A Child’s Nutrition and Epigenetics

The first 1,000 days of life, which starts from the time of conception to 2 years of age, is a time when the groundwork for optimum health, growth, and neurodevelopment is established. Aside from inherited genetic materials, environmental factors such as nutrition build the foundation for a child’s ability to grow, learn, and thrive. Proper nutrition early in life reaches far into a child’s future. Children are more likely to overcome childhood diseases leading to better school performance, better paying jobs, and eventually healthier families. This is also the period during which epigenetic activity influences individual susceptibility to noncommunicable chronic conditions later in life ^{[1, 2]}. 

Nutrigenomics, a growing field that has received increased attention over the past decade, investigates how genetic traits of an individual or a population interact with their diet and helps determine which food component is beneficial to the individual’s health. It provides an understanding on how nutrition affects the balance between health and disease by altering the expression of the individual’s genetic makeup ^[3]. The future of nutrition and genetics is highly promising; hence, a better understanding of the connection on how these are related to health is needed.

Role of Polymorphisms

Every normal human cell has 23 pairs of chromosomes, with each chromosome consisting of inherited genetic material that are transferred through generations. Chromosomes have a densely coiled DNA structure that is bound to histones. This “packaging” then allows these long DNA structures to fit into a cell. Each chromosome contains hundreds to thousands of genes. These genes carry information in their nucleotide sequences. 

DNA sequence variations, common among individuals, are known as polymorphisms. Polymorphisms are the most common form of variation in which the change is either just a single-nucleotide polymorphism, “SNP,” or unit of the DNA. Usually, genetic polymorphisms do not directly cause a disease but may instead serve as predisposing factors. Different individual responses to nutrition components may be due to SNPs, which may alter the way proteins interact with metabolites in the body. These SNPs can then amend gene expression, compelling the gene to produce more or produce less protein ^[4].

Interaction between a Nutrient and a Gene

Nutrition can affect growth, aging, and susceptibility to noncommunicable diseases by directly regulating metabolic processes where nutrients interact with the expression of enzymes, hormones, and receptors. When an individual is exposed to a food/nutrient, an SNP associated with that exposure modifies the individual’s response. The individual’s unique response depends on their version of the gene or “genotype.” An example is the cytochrome P450 1A2 (CYP1A2) gene, which codes for an enzyme involved in the metabolism of several different substances including caffeine. Intake of caffeine, which is a substrate and an inducer of CYP1A2, has been shown to increase focus and improve exercise performance. Consumption of caffeine has been reported to be influenced by both genetic and environmental factors ^[5].

One variation of CYP1A2 associated with caffeine metabolism is the rs726551 SNP. Studies showed that individuals with a homozygous genotype AA (fast metabolizers) once exposed to caffeine experience a positive or improved performance or even protection against disease; however, individuals with a CYP1A2 AC or CC genotype experience no effect and even cause diseases such as diabetes, heart attacks, and high blood pressure from caffeine use. Each individual, therefore, has a different response to the same nutritional component and each unique genetic makeup of an individual can influence the balance between disease and health ^{[6, 7]}.

Role of Epigenetics

Epigenetics, the study of heritable and often reversible modifications to genes without altering the nucleotide sequence of the DNA, works through chemical tags that highlight which genes are turned on or turned off. There are three main ways for epigenetics to activate or silence the genes, namely through DNA methylation, histone modification, and modulation of mRNA expression.

DNA methylation is the process wherein a methyl group is added to the 5′ site of a cytosine nucleotide. It is highly specific and always occurs at the cytosine nucleotide that is located next to a guanine nucleotide linked by a phosphate (CpG islands). When DNA becomes methylated, genes are inactivated or silenced. The pattern of DNA methylation in CpG islands varies by tissue type and likely accounts for why genes are expressed differentially among tissues.

Histone modifications, on the other hand, are epigenetic regulators that control chromatin structure and gene transcription. Histones, the primary components of chromatin, act as spools around which DNA can wind. They tightly wrap inactive genes making them unreadable, thus, technically, hiding them. For the active genes, histones relax them, making them easily accessible.

Genes can also be turned off by RNA, which may affect gene expression by causing heterochromatin to form, or by triggering histone modifications and DNA methylation. 

These three epigenetic processes (DNA methylation, histone modification, and modulation of mRNA expression) are activated when an individual is exposed to environmental triggers such as smoking, exercise, toxins, diet, infections, stress, cold, heat, and drugs ^[8].

Protective Effects of Bioactive Food Compounds

Research shows that consumption of bioactive compounds such as polyphenols, which are found in fruits and vegetables, is associated with chronic disease prevention. They elicit protective effects through complex mechanisms at the cellular, molecular, and epigenetic levels. According to the Developmental Origin of Health and Disease (DOHaD) paradigm, in utero exposure to certain stressors such as malnutrition through the mother’s diet impairs fetal development and epigenetically programs increased risk of metabolic diseases and some cancers in the child’s adult life. In addition, recent studies have shown that the fathers’ diet during preconception also plays a role in their offspring’s health and chronic disease susceptibility ^[9]. This highlights the child’s early life cycle as a promising window of opportunity for starting dietary interventions for both the parents and their offspring.

Focusing on preventing lifestyle-associated diseases resulting from exposure over long periods of time to unhealthy diets, unhealthy lifestyles, and unhealthy environments is important. High mortality rates due to unhealthy living practices and noncommunicable diseases have been responsible for most deaths during this past decade. Conditions such as obesity, cardiovascular disease (CVD), and type 2 diabetes mellitus (T2DM) share similar risk factors – slow progressing, noninfectious, and nontransmissible.

In recent decades, our environments now offer an abundance of calorie-rich foods and few opportunities for physical activity. There is now a global shift in diet toward increased intake of energy-dense foods high in fat and sugars but low in vitamins, minerals, and other micronutrients. The trend toward decreased physical activity due to the increased sedentary nature of many forms of work, changing modes of transportation, and increasing urbanization has led to a greater number of overweight individuals. Most individuals have higher food consumption than energy exhaustion, which causes fat buildup in the body. However, it is proven that there are several other risk factors for obesity such as unhealthy diets, age, socioeconomic status, family history, and genetic susceptibility. Recent studies state that obesity is not only directly caused by our environment, which offers few opportunities for physical activity, but also influenced by our genetic makeup [10]. It has been found that the strongest risk factor for childhood and adolescent obesity is parental obesity. Studies further show that maternal weight gain in pregnancy is positively correlated with a child’s body mass index ^{[11, 12]}.

It is reassuring to know that personalized nutrition can help people achieve a dietary behavior change leading to optimized health or prevention of chronic diseases such as T2DM, CVD, and cancers. Personalized nutrition offers nutritional interventions because it allows the understanding of relationships between an individual’s food consumption and phenotype. It can be applied in the dietary management of people with specific diseases and to those who need special nutritional support. It can also be applied to the development of more effective interventions for improving public health ^[13]. The goal, therefore, is to preserve or increase health and prevent disease using genetic, phenotypic, medical, and nutritional information about individuals to deliver more specific healthy eating guidance

Nutrigenomics

Nutrigenomics is the study of how different foods interact with particular genes to increase or decrease the risk of diseases. It addresses how diet influences gene transcription, protein expression, and metabolism. It views food as capable of reversing disease and stalling aging. It develops “personalized diets,” identifies molecular biomarkers or new bioactive food ingredients, and validates the effectiveness of these bioactive ingredients as functional food components.

Nutritional genomics is based on several considerations: (1) diet and dietary components can alter the risk of disease development by modulating processes involved with its onset, progression, and/or severity; (2) food components can act on the human genome to alter the expression of genes and gene products; (3) diet could potentially compensate for or accentuate the effects of genetic polymorphisms; and (4) the consequences of a diet are dependent on the balance of health and disease states and on an individual’s genetic background ^[14].

Several factors (genetic, epigenetic, environment, etc.) affect the individual’s response to dietary intake and its relation to health status. Nutritional biomarkers may reflect the effects of nutrient intake or a lack thereof. They can also indicate the potential risk of developing a pathology associated with either excess or deficit of the nutrient to which it is linked. These biomarkers reflect not only the intake but also the metabolism of nutrients and possibly the effects on disease processes. They may indicate improved health status and/or reduced risk of disease ^[15].

Several studies have been done on genes, diet, and their interactions to determine the etiopathogenesis and progression of T2DM. T2DM is characterized by an inadequate response to progressive insulin resistance that accompanies age, sedentary living, and weight gain. This accounts for substantial morbidity and mortality rates from adverse effects on cardiovascular risk and disease-specific complications (i.e., blindness and renal failure) ^{[16, 17]}.

Epigallocatechin gallate is a flavan-3-ol from grapes, its products, and dark chocolates. It improves viability of beta cells and insulin secretion by activation of insulin receptor proteins by aiding the signaling of protein kinase (Akt), insulin receptor (Ir), insulin receptor substrate 2 (Irs2), and pancreatic duodenal homeobox-1 (Pdx1). It reduces expression levels of carnitine palmitoyltransferase (L-Cpt1), a mitochondrial fatty acid transporter that reduces the level of fatty acids in blood circulation; DNA damage-inducible transcript 3 (Ddit 3), an endoplasmic reticulum stress marker; Cdkn1a; protein phosphatase 1; and regulatory subunit 15A (Ppp1r15a). It enhances pancreatic function and lowers insulin resistance in diabetic mouse models. Naringin and hesperidin flavanones showed antihyperglycemic effects in mouse models by increasing the expression of glucose transporter type 4 (Glut4) and glucokinase (Gk). Anthocyanin from grapes improves diabetes by downregulating gluconeogenic enzymes (PEPCK and G6Pase) and upregulating peroxisome protein–activated receptor alpha (PPAR-α), Glut4, and aconitase expression, while quercetin is a flavonol that increases cell proliferation of the liver and the pancreas ^[18].

Vitamins act as antioxidants that lower DNA damage or prevent disease. Research shows that vitamin D preserves beta cell function during insulitis by downregulating the expression levels of inflammatory mediators like interleukins and interferon-gamma inducible protein. Biotin increases insulin secretion and islet function by increasing gene expression of several genes, while riboflavin decreases inflammation by downregulating interleukin 6. Palmitate, on the other hand, decreases insulin secretion by reducing binding of transcription factors, while alpha lipoic acid improves glucose metabolism (Table 1) ^[18].

Potential Molecular Mechanisms for Nutrigenomic/Nutrigenetic Interactions in CVD Risk

CVD is characterized by the formation of intimal lesions due to lipid deposition, inflammatory responses, fibrosis, and cell death in blood vessels. It is responsible for about 17.9 million deaths annually ^[19]. 

Although both food and genes play a distinct role in determining health, the interactions among genes, diet, and downstream networks are not well understood. Specific food consumption alters CVD risk through multiple distinct and interrelated mechanisms, namely differential intestinal metabolism and uptake of nutrients depending on the gut microbiome composition, differential absorption, and nutrient binding, depending on individual genotype, modulation of gene expression through specific transcription factor binding, specific effects on methylation and epigenetic modification, and modulation of metabolic signaling through lipids, metabolites, and proteins ^[20].

Polyunsaturated fatty acids, i.e., omega 3 and omega 6, play an important role in carbohydrate and lipid metabolism. Intake of these essential fatty acids reduces the low-density lipoprotein cholesterol level in patients. They activate the APOA1, 5-LOX, eNOS, and PPAR genes to excrete fats, regulate cytokines, reduce atherosclerosis, and increase high-density lipoprotein cholesterol, respectively. 

Isoflavones, from soy proteins, are a subclass of flavonoids also presenting with antioxidant properties. Diadzein, genistein, and glycitein have been found to modulate the expressions of pro-inflammatory cytokines, improve vascular reactivity, and inhibit platelet aggregation, thereby improving CVD (Table 2) ^[18].

Potential Benefits

Children only develop as much as their families and communities enable them. Since epigenetic changes start as early as the first 1,000 days of life, focus should now be on the prevention of disease, which thereby will decrease morbidities and premature mortalities. Emphasis on the importance of healthy diets and lifestyles motivates a positive behavior change, promotes an increased awareness of certain high-risk conditions, and also identifies subgroups of individuals who might be particularly responsive or resistant to environmental (dietary) intervention. Consequently, better insights of the genetic mechanisms involved in disease susceptibility will lead to reduced healthcare costs.

Conclusions

Nutrition plays an important role in the growth of the fetus and infants with long-term outcomes for health. In crucial life stages (i.e., first 1,000 days of life) characterized by a rapid growth rate for the child, epigenetic changes induced by environmental factors can influence gene expression. This can permanently affect an individual’s development and lead to the development of chronic disease later in life. Applying genetics into our choice of nutrition would improve and/or restore an individual’s health and quality of life. Understanding the interaction between genetic susceptibilities, environmental influences (i.e., nutrition), and genetic studies increases our understanding of these diseases. Individuals cannot alter their genes, but they can eat the right foods to support genetic predispositions and take the right supplements to support gene variations and promote normal cell function. It would be highly beneficial if future research focuses on nutritional intervention during the critical period of human development. Public health efforts are also extremely necessary for effective preventive actions to be sustainable for the masses.

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