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Nutrition research, like most biomedical disciplines, adopted and often uses experimental approaches based on Beadle and Tatum's one gene-one polypeptide hypothesis, thereby reducing biological processes to single reactions or pathways. Systems thinking is needed to understand the complexity of health and disease processes requiring measurements of physiological processes, as well as environmental and social factors, which may alter the expression of genetic information. Analysis of physiological processes with omics technologies to assess systems' responses has only become available over the past decade and remains costly. Studies of environmental and social conditions known to alter health are often not connected to biomedical research. While these facts are widely accepted, developing and conducting comprehensive research programs for health are often beyond financial and human resources of single research groups. We propose a new research program on essential nutrients for optimal underpinning of growth and health (ENOUGH) that will use systems approaches with more comprehensive measurements and biostatistical analysis of the many biological and environmental factors that influence undernutrition. Creating a knowledge base for nutrition and health is a necessary first step toward developing solutions targeted to different populations in diverse social and physical environments for the two billion undernourished people in developed and developing economies.

The development of a chronic, low grade, inflammatory status named "inflammaging" is a major characteristic of ageing, which plays a critical role in the pathogenesis of age-related diseases. Inflammaging is both local and systemic, and a variety of organs and systems contribute inflammatory stimuli that accumulate lifelong. The NU-AGE rationale is that a one year Mediterranean whole diet (considered by UNESCO a heritage of humanity), newly designed to meet the nutritional needs of the elderly, will reduce inflammaging in fully characterized subjects aged 65-79 years of age, and will have systemic beneficial effects on health status (physical and cognitive). Before and after the dietary intervention a comprehensive set of analyses, including omics (transcriptomics, epigenetics, metabolomics and metagenomics) will be performed to identify the underpinning molecular mechanisms. NU-AGE will set up a comprehensive database as a tool for a systems biology approach to inflammaging and nutrition. NU-AGE is highly interdisciplinary, includes leading research centres in Europe on nutrition and ageing, and is complemented by EU multinational food industries and SMEs, interested in the production of functional and enriched/advanced traditional food tailored for the elderly market, and European Federations targeting policy makers and major stakeholders, from consumers to EU Food & Drink Industries., Maa- Ja Elintarviketalouden Tutkimuskeskus => Agriculture and Food Research Center

Aging is a biological process characterized by the progressive functional decline of many interrelated physiological systems. In particular, aging is associated with the development of a systemic state of low-grade chronic inflammation (inflammaging), and with progressive deterioration of metabolic function. Systems biology has helped in identifying the mediators and pathways involved in these phenomena, mainly through the application of high-throughput screening methods, valued for their molecular comprehensiveness. Nevertheless, inflammation and metabolic regulation are dynamical processes whose behavior must be understood at multiple levels of biological organization (molecular, cellular, organ, and system levels) and on multiple time scales. Mathematical modeling of such behavior, with incorporation of mechanistic knowledge on interactions between inflammatory and metabolic mediators, may help in devising nutritional interventions capable of preventing, or ameliorating, the age-associated functional decline of the corresponding systems

Background Resilience or the ability of our body to cope with daily-life challenges has been proposed as a new definition of health, with restoration of homeostasis as target resultant of various physiological stress responses. Challenge models may thus be a sensitive measure to study the body’s health. The objective of this study was to select a dietary challenge model for the assessment of inflammatory resilience. Meals are a challenge to metabolic homeostasis and are suggested to affect inflammatory pathways, yet data in literature are limited and inconsistent. Method The kinetic responses of three different dietary challenges and a water control challenge were assessed on various metabolic and inflammatory markers in 14 healthy males and females using a full cross-over study design. The dietary challenges included glucose (75 g glucose in 300 ml water), lipids (200 ml whipping cream) and a mix of glucose and lipids (same amounts as above), respectively. Blood samples were collected at baseline and at 0.5, 1, 2, 4, 6, 8 and 10 h after consumption of the treatment products. Inflammation (IFN¿, IL-1ß, IL-6, IL-8, IL-10, IL-12p70, TNF-a CRP, ICAM-1, VCAM-1, SAA, E-selectin, P-selectin, thrombomodulin, leukocytes, neutrophils, lymphocytes) and clinical (e.g. glucose, insulin, triglycerides) markers as well as gene expression in blood cells and plasma oxylipin profiles were measured. Results All three dietary challenges induced changes related to metabolic control such as increases in glucose and insulin after the glucose challenge and increases in triglycerides after the lipid challenge. In addition, differences between the challenges were observed for precursor oxylipins and some downstream metabolites including DiHETrE’s and HODE’s. However, none of the dietary challenges induced an acute inflammatory response, except for a modest increase in circulating leukocyte numbers after the glucose and mix challenges. Furthermore, subtle, yet statistically significant incre

Nutrigenomics is the science of analyzing and understanding gene-nutrient interactions, which because of the genetic heterogeneity, varying degrees of interaction among gene products, and the environmental diversity is a complex science. Although much knowledge of human diversity has been accumulated, estimates suggest that similar to 90% of genetic variation has not yet been characterized. Identification of the DNA sequence variants that contribute to nutrition-related disease risk is essential for developing a better understanding of the complex causes of disease in humans, including nutrition-related disease. The Human Variome Project (HVP; http://www.humanvariomeproject.org) is an international effort to systematically identify genes, their mutations, and their variants associated with phenotypic variability and indications of human disease or phenotype. Since nutrigenomic research uses genetic information in the design and analysis of experiments, the HVP is an essential collaborator for ongoing studies of gene-nutrient interactions. With the advent of next generation sequencing methodologies and the understanding of the undiscovered variation in human genomes, the nutrigenomic community will be generating novel sequence data and results. The guidelines and practices of the HVP can guide and harmonize these efforts.

Approaches through which reference values for micronutrients are derived, as well as the reference values themselves, vary considerably across countries. Harmonisation is needed to improve nutrition policy and public health strategies. The EURRECA (EURopean micronutrient RECommendations Aligned, http://www.eurreca.org) Network of Excellence is developing generic tools for systematically establishing and updating micronutrient reference values or recommendations. Different types of instruments (including best practice guidelines, interlinked web pages, online databases and decision trees) have been identified. The first set of instruments is for training purposes and includes mainly interactive digital learning materials. The second set of instruments comprises collection and interlinkage of diverse information sources that have widely varying contents and purposes. In general, these sources are collections of existing information. The purpose of the majority of these information sources is to provide guidance on best practice for use in a wider scientific community or for users and stakeholders of reference values. The third set of instruments includes decision trees and frameworks. The purpose of these tools is to guide non-scientists in decision making based on scientific evidence. This platform of instruments will, in particular in Central and Eastern European countries, contribute to future capacity-building development in nutrition. The use of these tools by the scientific community, the European Food Safety Authority, bodies responsible for setting national nutrient requirements and others should ultimately help to align nutrient-based recommendations across Europe. Therefore, EURRECA can contribute towards nutrition policy development and public health strategies. European Journal of Clinical Nutrition (2010) 64, S26-S31; doi:10.1038/ejcn.2010.206

The challenge of modern nutrition and health research is to identify food-based strategies promoting life-long optimal health and well-being. This research is complex because it exploits a multitude of bioactive compounds acting on an extensive network of interacting processes. Whereas nutrition research can profit enormously from the revolution in ‘omics’ technologies, it has discipline-specific requirements for analytical and bioinformatic procedures. In addition to measurements of the parameters of interest (measures of health), extensive description of the subjects of study and foods or diets consumed is central for describing the nutritional phenotype. We propose and pursue an infrastructural activity of constructing the “Nutritional Phenotype database” (dbNP). When fully developed, dbNP will be a research and collaboration tool and a publicly available data and knowledge repository. Creation and implementation of the dbNP will maximize benefits to the research community by enabling integration and interrogation of data from multiple studies, from different research groups, different countries and different-omics levels. The dbNP is designed to facilitate storage of biologically relevant, pre-processed-omics data, as well as study descriptive and study participant phenotype data. It is also important to enable the combination of this information at different levels (e.g. to facilitate linkage of data describing participant phenotype, genotype and food intake with information on study design and-omics measurements, and to combine all of this with existing knowledge). The biological information stored in the database (i.e. genetics, transcriptomics, proteomics, biomarkers, metabolomics, functional assays, food intake and food composition) is tailored to nutrition research and embedded in an environment of standard procedures and protocols, annotations, modular data-basing, networking and integrated bioinformatics. The dbNP is an evolving enterprise, which is only

Background- Excessive exposure to dietary fats is an important factor in the initiation of obesity and metabolic syndrome associated pathologies. The cellular processes associated with the onset and progression of diet-induced metabolic syndrome are insufficiently understood. Principal Findings - To identify the mechanisms underlying the pathological changes associated with short and long-term exposure to excess dietary fat, hepatic gene expression of ApoE3Leiden mice fed chow and two types of high-fat (HF) diets was monitored using microarrays during a 16-week period. A functional characterization of 1663 HF-responsive genes reveals perturbations in lipid, cholesterol and oxidative metabolism, immune and inflammatory responses and stress-related pathways. The major changes in gene expression take place during the early (day 3) and late (week 12) phases of HF feeding. This is also associated with characteristic opposite regulation of many HF-affected pathways between these two phases. The most prominent switch occurs in the expression of inflammatory/immune pathways (early activation, late repression) and lipogenic/adipogenic pathways (early repression, late activation). Transcriptional network analysis identifies NF-¿B, NEMO, Akt, PPAR¿ and SREBP1 as the key controllers of these processes and suggests that direct regulatory interactions between these factors may govern the transition from early (stressed, inflammatory) to late (pathological, steatotic) hepatic adaptation to HF feeding. This transition observed by hepatic gene expression analysis is confirmed by expression of inflammatory proteins in plasma and the late increase in hepatic triglyceride content. In addition, the genes most predictive of fat accumulation in liver during 16-week high-fat feeding period are uncovered by regression analysis of hepatic gene expression and triglyceride levels. Conclusions - The transition from an inflammatory to a steatotic transcriptional program, possibly driven by the r

Background: The application of high-throughput genomic tools in nutrition research is a widespread practice. However, it is becoming increasingly clear that the outcome of individual expression studies is insufficient for the comprehensive understanding of such a complex field. Currently, the availability of the large amounts of expression data in public repositories has opened up new challenges on microarray data analyses. We have focused on PPAR alpha, a ligand-activated transcription factor functioning as fatty acid sensor controlling the gene expression regulation of a large set of genes in various metabolic organs such as liver, small intestine or heart. The function of PPAR alpha is strictly connected to the function of its target genes and, although many of these have already been identified, major elements of its physiological function remain to be uncovered. To further investigate the function of PPAR alpha, we have applied a cross-species meta-analysis approach to integrate sixteen microarray datasets studying high fat diet and PPAR alpha signal perturbations in different organisms. Results: We identified 164 genes (MDEGs) that were differentially expressed in a constant way in response to a high fat diet or to perturbations in PPARs signalling. In particular, we found five genes in yeast which were highly conserved and homologous of PPAR alpha targets in mammals, potential candidates to be used as models for the equivalent mammalian genes. Moreover, a screening of the MDEGs for all known transcription factor binding sites and the comparison with a human genome-wide screening of Peroxisome Proliferating Response Elements (PPRE), enabled us to identify, 20 new potential candidate genes that show, both binding site, both change in expression in the condition studied. Lastly, we found a non random localization of the differentially expressed genes in the genome. Conclusion: The results presented are potentially of great interest to resume the currently availa

In quantifying the beneficial effect of dietary interventions in healthy subjects, nutrition research meets a number of new challenges. Inter individual variation in biomarker values often is larger than the effect related to the intervention. Healthy subjects have a remarkable capacity to maintain homeostasis, both through direct metabolic regulation, metabolic compensation of altered diets, and effective defence and repair mechanisms in oxidative and inflammatory stress. Processes involved in these regulatory activities essentially different from processes involved in early onset of diet related diseases. So, new concepts and approaches are needed to better quantify the subtle effects possibly achieved by dietary interventions in healthy subjects. Apart from quantification of the genotype and food intake (these are discussed in separate reviews in this series), four major areas of innovation are discussed: the biomarker profile concept, perturbation of homeostasis combined with omics analysis, imaging, modelling and fluxes. All of these areas contribute to a better understanding and quantification of the nutritional phenotype.

Personalised, genotype-based nutrition is a concept that links genotyping with specific nutritional advice in order to improve the prevention of nutrition-associated, chronic diseases. This review describes the current scientific basis of the concept and discusses its problems. There is convincing evidence that variant genes may indeed determine the biological response to nutrients. The effects of single-gene variants on risk or risk factor levels of a complex disease are, however, usually small and sometimes inconsistent. Thus, information on the effects of combinations of relevant gene variants appears to be required in order to improve the predictive precision of the genetic information. Furthermore, very few associations between genotype and response have been tested for causality in human intervention studies, and little is known about potential adverse effects of a genotype-derived intervention. These issues need to be addressed before genotyping can become an acceptable method to guide nutritional recommendations.

Background: Application of transcriptomics technology in human nutrition intervention studies would allow for genome-wide screening of the effects of specific diets or nutrients and result in biomarker profiles. Objective: The aim was to evaluate the potential of gene expression profiling in blood cells collected in a human intervention study that investigated the effect of a high-carbohydrate (HC) or a high-protein (HP) breakfast on satiety. Design: Blood samples were taken from 8 healthy men before and 2 It after consumption of an HP or an HC breakfast. Both breakfasts contained acetaminophen for measuring the gastric emptying rate. Analysis of the transcriptome data focused on the effects of the HP or HC breakfast and of acetaminophen on blood leukocyte gene expression profiles. Results: Breakfast consumption resulted in differentially expressed genes, 317 for the HC breakfast and 919 for the HP breakfast. Immune response and signal transduction, specifically T cell receptor signaling and nuclear transcription factor kappa B signaling, were the overrepresented functional groups in the set of 141 genes that were differentially expressed in response to both breakfasts. Consumption of the HC breakfast resulted in differential expression of glycogen metabolism genes, and consumption of the HP breakfast resulted in differential expression of genes involved in protein biosynthesis. Conclusions: Gene expression changes in blood leukocytes corresponded with and may be related to the difference in macronutrient content of the breakfast, meal consumption as such, and acetaminophen exposure. This study illustrates the potential of gene expression profiling in blood to study the effects of dietary exposure in human intervention studies.

The interaction between the human body and nutrition is an extremely complex process involving multi-organ physiology with molecular mechanisms on all levels of regulation ( genes, gene expression, proteins, metabolites). Only with the recent technology push have nutritional scientists been able to address this complexity. Both the challenges and promises that are offered by the merge of 'biomics' technologies and mechanistic nutrition research are huge, but will eventually evolve in a new nutrition research concept: nutritional systems biology. This review describes the principles and technologies involved in this merge. Using nutrition research examples, including gene expression modulation by carbohydrates and fatty acids, this review discusses applications as well as limitations of genomics, transcriptomics, proteomics, metabolomics, and systems biology. Furthermore, reference is made to gene polymorphisms that underlie individual differences in nutrient utilization, resulting in, e. g., different susceptibility to develop obesity. Copyright (c) 2005 S. Karger AG, Basel/ ILSI Europe, Brussels.

Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene-nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient-genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countries

Specific food compounds, especially from fruits and vegetables, may protect against development of colon cancer. In this thesis effects and mechanisms of various phytochemicals in relation to colon cancer prevention were studied through application of large-scale gene expression profiling. Expression measurement of thousands of genes can yield a more complete and in-depth insight into the mode of action of the compounds. Effects of quercetin (a flavonoid present in e.g. apples and onions), curcumin (a spice used e.g. in curries) and resveratrol (present e.g. in grapes) were studied in cultured colon cancer cells. These studies confirmed some hypothesized mechanisms of action of these compounds (e.g. effects on cell cycle) and yielded new interesting leads (e.g. effects on proteasome genes, DNA repair genes, tubulin genes). In addition, expression profiles of a panel of 14 human cell lines derived from colonic tissue were compared and related to expression profiles of human colon biopsies from normal and tumor tissue. Changes in expression profiles of a subset of colon cancer-specific genes (as a biomarker set) in cultured colon cancer cells could be useful to translate in vitro results to the in vivo situation. In addition to the in vitro studies, effects of wheat bran, curcumin,rutinand benzyl isothiocyanate on colon carcinogenesis were studied in a rat model. Wheat bran and curcuminshoweda protective effect (lower tumor multiplicity after 8 months compared to the control group). Expression profiles of differentially expressed genes in small intestinal tissue at intermediate time points were predictive of colon tumor development at the end of the study, confirming a correlation between effects in small intestine and colon. In summary, the studies in this thesis demonstrate the potential of large-scale expression profiling in nutrition studies. These studies also demonstrated that although the technological advancements in large-scale gene expression analysis allow

Toxicogenomics studies toxic effects of substances on organisms in relation to the composition of the genome. It applies the functional genomics technologies transcriptomics, proteomics and metabolomics that determine expression of the genes, proteins and metabolites in a sample. These methods could facilitate toxicological research and eventually, toxicogenomics could improve human health risk assessment. This thesis evaluated applications of toxicogenomics, especially to investigate mechanisms of toxicity, to obtain new toxicity markers and to assess toxicity of mixtures.In the first studies, protein and gene expression were characterised in livers of rats treated with bromobenzene, well-known to cause liver damage. The metabolite contents of plasma and urine were also measured. Many changes were found related to biotransformation, glutathione metabolism, oxidative stress and to unexpectedly involved processes like cholesterol, fatty acid and protein metabolism. The studies enabled to identify crucial events in the mechanisms of hepatotoxic by bromobenzene.The specificity of bromobenzene-induced liver gene expression changes was delineated by comparison with published effects of high doses of acetaminophen (paracetamol), that also caused liver necrosis. Subsequently, effects of abundant chemicals benzene and trichloroethylene, not typical liver toxicants, were analysed. Benzene primarily causes hematotoxicity and trichloroethylene nephrotoxicity. However, both compounds induced liver weight. They were also found to modulate liver gene expression. Effects were related to biotransformation, fatty acid metabolism and other processes. Benzene, trichloroethylene, bromobenzene and acetaminohen induced several common and many specific changes in liver gene expression.Transcriptomics, proteomics and metabolomics were applied to obtain new markers for identification of liver toxicity at early stages and low exposure levels. Potential markers were correlated to the liver da

Background: Curcumin is a spice and a coloring food compound with a promising role in colon cancer prevention. Curcumin protects against development of colon tumors in rats treated with a colon carcinogen, in colon cancer cells curcumin can inhibit cell proliferation and induce apoptosis, it is an anti-oxidant and it can act as an anti-inflammatory agent. The aim of this study was to elucidate mechanisms and effect of curcumin in colon cancer cells using gene expression profiling. Methods: Gene expression changes in response to curcumin exposure were studied in two human colon cancer cell lines, using cDNA microarrays with four thousand human genes. HT29 cells were exposed to two different concentrations of curcumin and gene expression changes were followed in time (3, 6, 12, 24 and 48 hours). Gene expression changes after short-term exposure (3 or 6 hours) to curcumin were also studied in a second cell type, Caco-2 cells. Results: Gene expression changes (>1.5-fold) were found at all time points. HT29 cells were more sensitive to curcumin than Caco-2 cells. Early response genes were involved in cell cycle, signal transduction, DNA repair, gene transcription, cell adhesion and xenobiotic metabolism. In HT29 cells curcumin modulated a number of cell cycle genes of which several have a role in transition through the G2/M phase. This corresponded to a cell cycle arrest in the G2/M phase as was observed by flow cytometry. Functional groups with a similar expression profile included genes involved in phase-II metabolism that were induced by curcumin after 12 and 24 hours. Expression of some cytochrome P450 genes was downregulated by curcumin in HT29 and Caco-2 cells. In addition, curcumin affected expression of metallothionein genes, tubulin genes, p53 and other genes involved in colon carcinogenesis. Conclusions: This study has extended knowledge on pathways or processes already reported to be affected by curcumin (cell cycle arrest, phase-II genes). Moreover, potential

In vivo studies have demonstrated that high fat fish oil (HFFO) diets with high levels ofn-3 polyunsaturated fatty acids (PUFAs) such as eicosapentaenoic acid (EPA; 20:5n-3) can inhibit the formation of chemically-induced colon tumors during both the initiation and post-initiation phases of colorectal carcinogenesis compared with high fat corn oil (HFCO) diets which are rich in n-6 PUFAs such as linoleic acid (LA: 18:2n-6).Studies described in this thesis show that HFFO diets also protect against the initiation of aberrant crypt foci (ACF; precursor lesions of colon cancer) in F344 rats compared to HFCO diets. Furthermore, EPA also inhibited the proliferation of human colon adenocarcinoma Caco-2 cells compared to LA. The mechanism responsible for the inhibitory effects of n-3 PUFAs such as EPA on colorectal tumors may partly be related to inhibition of PGE 2 synthesis from arachidonic acid (AA; 20:4n-6). Plasma levels of PGE 2 were indeed lower in HFFO fed rats compared to HFCO fed rats. However, reductions in PGE 2 synthesis by EPA compared to AA in Caco-2 cells did not lead to differential effects on cell proliferation, which suggests that PGE 2 is not directly involved in regulation of cell proliferation in colon cancer cells by n-6 and n-3 PUFAs.Our results suggest that lipid peroxidation-induced oxidative stress might be an important mechanism by which n-3 PUFAs possess anti-carcinogenic effects. This is supported by the fact that HFFO diets with a high amount of EPA increased the amount of lipid peroxidation in F344 rats compared to HFCO diets with a high amount of LA. Levels of malondialdehyde, which is an endproduct of lipid peroxidation were also increased after incubation of Caco-2 cells with EPA. Furthermore, transcription of genes involved in oxidative stress is increased in HFFO fed rats, whereas addition of antioxidants diminishes the anticancer effects of n-3 PUFAs in Caco-2 cells, which also suggests that oxidation of n-3 PUFAs underlies their antica