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NESTLÉ RESEARCH: Harnessing the power of epigenetics for targeted nutrition

Authors Diet and genomes interact. Because of its contin- products that are nutritious, safe, promote and Martin Kussmann*, Jennifer Dean*, uous and lifelong impact, nutrition might be the maintain health, and prevent disease. With the Rondo P. Middleton†, Peter J. van most important environmental factor for human advent and development of many new technolo- Bladeren* & Johannes le Coutre* health. Molecular nutrition research strives gies, molecular nutrition research has opened to understand this interaction. Nutrigenetics up new doors of understanding – not only con- *Nestlé Research Center, addresses how an individual’s genetic make-up cerning which dietary components may impact 1000 Lausanne 26, Switzerland. leads to a predisposition for nutritional health; an organism’s health, but also how. These new †Nestlé Purina Research, St. Louis, MO, nutrigenomics (encompassing transcriptomics, insights have allowed a greater understanding 63164 USA. proteomics and metabonomics) asks how nutri- of the systems involved at multiple levels, from tion modulates gene expression; and epigenetics whole animal to the cellular and molecular lev- provides insights into a new level of regulation els. Although challenges in this area still remain, involving mechanisms of development, parental the main focus continues to be the improvement gene imprinting and metabolic programming that of health through diet. Modern molecular nutri- are beyond genetic control. tional research aims at health promotion, dis- Tailoring diets and nutrient compositions to the ease prevention, performance improvement and needs of consumer groups that share the same benefit-risk assessment1. health state, life stage or life style is a main goal Nutrition has conventionally been considered of current nutritional research. While there are an integral part of health maintenance and dis- already food products available that address the ease prevention (especially in cultures such as specific requirements and preferences of certain the Chinese), and the science behind this idea groups, these products are based on empirical was based primarily on epidemiological studies. research rather than on genomic or (epi)genetic The task now is to take this foundational research assessment. Genetics and epigenetics build the to the next scientific level – to analyze gene, scientific foundations for understanding human protein and metabolite profiles of individuals in variability in nutritional preference, require- different health and nutritional conditions – to ments, and response to diet; and furthermore, find early signs (biomarkers) that indicate devia- epigenetics may reveal how environmental tions from healthy metabolism and possible tar- influences can alter this variability across the life gets for correcting these deviations by nutritional span. Inspired by the potential for personalized means2. A further objective is to reveal reactions nutrition counseling, epigenetics research may towards different diets at the systemic level to exert a major influence on consumer diagnos- demonstrate nutritional efficacy2. Therefore, tics to promote health maintenance and disease genomics and genetics applied within the con- prevention. text of nutrition and health have the potential to: Modern nutritional research spans from the deliver biomarkers for health status and health discovery of bioactive food ingredients and the effects, reveal early indicators for disease dis- investigation of their bioavailability and bioeffi- position, differentiate dietary responders from cacy, to the assessment of individual dietary needs non-responders, and, last but not least, uncover via genomic and genetic approaches. The present bioactive, beneficial food components1. paper summarizes current findings in the field of epigenetics and gives an outlook on potential Nutrition and genes health benefits and further research needs. Diet and food components are the prime envi- ronmental factors that affect the human genome, Nutrition research in the 21st century transcriptome, proteome and metabolome, and In light of the increasing importance of nutri- this life-long interaction largely defines the health tion in the development, prevention and man- or disease state of an individual. Most, if not all agement of chronic diseases, modern nutrition nutrients have at least indirect effects on gene research faces the challenge to holistically and protein expression and thus, metabolism. understand how dietary components interact While genomics is about expression and genetics with and within cells and organisms; and to use is about the disposition of an organism, epige- this knowledge to develop new strategies and netics is about development and programming.

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Genetics Epigenetics Transcriptomics Proteomics Metabolomics

METHYLATED DNA GENERATED DNA RNA PROTEINS HISTONES, RNAi METABOLITES SPONSOR FEATURE

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What may be What appears What makes it What has The Blueprint programmed to happen happen happened

DIET DIET DIET DIET

Figure 1 | Impact of diet on the genome and metabolism

Epigenetics represents an emerging set of mecha- in humans, are usually significantly smaller than imprinting, a genetic mechanism that controls nisms revealing how the environment, including pharmacological or toxicological effects. gene expression in a parent-of-origin-specific food and nutrition, constantly shapes and influ- manner4 (i.e. gene expression depends on ences the genome. With a prolonged life span Epigenetics whether an allele is inherited from the mother and changing lifestyles in developed countries, Whereas many earlier studies assumed that or the father). Furthermore, epigenetic regulation chronic diseases have become more prevalent, SNPs (single-nucleotide polymorphisms) were is involved in tissue-specific gene expression and and nutrigenomics, nutrigenetics and epigenet- the main source of human genetic variability, silencing. ics are the key scientific platforms to advance an increasing body of evidence now suggests During early embryogenesis, the mammalian the understanding of health maintenance and that additional layers of variability, including genome is ‘cleared’ of most epigenetic marks, disease prevention through nutrition3. epigenetic regulation, such as DNA methyla- which are then progressively re-established dur- Current nutritional and genetic epidemiologi- tion, are implicated in genetic variation. Many ing embryonic development. The epigenome is cal approaches can be difficult to apply at the complex diseases such as Inflammatory Bowel therefore most vulnerable to environmentally personalized or individual level. These methods Disease (IBD), encompassing Crohn’s Disease induced alterations during embryogenesis, when yield risk factors derived from population studies. and Ulcerative Colitis, are associated with SNPs, DNA synthesis is rapid and the DNA methylation These risk factors are statistical estimates of the particularly in chromosomal regions, but also pattern and chromatin structure is established for percentage of disease reduction in a population, with CNVs (copy number variants) of certain normal development. Once this has been accom- if the risk was to be avoided or the gene variant other genes4. Such discoveries suggest that a plished, these epigenetic alterations are passed was absent. Considering the genetic diversity of detailed description of the genetic background on to the daughter cells during somatic cell divi- human populations, the complexity of foods, of complex diseases is a challenging but nec- sion. Epigenetic marks that are not completely cultures and lifestyles, and the variety of meta- essary objective to better prevent pathological erased during gametogenesis or are not well re- bolic processes, identifying individual risk fac- development of such diseases. established during embryonic development can tors poses enormous challenges for personalizing Epigenetics literally means ‘above genetics’, affect health not only in the present, but also dietary advice. alluding to alterations of genetic material that do in future generations. Additionally, epigenetic Additionally, assessing the metabolic response not affect the DNA sequence itself: this includes marks may be transmitted across generations, to complex foods by Omics applications dif- DNA methylation patterns, chromatin structure either directly through meiosis or indirectly in the fers fundamentally from approaches in which and histone codes, as well as non-coding small next generation through replication of the condi- a single active principle is typically studied RNAs. DNA methylation can be exerted at sus- tions in which the epigenetic change occurred. (such as pharmacology or toxicology). Food ceptible life phases (especially around birth) Individuals have two alleles of most genes. contains macronutrients (carbohydrates, lipids and can be sustained throughout that precise One is inherited from the mother and one from and proteins) and micronutrients (vitamins, life phase, the entire lifespan, or even through the father. When both copies of a gene are active, minerals and trace elements) that exhibit effects the course of several generations. It seems to the system exhibits redundancy and is less sus- at RNA, protein and metabolite levels in a cell provide a mechanism for long-term metabolic ceptible to dysfunction. With imprinted genes, or organism. Thus, food delivers hundreds or programming of an organism in which nutrition one copy is turned off epigenetically by DNA more compounds simultaneously, causing an in early life may affect health outcomes later in methylation. These imprinted genes are suscep- organ-specific response which changes across life4. Similar to DNA methylation, histones and tible loci for disease since their normal func- space and over time, and involves multiple cell the entire chromatin structure can affect gene tion can be altered by a single genetic event. types within an organ possibly reacting differ- expression by rendering only certain parts of the Furthermore, if imprinted genes are not com- ently to the nutritional stimuli. Understanding DNA material spatially accessible for transcrip- pletely turned off, epigenetic events can cause the complexity of nutritional interactions and the tion. Moreover, small RNAs can bind to com- or contribute to disease. mammalian system, including mRNA expression, plementary transcripts and prevent them from Because epigenetic modifications alter gene control of the proteome, allosteric regulation, being processed further, thereby altering protein expression rather than gene sequence, char- and the maintenance of metabolite pools and expression. acterizing the expression profiles of epigeneti- their interactive regulation is most challenging. Two of the most comprehensively studied epi- cally controlled genes should reveal epigenetic Lastly, even the effects of single food compo- genetically regulated phenomena in mammals biomarkers for disease, exposure, intervention nents, when studied under controlled conditions are X-chromosome inactivation and genomic and efficacy. This could enable early diagnosis

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Figure 2 | Epigenetic events during development

of individuals with a propensity for adult-onset environmental epigenetic imprinting/program- Developing organisms appear to be particu- diseases and could lead to novel therapeutic ming, through nutritional or other means, is larly susceptible to epigenetic changes. The peri- approaches for the prevention and treatment mainly derived from animal models. However, conceptional period is very important, as shown of diseases, even before symptoms develop. human epidemiological studies increasingly by the sensitivity to suboptimal nutrition during Contemporary nutrition recommendations point toward associations between environmen- this developmental stage11, in which wide- focus on disease prevention and health mainte- tal impact – especially prenatal and early post- spread reprogramming of the epigenome occurs. nance; and epigenetics may provide the means natal – and long-term epigenetic modifications Nutritional constraints later in pregnancy7, post- to understand and achieve these ambitious manifesting in health and disease phenotypes7. natal over-nutrition that leads to rapid growth9, goals. Ultimately, comprehensive knowledge of as well as maternal–foetal over-nutrition12, can the human epigenome is required, as there is Early nutrition, epigenetics and cause metabolic dysfunction later in life. For each great variation depending on the tissue type and late-life consequences of these scenarios, relevant epigenetic changes stage-of-life, and also on the marked differences The foetal environment can influence suscep- have been reported13. Research in animal mod- between individuals and species. tibility to developing chronic disorders during els has demonstrated that impaired early-life The relationship between epigenetics and adulthood. Early evidence for this observation nutrition and the associated epigenetic changes nutrition is beginning to be revealed. One aspect was derived from increased rates of cardiovas- can be prevented14 or reversed13 by nutritional is the astonishing effect that nutrition can exert cular disease in historical cohorts with high interventions (such as folate supplementation) or on a genome. DNA methylation appears to pro- infant mortality rates. Further studies revealed endocrinological interventions (such as neonatal vide a format for long-term dietary (re-)program- an inverse relationship between birth weight leptin administration). ming of the genome, suggesting that nutritional and susceptibility to developing hypertension, Primary candidates for genes that retain epi- supplementation and well adapted diets at pre cardiovascular morbidity, insulin resistance, type genetic memories of early life experiences are – and postnatal stages may exert a fundamental 2 diabetes, hyperlipidaemia and obesity8. It was those directly associated with energy acquisi- and long-lasting positive impact. Some evidence therefore hypothesized that foetal metabolic pro- tion, storage and utilization. For example, the shows that chronic diseases and conditions in gramming under nutritionally adverse circum- leptin gene is involved in the development of adulthood are due to persistent perturbations or stances may result in increased risk of chronic obesity and considered one of the best such influences during early-life nutrition5. disorders later in life. Other data, like those from gene candidates, since it encodes for a hormone Nutritionally induced changes may signifi- survivors of the Dutch ‘Hunger Winter’ in 1944– which regulates energy intake and expenditure15. cantly affect the ontology of individual organisms. 1945, indicate that individuals exposed to unfa- Epigenetic variation of leptin expression could Evidence for this hypothesis has been provided vourable conditions in utero may subsequently possibly explain low plasma concentrations of by epigenetic research involving monozygotic exhibit adverse effects even if they do not have this hormone. The promoter region of leptin is twins6. Typically, such studies provide correla- a low birth weight7. This observation is consist- susceptible to epigenetic variation through the tions between differences in phenotypic and ent with the complex relationship between birth methylation of somatic tissues in both mice and DNA methylation patterns. While monozygous weight and cardiovascular disease risk and also humans16. It is speculated that leptin is sensitive twins have the same genotype, most of these twin with the observation that metabolic dysfunction to environmental cues and can acquire a thrifty pairs have discordant phenotypes. One possible correlates more strongly with neonatal adiposity epigenotype. Further promising candidates are explanation for this is the existence of epigenetic and maternal nutrition than with birth weight. genes listed in the human obesity gene map17, differences6. Other studies focus on the role of excess nutri- imprinted genes and genes close to or disrupted Nutritional influences can alter gene expression tion during pregnancy and rapid weight gain by transposable elements. and change phenotypes, in part by the modifica- in infants9, the risk of which increases if foe- tion of the epigenome. If these environmentally tal growth is impaired. Additionally, children Programming depends on induced epigenetic modifications occur at cru- exposed to hyperglycemia in utero and those genetics and environment cial stages of life, they can potentially change born to obese mothers are at increased risk of The remodeling of cells and tissues as a result of behaviour, disease susceptibility and, ultimately, developing metabolic disorders, especially type programming has been well documented, though survival. Today’s mechanistic evidence for 2 diabetes10. not yet fully understood. Adipocyte hyperplasia

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Genetics EpiGenetics -Omics to understand to understand to show Personalized predisposition programming efficacy Nutrition Transcriptomics Proteomics Metabolomics DNA picture © iStockphoto.com Glycomics

Figure 3 | Genetics, epigenetics and genomics for personalized nutrition

early in development is proposed to be one of the can only be fermented/utilized by certain bacte- enrolled in weight management trials at the factors that account for the high predisposition of rial populations24. Stimulated by the astonishing G protein level. adult obesity in children who are overweight18. discoveries of Gordon et al. on the influence Animal studies have documented that specific of specific bacteria on energy metabolism and Long-chain polyunsaturated fatty acids dietary factors (e.g. ω6 and ω3 polyunsaturated obesity predisposition25, the gut microbiota is Another case of genetically influenced dietary fatty acids) early in life stimulate or inhibit the increasingly viewed as a pivotal factor in human response is represented by the health effects proliferation of adipocytes. Moreover, muscle metabolism, immunity, sensation, disease resist- of ω-3 long-chain polyunsaturated fatty acids mass is also responsive to the combination of ance, inflammation, and comfort. (LC-PUFAs). It is suggested that individual conditioning and protein content of the diet19. response to LC-PUFAs depends on the host’s The presence of muscle mass, its influence on Nestlé’s research in nutritional PPAR (peroxisome proliferator-activated receptor) whole body energy metabolism, its metabolic epigenetics and genomics α/γ-genotype. ω-3 LC-PUFAs are associated with contribution post-training, and a larger store of Nestlé Research is keenly interested in nutritional benefits for lipid metabolism, insulin sensitivity amino acids in the form of muscle proteins are epigenetics and genomics because we want to and inflammation, and these PUFAs bind directly expected to alter an individual’s reaction to envi- better understand and leverage the interplay to the PPAR transcription factors. Human studies ronmental conditions such as diet20. beween diet, nutrients and the human genome have shown that the effect of this PPAR-PUFA The programming of sensory preference is per- for short-term efficacy and long-term benefits. interaction is modulated by polymorphisms in haps the most influential but the least understood At the Nestlé Research Center, we utilize a vari- the PPAR genes. Therefore, we leverage this inter- factor in the conditioning of modern humans to ety of research methods to build knowledge on dependence to better understand the genotype- their habitual diets. It is arguable that in modern this complex topic. For example, –Omics (tran- dependent health benefits of functional lipids. times, humans do not principally rely on nutrient scriptomics, proteomics, metabolomics) methods cues to guide their food choices; instead, they can show dietary efficacy and nutritional mech- Weight management for humans rely on acquired food preferences. The remark- anisms; genetics can clarify individual predis- Caloric restriction is to date the only nutritional able sensory property of olfactory preference position and stratify cohorts in clinical studies; intervention that has been shown to have a is the process by which liking and disliking of and epigenetics may help us better understand measurable effect on life span across many spe- particular flavours are acquired as a series of metabolic programming. cies, including mammals. In an in vivo study, contextual memories early in life21. This system we investigated the effects of caloric restriction of acquired flavour preferences underlies the cul- G proteins and specific nutrients at the whole transcrip- tural variation of food and cuisine around the Regarding genetics research, we target hypoth- tome level in different tissues. We are currently world. This also means that flavour preferences esis-driven approaches to assess variants of spe- addressing the epigenetic dimension of this study for foods of poor nutrient quality, if acquired cific, metabolically relevant genes in subjects through pursuit of this question: `which long- early in life, may guide a person’s life-long habit enrolled in nutritional interventions. G proteins, term gene expression changes are exhibited by of poor food choices, partly owing to the fact for example, are expressed in all cells of the DNA methylation changes?’ Then we can focus that the sensations will continue to be positively human body, and their main role is to trans- on the nutrients that appear to exhibit transcrip- perceived22. late signals from the cell surface into a cellular tome profiles similar to that of caloric restriction. Yet another mechanism by which early dietary response. The heterotrimeric composition of G exposure can program a person’s response to diet proteins, consisting of α-, β-, and γ –subunits, Weight management for pets in later life is the influence of an individual’s gut determines their receptor and effector specificity. Maintaining a lean body mass phenotype is microbiome (i.e. all microorganisms colonizing Due to the pivotal role of G proteins in virtually important to overall health, for humans as well the human intestine). Such dietary influences can all intracellular signal transduction processes, as companion animals. The maintenance of lean be achieved through both direct inoculation of metabolically relevant SNPs in G proteins have body mass plays a critical role in weight manage- particular microorganisms that are present in been characterized. Some of these gene variants ment. With increasing obesity prevalence, along foods23 or via the selective manipulation of sub- may be implicated in weight regulation. For these with its associated health risks, the maintenance sets of microorganisms by food components that reasons, we genotype healthy adult volunteers of healthy weight must be fully understood and

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applied. We have recently identified common considerably between humans. As nutrigenomics Endocrinol. 5 (7), 401–408 (2009). molecular mechanisms associated with lean and nutri(epi)genetics build the scientific founda- 9. Singhal, A. Early nutrition and long-term cardiovascular body mass phenotypes in order to understand tion for this concept, in addition to sequencing health. Nutr. Rev., 64 (5 Pt 2), S44–S49 (2006). and promote these changes via nutritional solu- and methylation technologies becoming more 10. Boney, C. M., Verma, A., Tucker, R. & Vohr, B. R. Metabolic tions. These phenotypes were induced using widespread and readily accessible, people may syndrome in childhood: association with birth weight, three different treatments which corresponded to gain valuable information from their personal maternal obesity, and gestational diabetes mellitus. changes associated with lean body mass, rather (epi)genetic code. Pediatrics 115 (3), e290-e296 (2005). than the individual treatment alone. In addition Furthermore, as the ability of scientific tools 11. Sinclair, K. D., Allegrucci, C., Singh, R., Gardner, D. S., SPONSOR FEATURE to biochemical and gene expression changes, to distinguish human physiological differences Sebastian, S., et al. DNA methylation, insulin resistance, epigenetic changes are now being identified. meets the industrial capability to deliver indi- and blood pressure in offspring determined by vidual solutions, food and nutrition will become maternal periconceptional B vitamin and methionine Taste sensomics increasingly personalized. This process is not status. Proc. Natl. Acad. Sci. USA 104 (49), 19351–19356 Dietary behaviours and nutritional phenotypes, a revolution, but rather reflects the continued (2007). especially their representation and frequencies diversification of food that has been ongoing for 12. Schaefer-Graf, U. M., Pawliczak, J., Passow, D., Hartmann, within a given population, are of great interest centuries. Consumers will benefit from practical R., Rossi, R., et al. Birth weight and parental BMI predict to Nestlé Research. As previously mentioned, applications such as food personalization based overweight in children from mothers with gestational the predisposition to certain nutritionally linked on validated nutritional solutions for specific sub- diabetes. Diabetes Care, 28 (7), 1745–1750 (2005). phenotypes such as overweight, diabetes or oste- sets of the population. Infants, pregnant and lac- 13. Gluckman, P. D., Lillycrop, K. A., Vickers, M. H.; Pleasants, oporosis, can be partially anticipated through the tating women, active or sedentary adults, athletes, A. B., Phillips, E. S., et al. 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