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NESTLÉ RESEARCH:

Harnessing the power of epigenetics for targeted nutrition

Authors

Diet and genomes interact. Because of its contin-

uous and lifelong impact, nutrition might be the most important environmental factor for human health. Molecular nutrition research strives gies, molecular nutrition research has opened to understand this interaction. Nutrigenetics up new doors of understanding – not only conaddresses how an individual’s genetic make-up cerning which dietary components may impact leads to a predisposition for nutritional health; an organism’s health, but also how. These new products that are nutritious, safe, promote and maintain health, and prevent disease. With the

advent and development of many new technolo-

Martin Kussmann*, Jennifer Dean*, Rondo P. Middleton^†, Peter J. van Bladeren* & Johannes le Coutre*

*Nestlé Research Center, 1000 Lausanne 26, Switzerland. ^†Nestlé Purina Research, St. Louis, MO,

• nutrigenomics (encompassing transcriptomics,
• insights have allowed a greater understanding

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-

63164 USA.

provides insights into a new level of regulation

involving mechanisms of development, parental

gene imprinting and metabolic programming that

are beyond genetic control.

els. Although challenges in this area still remain,

the main focus continues to be the improvement

of health through diet. Modern molecular nutritional research aims at health promotion, dis-

ease prevention, performance improvement and

Tailoring diets and nutrient compositions to the

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 disalready food products available that address the ease prevention (especially in cultures such as

specific requirements and preferences of certain

groups, these products are based on empirical research rather than on genomic or (epi)genetic the Chinese), and the science behind this idea

was based primarily on epidemiological studies.

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 deviaepigenetics may reveal how environmental tions from healthy metabolism and possible tar-

influences can alter this variability across the life

span. Inspired by the potential for personalized

gets for correcting these deviations by nutritional

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 conprevention. 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 disinvestigation of their bioavailability and bioeffi- position, differentiate dietary responders from

text of nutrition and health have the potential to:

cacy, to the assessment of individual dietary needs

via genomic and genetic approaches.The present

paper summarizes current findings in the field of epigenetics and gives an outlook on potential health benefits and further research needs. non-responders, and, last but not least, uncover bioactive, beneficial food components¹.

Nutrition and genes

Diet and food components are the prime envi-

ronmental factors that affect the human genome,

transcriptome, proteome and metabolome, and

this life-long interaction largely defines the health

Nutrition research in the 21st century

In light of the increasing importance of nutrition 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 with and within cells and organisms; and to use this knowledge to develop new strategies and

While genomics is about expression and genetics

is about the disposition of an organism, epigenetics is about development and programming.

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• Genetics
• Epigenetics
• Transcriptomics
• Proteomics
• Metabolomics

METHYLATED DNA HISTONES, RNAi
GENERATED METABOLITES

• DNA
• RNA
• PROTEINS

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

• 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.

food and nutrition, constantly shapes and influgene expression in a parent-of-origin-specific manner⁴ (i.e. gene expression depends on whether an allele is inherited from the mother

Epigenetics

ences the genome. With a prolonged life span 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 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-

During early embryogenesis, the mammalian
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 divihuman 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

dietary advice.
Epigenetics literally means ‘above genetics’, affect health not only in the present, but also

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 condia 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 susat 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 susceporgan-specific response which changes across life⁴. Similar to DNA methylation, histones and tible loci for disease since their normal funcspace 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 comently 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

control of the proteome, allosteric regulation, being processed further, thereby altering protein expression rather than gene sequence, charand the maintenance of metabolite pools and expression. acterizing the expression profiles of epigenetitheir interactive regulation is most challenging. Two of the most comprehensively studied epi- cally controlled genes should reveal epigenetic
Because epigenetic modifications alter gene
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 periapproaches 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 widefocus 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, postto understand and achieve these ambitious manifesting in health and disease phenotypes⁷. goals. Ultimately, comprehensive knowledge of natal over-nutrition that leads to rapid growth⁹, as well as maternal–foetal over-nutrition¹², can

cause metabolic dysfunction later in life. For each

of these scenarios, relevant epigenetic changes

Early nutrition, epigenetics and

the human epigenome is required, as there is great variation depending on the tissue type and

late-life consequences

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 induced epigenetic modifications occur at cru- exposed to hyperglycemia in utero and those

Programming depends on 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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NUTRITIONAL INTERVENTION
NUTRITIONAL INTERVENTION

• FOLLOW-UP
• READ-OUT
• STRATIFICATION

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3

Genetics

to understand

predisposition

EpiGenetics

to understand

programming

-Omics

to show

efficacy

Personalized Nutrition

Transcriptomics Proteomics Metabolomics Glycomics

DNA picture © iStockphoto.com

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

response to LC-PUFAs depends on the host’s

PPAR (peroxisome proliferator-activated receptor)

α/γ-genotype. ω-3 LC-PUFAs are associated with

conditioning and protein content of the diet¹⁹.

Nestlé’s research in nutritional epigenetics and genomics

The presence of muscle mass, its influence on whole body energy metabolism, its metabolic 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.

The programming of sensory preference is per- for short-term efficacy and long-term benefits.