Nutrigenomics In Action: How Nutrients Turn Genes On and Off

INTRODUCTION

The discovery that nutrition can affect both metabolism and gene activity has fundamentally changed our knowledge of human health. Nutrition conventionally focuses on the provision of macronutrients and micronutrients for growth and energy. However, advances in molecular biology have shown that bioactive food chemicals are signaling molecules that can affect the functioning of the genome. This is the interaction between nutrition and genetics which forms the foundation of nutritional epigenomics (Farhud & Yeganeh, 2010). The ultimate goal is to determine which foods may positively or negatively change genes linked to health and disease, with the purpose of developing more targeted and valuable dietary practices. Nutrients have numerous interrelated mechanisms by which they influence gene regulation. They act as ligands for transcription factors and for nutrient sensing receptors such as the peroxisome proliferator activated receptor (PPAR) family that responds to fatty acids, and they affect the availability of cofactors and substrates required in biochemical reactions, including those of DNA methylation. Meals can also activate signaling cascades that affect transcription and mRNA stability and exert an effect on protein synthesis and metabolic processes such as lipid metabolism glucose homeostasis and inflammation.

To investigate these connections, scientists employ high-throughput “omics” technologies that can detect extensive alterations in biological systems. Transcriptomics examines shifts in mRNA levels. Proteomics assesses alterations in protein abundance and metabolomics analyzes changes in small-molecule metabolites (Felisbino et al., 2021).

Specific nutrient groups have been well studied for their gene-regulatory effects. Polyphenols, found in fruits, vegetables, and tea, can modify the expression of genes involved in antioxidant defense and insulin sensitivity. Certain fatty acids modulate lipid metabolism by binding to nuclear receptors, while methyl-donor nutrients like folate, choline, and vitamin B12 influence epigenetic marks that can change gene expression for long periods. These interactions are directly relevant to chronic conditions such as obesity, type 2 diabetes, cardiovascular disease, and some cancers, making nutrigenomics a valuable tool for preventive and therapeutic nutrition strategies (Hosseiniara & Hosseini Zijoud, 2024).

Nutrigenetics and nutrigenomics are defined as the science of the effect of genetic variation on dietary response and the role of the nutrient and the bioactive food compound in gene expression. Three central factors underpin nutrigenetics and nutrigenomics as an important science. First, there is great diversity in the inherited genome between ethnic groups and individuals, which affects nutrient bioavailability and metabolism. Second, people differ greatly in their food/nutrient availability and choices depending on cultural, economic, geographical and taste perception differences. Third, malnutrition (deficiency or excess) itself can affect gene expression and genome stability; the latter leading to mutations at the gene sequence or chromosomal level, which may cause abnormal gene dosage and gene expression leading to adverse phenotypes during the various life stages (Basilicata & Keller Valsecchi, 2021).

An example of our nutrigenomics is the link between a compound in red wine called resveratrol and cancer. Resveratrol can stimulate a gene that protects tissue from free radical damage and thus can help prevent cancer. Folate, a nutrient found in deep green leafy vegetables, is important for making DNA. Thus, when folate is deficient, one has an increased cancer risk. Another example of nutrigenomics is the link between a compound called polyphenols in dark chocolate and cancer. These polyphenols have been shown to cause a change in gene expression and potentially decrease one’s risk of free radical damage, which can lead to cancer (Mileo & Miccadei, 2016).

HOW NUTRITION INTERACTS WITH GENES

Nutrients influence the body at the molecular level by acting as signals that can activate or suppress specific genes. Dietary components such as fatty acids, amino acids, vitamins, and plant-derived compounds can interact with nutrient-sensitive receptors or transcription factors, triggering a cascade of cellular events that modify gene expression. By controlling vital physiological systems, including metabolism, inflammatory management, and cell proliferation, these changes influence overall health outcomes and disease risk. There are many ways that genes and nutrition interact. Nutrients directly on gene transcription, alter signaling pathways to influence protein synthesis and stability of Mrna, or influence the availability of cofactors needed by epigenetic enzymes. The result is a reciprocal relationship where diet can actively affect gene action while individual genetic differences determine the response to the same nutritional conditions. Taken together, these associations provide the foundation for personalized programs based on patients’ genetic makeup (Weitzel et al., 2011). In short, nutrigenomics is the study of the effects of nutrition on gene action, while nutrigenetics investigates genetic variations that affect the body’s response to nutrients. They are co-related and together form the complementary aspects of nutritional genomics with the same goal of tailoring nutrition plans (Toader et al., 2025).

NUTRIGENOMICS – EFFECTS ON GENE EXPRESSION

The study of the biochemical mechanisms by which nutrients control gene expression is known as nutrigenomics. Certain nutrients or bioactive food ingredients can function as ligands, binding to nuclear transcription factors or nutrient-sensitive receptors within cells. By changing the shape of the receptor, this interaction enables it to bind to specific DNA sequences found in gene promoters or enhancers, either starting or stopping transcription. Certain nutrients, such as fatty acids, activate nuclear receptors like PPARs, which subsequently attract RNA polymerase and co-activator proteins to start the synthesis of MRNA. Others, such as certain amino acids or plant polyphenols, affect the kinase signaling cascade that phosphorylates transcription factors to alter their activity. The availability of cofactors, such as S-adenosylmethionine for methylation processes, can also be impacted by nutrition, which can have an impact on enzymes that control chromatin shape

Nutrients can also cause epigenetic changes that affect gene activity without changing DNA sequences, in addition to this direct transcriptional impact while substances like butyrate restrict histone deacetylases, resulting in a more open chromatin structure and increased transcription. Methyl-donor foods like folate and vitamin B12 allow DNA methylation, which can mute specific genes. Long term stability of these alterations can impact health trajectories and, in certain situations, transmit molecular patterns to the following generation. According to nutrigenomics, diet is a regulatory mechanism that can adjust gene expression in addition to being a source of energy. Scientists want to create nutrition strategies that maximize metabolic function, avoid disease, and tailor dietary recommendations depending on genetic composition by comprehending these molecular and epigenetic linkages (Kavya, 2025)

NUTRIGENETICS

Studies in nutrigenetics reveal differences in genes that impact how our systems absorb and use nutrition. Enzyme activity can be altered by single-nucleotide polymorphisms (SNPs) in important metabolic genes, changing the need for vitamins and minerals. For instance, if folate intake is inadequate, the MTHFR C677T variation lowers the efficiency of folate metabolism, which might raise homocysteine levels. Similar to this, even with sufficient consumption, mutation in TCN2, a gene that codes for the vitamin B12 transport protein, might decrease B12 delivery to tissue, raising the risk of insufficiency (Ghosh et al., 2023).

Genetic Influence on Nutrient Metabolism

Some genetic differences determine how efficiently the body responds to a specific meal. Different forms of the BCO1 gene can reduce the conversion of beta carotene to vitamin A; for example, mutations in SLC23A1 change the amount of vitamin C absorbed and transported throughout the body. Likewise, mutations in GC and CYP2R1 change the synthesis of vitamin D (Weitzel et al., 2011).

Personalized Nutrition Potential

Nutrigenetics allows for more individualized dietary recommendations by discovering genetic variants that affect nutrient digestion. To promote optimal health, people with specific SNPs can be directed toward specific dietary changes, such as increased folate for MTHFR variations or modified fat intake for lipid-metabolism gene variances. This strategy has potential for precision nutrition, although it is still in its infancy (Niforou et al., 2020).

MECHANISM OF DIET-INDUCED GENE REGULATION

Biochemical Pathways of Nutrient-Gene Interaction

Through a variety of biochemical mechanisms, nutrients and bioactive dietary substances can affect gene expression either directly or indirectly. Certain nutrients function as ligands or signaling molecules for nuclear receptors, like LXR (Liver X Receptor) and PPARs (peroxisome proliferator-activated receptors), which attach to DNA response regions to either activate or inhibit target genes. Others act as cofactors for epigenetic modification-related enzymes, such as histone acetyltransferases/deacetylases (acetylation) and DNA methyltransferases (methylation). For instance, the one-carbon cycle, which produces S-adenosylmethionine (SAM), an essential methyl donor for DNA methylation, is facilitated by folate and vitamin B22. Sirtuins, which control chromatin shape and affect transcription, can also be activated by polyphenols such as resveratrol. These conditions can directly link nutrition to genomic activity by changing immunological response, metabolic pathways, and cell signaling (Cialdella-Kam et al., 2016).

Epigenetic Modulation by Diet

Long-term alterations in gene expression can be brought about by diet without changing the DNA sequence. DNA methylation, histone changes, and non-coding RNA control are examples of epigenetic mechanisms that do this. A high methyl diet, for example, which is strong in folate, choline, and methionine, might enhance DNA methylation in some gene promoters, thus suppressing their expression. On the other hand, dietary excesses or deficiencies may cause histone acetylation or demethylation, which may activate disease-related processes (Geneski et al., 2014).

Nutrients as Signaling Molecules

Nutrients can exert functions beyond their classic metabolic roles by acting as cellular signaling molecules that directly affect gene expression and physiological events. Vitamins, amino acids, fatty acids and phytochemicals are only a few of the bioactive food components that react with nuclear receptors or intracellular signaling proteins to activate transcriptional events. For instance, long-chain polyunsaturated fatty acids bind to liver X receptors (LXRs), retinoid X receptors (RXRs), and peroxisome proliferator-activated receptors (PPARs) to form complexes that react with DNA to alter metabolic genes involved in glucose and lipid homeostasis. Whereas amino acids such as leucine stimulate the mTOR pathway, which promotes protein synthesis and cell growth, activate carbohydrate response element binding protein (ChREBP), which affects genes related to carbohydrate metabolism. Likewise, vitamin D, by acting on vitamin D receptors (VDR), modulates calcium homeostasis, immunological control and cell differentiation. These nutrient-mediated signaling events couple dietary inputs to genetic regulation, enabling the organism to change metabolic and physiological processes based on nutritional availability (Kamioka et al., 2021)

ROLE OF TRANSCRIPTION FACTORS

Peroxisome Proliferator-Activated Receptors (PPARs)

Fatty acids and their derivatives activate PPARs, nuclear receptors that control genes related to inflammation, glucose homeostasis, and lipid metabolism. PPARs connect to a specific DNA sequence known as PPAR response elements and form heterodimers with retinoid X receptors (RXRs) when they bind to ligands like omega-3 fatty acids. This modulates gene transcription in metabolic tissues such as the liver, muscle, and adipose tissue (Lee et al., 2008).

Liver X Receptors (LXRs)

LXRs are essential to regulate inflammation, lipid metabolism, and cholesterol homeostasis. They are activated by oxidized cholesterol derivatives, termed oxysterols. Once LXRs are activated, the genes modulated in this pathway protect the cardiovascular system by inhibiting inflammatory signals and by facilitating the clearance of cholesterol from the cells (Wang & Tontonoz, 2018)

Carbohydrate Response Element binding protein (ChREBP)

Glucose and its metabolites activate a transcription factor termed ChREBP. Once activated, it binds to carbohydrate response elements in target gene promoter regions, increasing the expression of enzymes associated with glycolysis and lipogenesis. This way, the body responds to the variation in carbohydrate availability by altering metabolic pathways toward energy storage.

Vitamin D Receptor (VDR)

VDR is a ligand-activated transcription factor that, in its activated form, binds to calcitriol, an active form of vitamin D. When activated, VDR associates with the nuclear receptor RXR and consequently regulates genes responsible for cell growth, immune response and calcium and phosphorus absorption. This nutrient-sensitive mechanism controls immune function and bone health (Fotschki et al., 2018).

Epigenetic Changes

Epigenetic changes, which are heritable alterations in gene expression occurring without a change to the DNA sequence itself, are now being recognized to have an integral influence on how nutrition affects health. The three main mechanisms by which nutrients and bioactive dietary components can act as epigenetic modulators are through DNA methylation, histone modification and non-coding RNA regulation. For instance, methyl donor foods, such as folate, vitamin B12 and choline, contribute to the production of S-adenosylmethionine, needed to transfer methyl groups to cytosine residues in DNA and typically result in gene silencing. Likewise, polyphenols from green tea and curcumin from turmeric can change the patterns of histone acetylation, thus changing the accessibility of transcription machinery by either making chromatin more open or compact. Specific fatty acids and minerals also influence the expression of microRNAs, small RNA molecules capable of post-transcriptionally silencing or degrading messenger RNAs. All these diet-induced epigenetic changes affect metabolic pathways, cellular processes and disease risk throughout the life course (Li et al., 2018).

Nutrition, Epigenetics, and Chronic Diseases

Epigenetic modifications have a significant effect on human health and disease. While genetic mutations irreversibly change the DNA sequence, epigenetic changes are normally reversible. Examples of these modifications include histone modifications, DNA methylation, and non-coding RNAs, including miRNAs. Importantly, nutrition and diet significantly influence these epigenetic modifying events with consequences for the etiology, progression and outcomes of many chronic diseases. Of these, metabolic diseases, cancer and CVDs are particularly significant due to the widespread nature of the conditions. Understanding how nutrients and bioactive food components change epigenetic landscapes may further inform both therapeutic approaches and nutrition-based prevention (Li et al., 2018)

DNA Methylation

DNA methylation typically refers to the addition of methyl groups to DNA, with the majority of this modification occurring at the cytosine residues in CpG islands. This often leads to the suppression of gene transcription. This process is notably sensitive to nutrient availability, particularly to the availability of methyl donors like choline, vitamin B12, folate and methionine (Table 1). These nutrients assist in the synthesis of S-adenosylmethionine (SAM), the major methyl group donor for methyltransferase enzymes. Methylation patterns affect developmental processes, cancer risk, and immune system function (Trowbridge et al., 2020).

Histone Modification

DNA is packaged into chromatin by histone proteins, and their chemical modification can alter the degree to which DNA is tightly and loosely bound. Histone acetylation, methylation, phosphorylation, and ubiquitination are all impacted by nutrient and bioactive components. Butyrate, for instance, is a short-chain fatty acid product of fiber fermentation that inhibits histone acetylation, or HDACs, promoting more open chromatin and increased transcription of certain genes. Polyphenols, including resveratrol, also impact histone-modifying enzymes to promote a favorable gene expression profile (Lorente-Cebrián et al., 2025).

mRNA

Non-coding RNAs, especially microRNAs (miRNAs), attach to complementary sequences in messenger RNAs (mRNAs) to either degrade or impede translation, hence regulating gene expression post-transcriptionally. Nutrients, including curcumin, omega-3 fatty acids, and other vitamins, can change the expression of particular miRNAs. These alterations can regulate pathways associated with inflammation, metabolism, and chronic disease development (Kazi et al., 2019).

EPIGENETICS AND CANCER

Cancer is fundamentally a disease of dysregulated gene expression, where normal controls over cell growth and differentiation are disrupted. While genetic mutations contribute to tumor initiation, epigenetic alterations are equally critical in tumor progression. One of the most studied mechanisms is where the addition of methyl groups to cytosine residues can either silence tumor suppressor genes (TSGs) or activate oncogenes (Bakrim et al., 2025).

Hypermethylation of TSGs: In many cancers, excessive methylation silences protective genes that normally control cell division or repair damaged DNA.

Hypomethylation of oncogenes: Conversely, loss of methylation can lead to the overactivation of genes that drive uncontrolled proliferation.

Both conditions contribute to malignancy, highlighting the delicate balance required in methylation patterns. Nutrients such as folate (B9), vitamin B12, and S-adenosylmethionine (SAM) are central to one-carbon metabolism, the biochemical pathway that provides methyl groups for DNA methylation. Inadequate intake of these methyl donors is linked to oncogene hypomethylation, particularly increasing the risk of colorectal cancer. On the other hand, excessive folate intake can paradoxically stimulate cancer growth by hypermethylating TSG promoters. Thus, both deficiency and overconsumption of B vitamins can be harmful, emphasizing the importance of balanced dietary intake (Pieroth et al., 2018).

Beyond DNA methylation, histone modifications also play an important role in carcinogenesis. Histones are proteins around which DNA is wrapped, and their acetylation or deacetylation can determine whether genes are active or silent. Plant-derived bioactive substances, including polyphenols, are particularly effective in changing histone modifications. Examples include: Epigallocatechin gallate from green tea and resveratrol from berries and grapes act as inhibitors of histone deacetylases. Curcumin, the active polyphenol in turmeric, has been found to demethylate promoter regions of silenced TSGs, thereby reactivating those TSGs in cancerous cells. By inhibiting HDACs, they facilitate histone acetylation, reactivating tumor suppressor genes and restabilizing normal cell growth control (Wu et al., 2023).

These findings suggest that dietary polyphenols exert anti-cancer properties not only by acting as antioxidants but also through direct modulation of epigenetic signaling pathways. Finally, a hallmark of cancer is dysregulation of miRNA. miRNAs are small non-coding RNAs that regulate post-transcriptional gene expression. When aberrantly expressed, they can enhance oncogene activity or suppress TSGs. Another factor here, which will bring us full circle to the topic at hand, is diet: polyphenols such as resveratrol and EGCG and omega-3 PUFAs have been shown to modify miRNA expression, dampening proliferative and inflammatory signals. This again supports the concept that eating is a form of epigenetic therapy and could be usable in concert with conventional cancer treatments.

EPIGENETICS AND CARDIOVASCULAR DISEASES

The leading cause of death in the world remains cardiovascular diseases. Epigenetic changes are emerging as an important constituent in their development and progression. Similar to cancer, CVDs arise due to the interaction between environmental factors and genetic predisposition; nutrition is one of the major modifiable factors. DNA methylation of genes regulating inflammation and lipid metabolism is one of the best-studied epigenetic mechanisms in CVDs. For example, atherosclerosis, an accumulation of plaques in the arterial wall, leading to narrowing of blood vessels, can be enhanced by hypermethylation of genes involved in inflammatory signaling or cholesterol transport.

Adequate ingestion of vitamin B12 and folate is beneficial because they maintain normal methylation patterns and reduce homocysteine levels, a known risk factor for CVD. Although diets high in methyl donors can raise homocysteine levels and lower cardiovascular risk, the increased levels of homocysteine also damage blood vessels and lead to thrombosis.MiRNA-mediated epigenetic regulation also influences the aetiology of CVD. Dysregulated miRNAs affect endothelial function, inflammation and lipid metabolism. These patterns can be positively influenced by nutritional interventions (Quintanilha et al., 2017).

Omega-3 PUFAs improve lipid profiles, lower the expression of inflammatorymiRNAs and especially those derived from fish oil. For example, they improve vascular health through downregulation of the cholesterol-controlling miR-33. Their resveratrol improves endothelial function by upregulating miRNAs that favor vascular relaxation and reduce inflammation. Quercetin, a flavonoid found in tea, apples and onions, through changes in miRNA expression, controls the activity of vascular smooth muscle cells. This decreases the chances of hypertension and avoids arterial stiffness.

Epigenetic changes are also linked to hypertension, a substantial risk factor for CVD. Persistent hypertension is caused by altered DNA methylation in the renin-angiotensin system (RAS) genes, which impact blood pressure regulation. By causing aberrant methylation of genes like vascular endothelial growth factor (VEGF), excessive salt consumption may exacerbate high blood pressure. On the other hand, diets rich in polyphenols, omega-3 fatty acids and antioxidants guard against such harmful changes.

All of these findings suggest that epigenetic diets high in polyphenols omega-3 fatty acids and methyl donors can help prevent or manage cardiovascular disease by regulating the expression of genes linked to inflammation, vascular function and lipid metabolism. Type 2 diabetes (T2D) and obesity are examples of metabolic disorders that are complicated illnesses influenced by environmental exposures, lifestyle choices and genetic predispositions. It is becoming recognized that epigenetic changes play a crucial mediating role in their pathogenesis. For instance, there is a strong correlation between T2D and changes in DNA methylation in genes associated to insulin signaling and glucose metabolism. Hypermethylation of genes like PPARƴ which controls adipocyte growth and IRS1, which is involved in insulin signaling, reduces insulin sensitivity and predisposes to metabolic dysfunction. Consuming adequate folate and vitamin B12 helps maintain good methylation patterns, improve glucose management and reduce the risk of diabetes. Inflammation is another hallmark of metabolic disease. Hypomethylation of inflammatory genes like TNF-α promotes chronic low-grade inflammation, driving obesity and insulin resistance. Here, diet again provides potential for intervention. Histone acetylation of glucose metabolism genes improves insulin sensitivity by making chromatin more accessible for transcription, enhancing glucose uptake. Conversely, histone methylation of FOXO1, a gene regulating gluconeogenesis, increases glucose production and worsens insulin resistance. Nutritional polyphenols such as resveratrol and curcumin beneficially alter histone modifications, reducing inflammation and improving lipid metabolism. miRNAs also act as critical regulators of metabolic pathways. Dysregulated expression of miR-103 and miR-107 is associated with insulin resistance and T2D. Diet-derived compounds can reverse these changes (Martino et al., 2024).

Omega-3 fatty acids suppress pro-inflammatory miRNAs linked to insulin resistance. Quercetin and EGCG modify miRNA expression, reducing inflammation and improving metabolic regulation

Fatty Acids and Epigenetic Modification: Linoleic acid (LA), a major ω-6 PUFA, has been linked to obesity risk, with studies showing associations between higher intake and increased fat accumulation, BMI, and waist circumference. Experimental evidence further suggests that diets rich in LA and low in ω-3 fatty acids can drive multigenerational epigenetic changes, altering the expression of genes related to adiposity and inflammation and contributing to progressive weight gain.

High intake of ω-6 PUFAs has also been associated with colon cancer through CYP-mediated metabolites and epigenetic changes, including FXR activation, APC suppression, and TNFα promoter hypomethylation, all contributing to inflammation and tumorigenesis. Supporting this, longitudinal data show that linoleic acid stored in human body fat has risen dramatically over recent decades. Between 1961 and 2008, the percentage of LA in U.S. subcutaneous fat more than doubled, reflecting increased seed oil consumption. For instance, chimpanzees maintain LA levels near 7%, whereas modern humans now approach 20%, underlining how dietary shifts have transformed human fat composition and, potentially, long-term health consequences (Alt et al., 2022).

DIETARY POLYPHENOLS AND GENETIC MODIFICATION

Oxidative Stress and Disease Development

Oxidative and nitrosative stress have been widely investigated in the context of non-communicable diseases (NCDs). A change in redox homeostasis can damage biomacromolecules and affect protein function, prompting the start and progression of metabolic and inflammatory illnesses. While reactive oxygen and nitrogen species (ROS and RNS) are natural by-products of metabolism with critical physiological roles, their overproduction leads to oxidative damage and decreased detoxifying capacity (Di Meo et al., 2016).

Polyphenols as Redox Regulators

Rich in fruits, vegetables, tea, cocoa and other foods produced from plants, polyphenols have become powerful redox equilibrium modulators. They aid in the restoration of redox equilibrium by scavenging free radicals, boosting endogenous antioxidant defenses and modifying redox-sensitive transcription factors (Trowbridge et al., 2020).

Epigenetic Effects of Polyphenols

Polyphenols have both genetic and epigenetic effects. They regulate DNA methylation, histone acetylation and chromatin remodeling all of which have an impact on gene expression without altering DNA sequence. It is generally known that compounds like EGCG (green tea), resveratrol (grapes) and curcumin (turmeric) block DNA methyl transferases change histone deacetylases and activate sirtuins (Alyamani & Almatrafi, 2023).

Individual Variability and Personalized Nutrition

Individual responses to polyphenols are influenced by baseline redox status gut microbiota composition and genetic polymorphisms. This variation highlights dietary polyphenols potential in tailored nutrition strategies.

CONCLUSION

The studies of nutrigenomics and nutrigenetics are quickly evolving, bringing intriguing insights into how nutrition and genes interact to impact human health. As technology progresses, the integration of multi-omics techniques combining genomes, transcriptomics, proteomics, metabolomics, and epigenomics will allow a more thorough knowledge of how nutrients alter cellular pathways. In addition to finding new indicators of dietary response, this systems biology approach will aid in the development of targeted nutrition programs that are both curative and preventive. One of the most interesting areas is in the merging of artificial intelligence and big data analytics into nutritional genomics. Machine learning methods, guided by enormous genomic and nutritional datasets, hold the potential to predict individual responses to foods with surprising precision. When combined with reasonably priced genetic testing, this will enable more people to get customized nutritional therapies by integrating personalized diet planning into mainstream healthcare. In terms of public health, nutrigenomics and nutrigenetics are equally important. By discovering population-specific genetic variations and dietary risk factors, these disciplines can guide national dietary policy, fortification initiatives, and culturally adapted nutritional standards. This dual focus, combining individual precision and population-wide prevention, can help address the globally expanding burden of chronic diseases such as obesity, type 2 diabetes, cardiovascular ailments, and certain malignancies.