigenomics researchers have to address the management and storage of quite different types of data derived from the various technological platforms used and the development and application of new algorithms. A robust research hypothesis and study design will help to ensure the research question is adequately addressed by the experimental design (avoiding the so-called ‘fishing experiments’). The use of adequate transgenic mouse models for functional genomics significantly enhances the success of the experiment and should be employed wherever possible. The most challenging part of the process occurs after the array data are obtained, when the data must be interpreted in terms of its biological significance. Several commercial (e.g. Ingenuity, Metacore or Genomatrix) and non-commercial tools (GSEA, Genmapp) have been developed that assist with the extraction of significantly altered genes and the visualisation of altered pathways or related networks.

Role of transcriptomics

As a paradigm for the efficient use of microarrays in nutrition research we have used the analysis of genes that are regulated by peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated transcription factors that mediate the effect of unsaturated fatty acids and certain drugs on gene expression. Physiologically, they act as fatty acid sensors in metabolic active organs, regulating a wide range of pathways and allowing cells to modulate their function and metabolic capacity and flexibility. We have used state-of-the-art microarray analysis of organ samples from transgenes and intervention with highly specific PPAR-ligands or fatty acids that allows for the characterisation and comparison of organ-specific PPAR-related transcriptomes. Such “organ transcriptome mapping” allows a comprehensive characterisation of whole-body biology that is under the control of PPARs that point to its physiological relevance. We have identified around 1,000 to 4,000 genes (depending on the organ) that are regulated in a PPARa-dependent manner. This demonstrates the broad physio­logical impact of these fatty acid sensors and their relevance for nutrition, allowing organs such as the liver, small intestine, heart or adipose tissue to control nutrient handling and, at the same time, to modulate inflammatory responses.

Nutrition and disease

Another important aim of current research is to study genome-wide influences of nutrition in the genesis of common diseases such as metabolic syndrome, the collection of phenotypes combining inflammation, metabolic stress, insulin resistance, and diabetes. This goal is rather ambitious but based on the idea that nutrition should focus primarily on health and disease prevention and be complementary to pharmacological therapy, which targets the pathophysiological aspects of disease. To realise this goal, new genomics-based phenotypical biomarkers are needed that allow early detection of the onset of disease or, ideally, the pre-disease state of the metabolic syndrome, a condition called metabolic stress. To approach this complex condition, mole­cular nutrition research on organ-specific dietary response patterns using transgenic and knock-out mouse models is combined with genomic technologies such as comprehensive microarray analysis or meta­bolome analysis e.g. focusing on the broad class of lipids (“lipidome”). On a genomic level, these molecular changes serve as dietary “signatures” or fingerprints that can precisely annotate the phenotype allowing comprehensive phenotyping, particularly under conditions of metabolic stress, early phases of organ-specific insulin resistance and decreased metabolic flexibility.
Nutrigenomics offers exciting opportunities to revolutionise and advance nutrition research. We have to put all our efforts into the development of an extensive research foundation on a national and international level. There is no alternative, as further developments in nutrition and food development are impossible without first exploring the mechanisms underlying nutrition. Can foods be tailored to promote the health and wellbeing of groups in the population identified on the basis of their individual genomes? The potential is there but it is important to take a reality check on a regular basis. What can we achieve within the scope of the expertise and techniques that are available to us now and in the near future? We must continue to put all our efforts into gaining a thorough understanding of how nutrients interact with the human genome at a molecular level. To be able to use genetic blueprints or genotypes in dietary prevention of disease, we must first identify the mechanisms driving the connection between diet and the outward manifestation of our genes, our phenotype.

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