Nutrigenomics is the holistic study of how nutrients affect an individual's genome as a whole. Nutrients can have both beneficial and detrimental effects on different components of the genome (Fig 1.2), which includes DNA sequence (eg, DNA damage) and the epigenome (eg, DNA methylation). Nutrients can also affect the downstream products of the genome, such as the transcriptome (RNA transcribed from the genome) and the proteome (proteins translated from RNA), and systemic molecular mechanisms in the body that interact with the genome, such as the lipidome and metabolome (lipids and other intermediate metabolites) and the microbiome (the genomes of resident microbial and fungal communities that not only live throughout the body but are required for health). The effects of nutrition on the molecular pathways in the body greatly depend on genetic makeup, developmental stage (eg, fetus vs adult), life stage (eg, pregnancy), and health.
Nutrigenomics makes use of -omics technology (eg, genomics, epigenomics, transcriptomics, metabolomics) to assess the features of the genome as a whole, instead of as individual genes or molecules.6 This technology allows researchers to use systems biology to measure and dissect complex interactions between molecular pathways and molecular systems (eg, transcriptome and metabolome) that mediate the relationship between nutrition and health. Nutrigenomics has the potential to identify novel genetic predictors of disease from relevant responses to diet. Examples include (1) individual adaptation to increased dietary cholesterol intake by increasing 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase concentrations; (2) the effect of carbohydrate intake in early life on the likelihood of an individual developing metabolic syndrome in adulthood; and (3) the effect of caloric restriction on increased life span. All this is applicable to the concept of personalized nutrition, though the evidence base thus far is very limited.13
The transcriptome is the primary product of the genome and is made up of RNA generated through gene transcription (ie, gene expression) across the genome. These gene products include coding RNA, which is often processed further into proteins, and noncoding RNA, which does not get translated into protein but instead regulates genetic sequence integrity, gene expression, protein function, and pathway signaling. Both types of RNA are equally important in regulating cellular function and physiological health, and both can be altered by nutrients. High-throughput transcriptomics can be used to simultaneously survey the nutrient-induced responses of all the transcripts in a cell or tissue, which allows for detection of changes in multiple genes simultaneously, mapping of pathways, and analysis of the mechanisms involved. This depth of analysis is either difficult or impossible with single molecule analyses.
Some of the most high-profile nutrigenomics effects of diet are on the epigenome. Epigenetic mechanisms are molecular mechanisms that can act independently of genotype to regulate differences in gene expression; RNA and protein function, stability, and localization; genome structure (eg, chromatin accessibility); and DNA sequence stability. There are 3 distinct but closely interacting markers of epigenetic mechanisms: DNA methylation, post-translational histone modifications, and noncoding miRNA. Diet is a key modulator of the epigenome, and epigenetic mechanisms are key mediators of the effects of diet on health outcomes.14 The earliest diet-related health studies focused on the roles of macronutrients (fat, carbohydrates, proteins) and their caloric contributions. However, micronutrients have become a recent focus because of their demonstrated importance in epigenetic mechanisms, in acting as substrates for molecular markers, coactivators for enzymes, and even as signaling molecules.14
Although epigenetic mechanisms are sometimes thought to be transient effects, recent studies provide evidence to support that diet-induced epigenetic effects may have a more heritable or stable role and that negative effects can have far-reaching consequences. These include persistent effects of diet in an individual's epigenome as well as persistent effects of diet that influence the epigenomes and phenotypes of multiple downstream generations (multi- or transgenerational effects). The basis of the developmental origins of adult health and disease (DOHAD) paradigm is that epigenetic mechanisms play a role in programming long-term or persistent effects of nutrition during developmental stages after birth.12 Supported by existing evidence, the DOHAD concept is that the nutrients a child is exposed to during development can result in early nutritional programming of phenotypes that may lead to diseases occurring later in life.12 The earliest example of this was the "thrifty phenotype," in which poor cardiometabolic health was linked to fetal nutritional deprivation followed by overnutrition later in life.15 Researchers propose this effect is likely due to nutritional programming of metabolism to accommodate the lack of nutrients, but this metabolic state is unable to adapt to the overabundance of nutrients (particularly high caloric nutrients such as dietary fat and cholesterol) later in life. The persistence of this adaptation is thought to contribute to the development of the metabolic syndrome and other cardiometabolic diseases in adults.
Recent evidence, using advances in epigenomics methods, has demonstrated the ability of nutritional changes to affect the epigenome and the pathways it regulates in animal models,14 though human studies pose some challenges of confounding effects of other environmental factors. Nonetheless, there is evidence of dietary effects on the human epigenome. Some of the earliest evidence came from studies conducted with people who experienced famine during World War II in the Netherlands as a result of the Nazi blockade of food transport. The multigenerational effects of this famine were such that offspring were found to be at increased risk of chronic cardiometabolic diseases and some types of cancer.16,17,18,19 These effects have in part been linked to epigenetic changes. In a more recent example, seasonal changes (dry vs wet seasons) in the diets of pregnant women in The Gambia were associated not only with changes in circulating maternal methyl donor metabolites but also with changes in DNA methylation patterns in the genome of offspring.20
Metabolomics offers great potential to understand how nutrition affects metabolic pathways. It can be used to assess the concentrations of a wide range of nutrients and their metabolites, including lipids, amino acids, carbohydrates, peptides, and even vitamins. Metabolomics can be used to define differences between individuals in how their bodies metabolize nutrients for activation or excretion. It is also valuable in identifying patterns of metabolic profiles among individuals that reflect differences in dietary intake or identify individual metabolic activity that explains variation in dietary responses. Characterizing the metabolome relies on nuclear magnetic resonance mass spectrometry, coupled with other separation techniques. Current methods can measure the profiles of metabolites circulating in the blood or serum as well as the profiles of specific tissues. Some have speculated that metabolomics is more effective at identifying biomarkers of dietary intake than the current dietary assessment tools such as dietary recall or intake surveys.21
Lipidomics is the comprehensive characterization of lipid profiles. There is a strong relationship between dietary fat intake and cardiometabolic outcomes; this relationship depends on the genetic regulation of lipid metabolism.22,23
Similarly, proteomics is the comprehensive characterization of proteins and their functional metabolites, including those with posttranslational modifications. Methods for performing proteomics analysis include mass spectroscopy with liquid chromatography; such analysis is necessary to understand the relationships between dietary and genetic factors affecting health and disease.
The microbiota encompasses the trillions of microorganisms that inhabit different organs in the human body. Most of the focus of nutrigenomics research remains on the microbiome of the gastrointestinal tract (gut microbiome). However, there are actually resident microbial communities of bacteria, fungi, and in some cases viruses found across external (eg, hands, feet, groin) and some internal (eg, ear canal, mouth) components of the body. Microbial DNA has also been found in plasma as well as tissues such as liver and adipose but remains unclear if these are from living microbes in those tissues or merely fragmented DNA remnants. There are similarities between healthy individuals' microbiome, and some of these have been linked to diet composition. However, the genetic material of the microbiome has been estimated to contain as many as 9.9 million genes (approximately 100 times more than the human genome), with great interindividual genetic variability among microbes.24 Thus, it is not surprising that the microbial population in each person is unique.
Microbes live in symbiosis with the host, metabolizing various nutrients into metabolites that can be used by both microbe and host. They have also been shown to break down toxic food compounds. Its functional capacity is relatively consistent in healthy persons with pathways involved in nutrient metabolism (eg, folate), fermentation, methanogenesis, oxidative phosphorylation, and lipopolysaccharide biosynthesis.24 The gut microbiome performs many essential metabolic functions not encoded by the human genome-energy production from nondigestible carbohydrates, the production of several water-soluble B vitamins, modulation of the immune system (probiotic bacteria), increased synthesis of small chain fatty acids, and the synthesis of vitamin K2 (menaquinones) that are important to the coagulation system.
The study of the effects of diet on the microbiome and microbiome roles in health usually includes assessment of the types of microbes and the proportions of microbes present. This is often measured using metagenomics analyses, which sequence and perform comparative analyses of the genomes of all the microbes in a particular community. More recently, metagenomics has been combined with metabolomics to integrate not only changes in the microbiota but also changes in the beneficial or sometimes detrimental metabolites they produce.6 These methods have been used to show that dietary differences can greatly alter the microbiome in ways linked to disease outcomes. Disruptions of the resident gut microbiome have been linked to impaired gut function and far-reaching effects on cardiometabolic health (with links to diseases such as obesity, nonalcoholic fatty liver disease, and diabetes).25
Ongoing research in the field of precision nutrition aims to understand how the gut microbiome is affected by diet and how the microbiome may be used as a biomarker to diagnose diet-induced disease and test for efficacy of dietary interventions. Work is also ongoing to understand how to induce specific changes in the microbiome through diet to improve disease.26 Overall, the study of interaction of the diet and microbiota is in its infancy, and its effect on nutritional health without a doubt will be of great importance.