2. Human Nutrigenomics

A. PBMCs as biomarkers to access metabolic health (Dr. Lydia Afman)

   In recent years our group was pioniering to demonstrate that PBMCs can reflect metabolic changes such as fasting or caloric restriction. More remarkably, PBMCs can mirror changes in nutritional status, both in short and long term intervention, even after modifying the type of fatty acid type, only. We also observed that a specific nutritional intervention could result in an anti-inflammatory transcriptional blood cell profile potentially reflecting a more “healthier” phenotype. Therefore PBMCs are excellent candidate cells for the identification of biomarkers for health and we currently are further exploring this. In addition, PBMCs show great potential for product evaluation with consecutive health claims. We currently setting up a human PBMC phenotype DB that is related to this research activity and allows structured exploitation of its results. This PBMC database is indispensable for “blood” omics-based comprehensive phenotyping for sensitive diagnostics after low stress challenges. It contains numerous datasets from several well-controlled human intervention studies. These studies are performed in different study populations varying from healthy young, middle aged and elderly men and women, to overweight subjects with elevated risks and patients with the metabolic syndrome. The database covers nutritional studies involving acute (hours) and chronic (month) exposures. Importantly, it provides a unique opportunity for expansion through sampling from ongoing trials and existing, well-phenotyped cohorts and correlating the results to the existing data. In current human dietary intervention studies  PBMC transcriptomics will be performed in a highly standardized way (samples will be taken from each person before and after a nutritional challenge or a well-controlled dietary intervention). These datasets are analyzed and mined on the background of the PBMC DB data sets and will be linked to relevant other functional or phenotype measurements.

B. Role of metabolic plasticity for optimizing human health (Dr. Lydia Afman)

C. Nutritional Science 2.0 (Prof. Michael Müller)

3. Nutritional Systems Biology

A. Systems Biology of Fatty Acid Homeostasis (Dr. Guido Hooiveld)

B. The Intestine as Gatekeeper (Prof. Michael Müller)

   The intestine serves as a primary gatekeeper at the physical interface between body and diet. It is not only an important organ for efficient absorption and metabolic processing of nutrients, but mucosal tissues in the small intestine are also responsible for sensing of luminal contents that are modulated by the diet. As a result of this sensing, the intestine secretes signaling molecules, such as gut hormones and pro- and anti-inflammatory cytokines, to which liver, muscle, adipose tissue and the systemic immune system might respond by modulating their functionality to maintain homeostatic control. Importantly, it is increasingly recognized that the complex microbial population present in the human intestine plays a prominent role in human health. We have systematically “sliced” the small intestine of mice to sample intestinal cell scrapings (supported by additional laser capture microdissection analysis) and intestinal luminal content and performed microarray, metabolome and metagenome analysis. The data is used in collaboration with partners of the Wageningen Center for Systems Biology to reconstruct in silico the intestine gatekeeper function in order to analyze effects of foods (nutritional challenges such as low fat or high fat) on microbiota (metagenomics) and host responses in time (hours, days) and space (crypt-villus, jejunum to ileum). 

4. Nutrigenomics of Aging

The role of epigenetics in the process of ageing (Dr. Wilma Steegenga)

Aging is a complex biological process occurring at molecular, cellular and organismal level. As a consequence, the aging body shows a declining ability to respond to stress, increasing homeostatic imbalance and an increasing incidence of chronic, ageing-related diseases. An overwhelming body of evidence indicates that changes in the epigenetic state of the genome play a causal role in the aging process. Within the large EU collaborative project IDEAL (Integrated research on DEvelopmental determinants of Aging and Longevity). We are aiming to the improve the phenotypic plasticity at advanced age by exposing mice to a diet strongly variable in energy and fat content. After life-long exposure to either the variable diet or a control diet containing a constant energy and fat content the capacity of the system will be challenged prior to sacrifice. Transcriptomics analysis will be carried out to compare the capacity of liver isolated from mice fed either the variable or the constant diet to respond to the specific challenge. Genes showing differential gene expression between the groups of mice will be identified and pathway analysis will be applied to determine the biological changes induced by the diets. Furthermore, on the identified genes DNA methylation, histone modification and microRNA analysis will be carried out to determine whether epigenetic modifications are the underlying mechanism responsible for the observed changes in gene expression. Within the IDEAL project our data will be linked to human cohorts to determine if the identified changes in our mouse aging study are valuable markers for healthy aging and age-related disease development in humans.
  In a recent STW-project (You are what you ate: Metabolic programming by early nutrition) we focus on improving adult health (“successful ageing”) by the rational administration of the optimal nutrition in early life (in collaboration with Department of Pediatrics at the UMCG). To optimize nutrition, we will modify the composition of early nutrition through elimination or modification of components with negative long-term health effects. We will introduce novel or increase the content of existing nutritional components with positive long-term health effects. We aim to unravel long-term, epigenetic effects of different nutritional components at early life with regards to health at adult age (“metabolic programming”). We study the long-term epigenetic and physiological effects of in utero nutritional manipulations and of breast feeding versus formula feeding with the ultimate aim to improve formula diets to match long-term health.

5. Nutrigenomics of the "two hits" (Prof. Michael Müller)

   Here we study the effect of chronic metabolic and proinflammatory stress ("two hits") on the metabolic health of organs such as liver or adipose tissue. If we eat too much calories, the body stores the extra energy as fat in the white adipose tissue. In particular subcutanous adipose tissue is an excellent storage place for excess fat whereas organs e.g. liver, heart or sceletal muscle are not - it makes them extra vulnerable to inflammation. We are interested in the important and delicate interaction between organs cells such as hepatocytes or adipocytes and organ macrophages that are crucial for organ health and the early processes involved in organ inflammatory diseases.
In a liver the organ macrophages are called Kupffer cells and have been implicated in the pathogenesis of various liver diseases. We recently studied the cross-talk between Kupffer cells and hepatocytes in the regulation of hepatic triglyceride storage and found that the effect of Kupffer cells on liver triglycerides are at least partially mediated by IL-1b, which suppresses PPARa expression and activity. 
In the adipose tissue macrophages can contribute to an elevated inflammatory status by secreting a variety of proinflammatory mediators in particular during diet-induced obesity when the phenotype of adipose-resident macrophages changes from alternatively activated macrophages toward a more classical and pro-inflammatory phenotype (M1). We showed recently that PPARg activation increases infiltration of alternatively activated macrophages (M2) in adipose tissue and these more antiinflammatory macrophages might play a role in the expansion and remodeling of adipose tissue.
More recently we studied in more detail the interaction of the liver and the adipose tissue as non-alcoholic steatohepatits (NASH) is strongly linked to obesity. We found a tight relationship between adipose tissue dysfunction and NASH pathogenesis and point to several novel potential predictive biomarkers for NASH. 

6. Nutrigenomics Databases

A. DIETome DB  (Dr. Mark Boekschoten)

   DIETome DB is a web-based platform for integrative analysis of well annotated nutrigenomics data, in particular from functional genomics experiments using numerous transgenic mouse models. The portal integrates access to extensive knowledge base and a large database of diverse genomics data with basic analytical tools and visualization routines. Primary nutrigenomics data stored in the back-end databases consist of all experiments performed within the NGC & NNC, of which many are yet unpublished, supplemented with public domain measurements, for example from GEO or ArrayExpress datasets. Various experimental assays are and will be included (mRNA and miRNA expression microarrays, RNA-seq, ChIP-chip and ChIP-seq, miRNA expression arrays, SNP arrays). Functional knowledge base is encoded in functionally coherent gene lists derived from numerous sources, including in-house experiments but also proprietary and public sources, such as KEGG, Biocarta, BIND, and Ingenuity. In addition, datasets are and will be further annotated using machine learning techniques with focus on the computational identification of genes encoding potentially secreted proteins (secretome) and mapping of mouse data to human. The current participation of the NNC in the Nutritional Phenotype project (dbNP in collaboration with NuGO/TNO) allows the proper storage of study descriptive and phenotype data which, enabling the combination of this information at different levels (e.g. link phenotype, genotype, food intake, information on study design and Genomics measurements and to combine all of this with existing knowledge). Ultimately, DIETome DB will enable better nutritional/biological interpretation of genomics data as well as improve experimental design of newly planned studies.

B. MADMAX (Dr. Philip de Groot)

  MADMAX is an integrated repository for the management and analysis of multiplatform microarray experiments of the NNC. MADMAX organizes microarray data in experiments and allows the storage of the raw data, regardless the array platform used. Moreover, metadata exactly describing all expects of an experiment is stored using a controlled vocabulary (MIAME/Nut) which can be queried across experiments. MADMAX is linked through web services to a computational pipeline that implements state-of-art methodologies, e.g. offered by the Bioconductor project, for biologists simplifying the complexities of quality control, advanced statistical analyses and visualization, and therefore functional interpretation. Biologically relevant results are already obtained within a few hours to days instead of (at least) several months. Data can be exported in a standardized format (MAGE-TAB). MADMAX is primarily designed for use by biologists lacking detailed knowledge on biostatistics and bioinformatics, and provides a complete life cycle for microarray experiments. MADMAX currently hosts over 6,000 Affymetrix hybridizations covering a variety of species, including Homo sapiens, Mus musculus, and Rattus norvegicus. We welcome collaborations to use MADMAX.