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Review
Primers on nutrigenetics and nutri(epi)genomics: Origins and
development of precision nutrition
Laura Bordoni, Rosita Gabbianelli
*
Unit of Molecular Biology, School of Pharmacy, University of Camerino, 62032, Camerino, MC, Italy
article info
Article history:
Received 4 December 2018
Accepted 8 March 2019
Available online 13 March 2019
Keywords:
Nutrigenetics
Nutrigenomics
Epigenetics
Gene-environment interaction
Personalized nutrition
abstract
Understanding the relationship between genotype and phenotype is a central goal not just for genetics
but also for medicine and biological sciences. Despite outstanding technological progresses, genetics
alone is not able to completely explain phenotypes, in particular for complex diseases. Given the exis-
tence of a “missing heritability”, growing attention has been given to non-mendelian mechanisms of
inheritance and to the role of the environment. The study of interaction between gene and environment
represents a challenging but also a promising field with high potential for health prevention, and epi-
genetics has been suggested as one of the best candidate to mediate environmental effects on the
genome.
Among environmental factors able to interact with both genome and epigenome, nutrition is one of
the most impacting. Not just our genome influences the responsiveness to food and nutrients, but vice
versa, nutrition can also modify gene expression through epigenetic mechanisms. In this complex pic-
ture, nutrigenetics and nutrigenomics represent appealing disciplines aimed to define new prospectives
of personalized nutrition. This review introduces to the study of gene-environment interactions and
describes how nutrigenetics and nutrigenomics modulate health, promoting or affecting healthiness
through life-style, thus playing a pivotal role in modulating the effect of genetic predispositions.
©2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights
reserved.
Contents
1. Gene-environment interactions: from genetics to epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................... 157
1.1. Healthy or unhealthy phenotype: is it nature or nurture? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........................157
1.2. Genetic determinants of health . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . ..........................................157
1.3. Limits and pitfalls of the genetic approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . ......................................158
1.4. The epigenome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..................................................158
1.5. Interaction between genetics and epigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................................160
1.6. Epigenetics as a bridge between the environment and the genome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........................160
1.7. The role of environment as a strong determinant of health . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........................161
2. Nutrigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................... 161
2.1. Introduction to nutrigenetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........................................161
2.2. The role of genetic variants in nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................................162
2.3. Genetic determinants of responsiveness to dietary interventions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ...........................163
2.4. Nutrigenetic tests for personalized nutrition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................................163
3. Nutrigenomics . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ....................... 164
3.1. Introduction to nutrigenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..........................................164
3.2. Nutritional factors that can influence the epigenome and the mechanisms involved . . . . . . . . . . . . . . . . . . . . . . . . . . . ......................164
3.3. Susceptible period of exposure, epigenetic reprogramming and transgenerational effects in nutrigenomics . . . . . . . . . . . . . . . . . . . ...........165
*Corresponding author.School of Pharmacy, University of Camerino, Via Gentile
III da Varano, Camerino, MC, Italy.
E-mail address: rosita.gabbianelli@unicam.it (R. Gabbianelli).
Contents lists available at ScienceDirect
Biochimie
journal homepage: www.elsevier.com/locate/biochi
https://doi.org/10.1016/j.biochi.2019.03.006
0300-9084/©2019 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.
Biochimie 160 (2019) 156e171
3.4. Interactions between nutrigenetics and nutrigenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......................165
3.5. Personalized epigenomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......................166
4. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................ 166
Author contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................ 166
Declaration of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................ 167
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ................................................ 167
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......................167
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .......................167
1. Gene-environment interactions: from genetics to
epigenetics
1.1. Healthy or unhealthy phenotype: is it nature or nurture?
As early as 350 BCE, trying to understand the origin of human
behavior, philosophers such as Plato and Aristotle epistemologi-
cally gave raised to the Nature vs Nurture debate. About 2000 years
after, we are nowadays almost sure that nor nature or nurture can
exist in a manner that can be considered independently quantifi-
able [1]. To paraphrase Richard Lewontin [2], “There are no genetic
factors that can be studied independently of the environment, and
there are no environmental factors that function independently of
the genome”.
After the advent of the Human Genome Project [3], genome
scientists, medical geneticists, and science policy leaders worked to
establish the value of genomic science by defining the fields of
public health genomics and precision medicine. These fields gave
rise to a new post-genomic combination of methods and disciplines
who made a shift from a “nature versus nurture”dichotomy to a
more systemic vision of the gene-environment interactions,
promising to lead to more accurate and consistent explanations for
diseases and a future based on personalized prevention and treat-
ment. Nevertheless, despite the consensus about the presence of
gene-environment interactions and their influence on health and
disease, researchers struggled to define, analyze and quantify the
environmental effects on the genome.
The concepts explained in this first section introduce
strengthens and weakness of genetic and epigenetic approaches to
study gene-environment interactions. These notions are propae-
deutic to clearly comprehend origins and development of nutri-
genetics and nutrigenomics, their limits and pitfalls, and the
importance of the integration between genetic and epigenetic in-
formation in precision nutrition.
1.2. Genetic determinants of health
Inheritable information given by the primary sequence of DNA
plays a key role in determining variations in the susceptibility and
severity of disease. The human genome includes about 3 10
9
base
pairs of DNA, and the amount of genetic variation in humans is such
that no two subjects (except for identical twins), have ever been
genetically identical. The amount of genetic variation between any
two humans is about 0.1%. This signifies that about one base pair
out of every 1000 is different between any two individuals [4]. In
both plant and animal genomes, the predominant forms of
sequence variations is represented by single nucleotide poly-
morphisms (SNPs), which distinguished from rare variations by
having a frequency of the least abundant allele of 1% or more [5].
Copy number variants (CNVs) or copy number polymorphisms
(CNPs), including duplications, deletions, insertions and complex
multi-site variants, are again other source of variation in the
genome [6]. Genetic variants can differ between ethnicities, are
inherited from ancestors and can take place through the entire
genome. Whether functional role of various non-synonymous
variants (comprising nonsense, missense, frameshift and other
types of variations) occurring in the coding region has been hy-
pothesized, it is still matter of debate how genetic variants taking
Abbreviations
5caC 5-carboxylcytosine
5 fC 5-formylcytosine
5hmC hydroxymethylcytosine
AKU alkaptonuria
ASM alleles specific DNA methylation
BMI body mass index
CGIs CpG islands
CNP copy number polymorphisms
CNV copy number variant
DNMT DNA methyl transferases
DOHaD developmental origin of health and disease
DTC direct-to-consumer
eQTL expression quantitative trait locus
GxE gene-environment interactions
HDAC histone deacetylase
Insdel insertion/deletion
LCT lactase
LD linkage disequilibrium
LEARn latent early life associated regulation
LINE long interspersed nuclear elements
LTR long terminal repeat
MTHFD1 5,10-methylenetetrahydrofolate dehydrogenase 1
MTHFR methylenetetrahydrofolate reductase
PAR predictive adaptive response
PEMT phosphatidylethanolamine-N-methyltransferase
PGCs primordial germ cells
PKU phenylketonuria
SAH S-adenosylhomocysteine
SAM S-adenosylmethionine
SINEs short interspersed nuclear elements
SNP single nucleotide polymorphism
TET Ten-Eleven Translocation
WHO World Health Organization
L. Bordoni, R. Gabbianelli / Biochimie 160 (2019) 156e171 157
place in the non-coding genome can actually have an impact [7].
That question is particularly challenging considering that genetic
variants in the non-coding genome are the most abundant in
general, and also that most of the single-nucleotide variants
significantly associated with an increased risk of complex diseases
have been mapped to non-coding regions [7].
However, understanding the connection between genotype and
phenotype is one of the main goals which several projects are
contributing to achieve. First of all, the reference human genome
sequence provided the basis for the study of human genetics; then
the public catalogue of variant sites (dbSNP 129) archived
approximately 11 million SNPs and 3 million short insertions and
deletions (insdels) identified in the genome; again, the Interna-
tional HapMap Project indexed both allele frequencies and the
correlation patterns between nearby variants (i.e. the linkage
disequilibrium), across several populations for 3.5 million SNPs
[3,8,9]. This knowledge leds to the genome-wide association
studies (GWAS), which analyze numerous hundred thousand of
variant sites, combining them with the information about linkage
disequilibrium structure and permitting to test the majority of
common variants (those with 5% minor allele frequency) for their
association with disease. The 1000 Genomes Project (describing the
genomes of 1092 individuals from 14 population) clarified the
properties and distribution of common and rare variations,
providing insights into the processes that shape genetic diversity,
and strongly increased the knowledge about disease biology
[10,11]. As a result, GWAS and other genetic studies identified the
association of more than 15000 SNPs with numerous pathologies or
traits [12]. They have impressively extended our knowledge about
how germline genetic variations impact disease susceptibility and
outcome [13,14], and also about how somatic changes in DNA
sequence severely impair gene expression, leading to the genesis
and advancement of disease [15].
However, these increased knowledge of genotypic information
were rarely flanked with downstream functional studies, that are
still needed to identify causal variants that contribute to human
phenotypes. Expression quantitative trait locus (eQTL) assays were
performed to ascertain associations between genotypes and gene
expression variations, but in most eQTLs the causal variant was
unidentified, and even when the expected causal variant could be
reliably identified, the involved regulatory mechanism was largely
challenging to be recognized [16,17]. Furthermore, whether genetic
influence is clearly established for monogenic traits, the landscape
becomes more and more intricate for complex polygenic
characters.
1.3. Limits and pitfalls of the genetic approach
For more than a century, individual differences in human traits
have been studied; nevertheless the causes of variation in human
traits, complex traits in particular, still remain controversial
[18e23]. Actually, in the last years, research has definitely estab-
lished that GWAS findings alone, besides large investments and
scientific efforts, does not tent to identify causal loci of complex
diseases and predict individual disease risk [13]. This has been
hypothesized to be due, among other factors, to the fact that GWAS
avoid to consider CNV and, above all, environmental factors in the
analysis. Large-scale GWAS demonstrates that many genetic vari-
ants contribute to the complex traits variation, but the effect sizes
for these traits are typically small. Furthermore, the sum of the
variance explained by the noticed variants is much smaller than the
reported heritability of the trait. This surprising and interesting
concept has been referred as ‘missing heritability’[24,25].
These observations contrast with the common diseaseecommon
variant hypothesis [13], which advocated that common variants
distributed in all populations determine phenotypic variation or
disease risk and that these variants all together are responsible for
an additive or multiplicative effect on trait variation or disease risk.
On these behalf, several explanations have been suggested to clarify
the architecture of complex traits and diseases: (A) the hypothesis
that a large number of common variants exerting a small-effect
account for disease risk and quantitative trait variation; (B) the
hypothesisthat a large number of rare variants having a large-effect
motivates the observed associations; or (C) the theory that a com-
bination of genotypic, epigenetic, and environmental interactions
can explain the observed relations [13]. This complex scenery leads
some researchers to focus on the importance of non-additive vari-
ation models in genetics [26,27]. Beside, considering that the nature
of complex diseases is multi-factorial, many researchers have sup-
ported the idea that major factors contributing to the missing her-
itability are the interactions among genetic loci, so-called epistatic
interactions. Indeed, multifaceted interactions between environ-
mental factors and genetic variants, both potentially associated to
disease risk, have been suggest to be taken into account.
For all these reasons, while numerous studies in the last decades
centered their attention to the identification of different genetic
variants that could explain a certain phenotype, nowadays concepts
such as epistasis, gene-gene interaction and gene-environment in-
teractions represent the research focus that could provide further
information about the genetic determinants of a certain phenotype
[24]. Moreover, this landscape highlights opportunities to consider
epigenetics as a functional modifier of the genome and a major
contributing factor for disease etiology [28]. If heritability is classi-
cally described as the ratio of the genetic to the total phenotypic
variance, in a population [29], the more contemporary concept of
‘broad sense heritability’denotes the genetic effect including non-
additive components, such as gene-gene interactions, gene-
environment interactions (G E), and epigenetics [13].
1.4. The epigenome
Beginning over 70 years ago, the field of epigenetics massively
grew to elucidate mechanisms through which various cellular
phenotypes originate from a single genotype throughout the
intricate process of developmental morphogenesis termed
epigenesis. The word ‘‘epigenetics’’ was firstly coined by Conrad
Waddington (1905e1975) in 1940s. He used it to define “the branch
of biology which studies the causal interactions between genes and
their products, which bring the phenotype into being”[30]. After
some debates, a consensus definition was delineated and epige-
netics was defined as “stably heritable phenotypes resulting from
changes in a chromosome without changes in gene sequence”[31].
Epigenetic mechanisms of gene regulation, which collectively make
up the epigenome, mainly encompass enzymatic methylation of
cytosine bases (DNA methylation), post-translational modification
of tail domains of histone proteins (histone modifications) and
chromatin remodeling. These modifications arise all over the
developmental stages or ensue to environmental factors exposure,
providing both variability and rapid adaptability, that allow or-
ganisms to respond to external stimuli both in the short and in the
long term.
The relevance of epigenetics in the development is connected to
the ability of a single-cell zygote with a fixed genomic sequence to
give rise to an organism with hundreds of cell types thanks to its
ability to control subset of genes expressed in each cell type. Spe-
cifically, extensive removal and reestablishment of lineage-specific
epigenetic signatures, through a process designated as epigenetic
reprogramming, are at the basis of cellular differentiation [32].
Conservation and inheritance of these epigenetic marks during cell
division is fundamental to preserve a committed cell lineage and
L. Bordoni, R. Gabbianelli / Biochimie 160 (2019) 156e171158
cellular phenotype in descendant cells, and establish a memory of
transcriptional status. In detail, epigenetic marks are reprog-
rammed in a global scale, concomitantly with restoration of
developmental potency, at two points in the life cycle: firstly on
fertilization in the zygote, and secondly in primordial germ cells
(PGCs), that are the direct precursors of sperm or oocyte. A
distinctive set of mechanisms regulates epigenome erasure and re-
establishment [32e34]. In this picture, ‘epigenetic’marks describe
the developmental potency of the zygote and promote differenti-
ation towards a specific cell fate in future cell generations.
Methylation of the fifth carbon of the cytosine base in DNA and
post-translational histone tail modifications are probably the best-
studied epigenetic modifications in mammals [35]. DNA methyl-
ation is the covalent addition of a methyl group at the 5-carbon of a
cytosine ring, resulting in 5-methylcytosine (5 mC), likewise
informally defined as the “fifth base”of DNA. This reaction is
catalyzed by DNA methyltransferases (DNMTs) enzymes [36]. There
are three main DNMTs: DNMT1 copies methylation marks from the
parental strand of DNA to the newly synthesized strand during the
process of DNA replication (thus it is defined as the maintenance
DNMT, which allows transmission of DNA methylation patterns
from cell to cell), while DNMT3A and DNMT3B establish a de novo
DNA methylation [36,37]. DNA methylation is the most chemically
stable epigenetic modification and it is unambiguously stably
transmitted during cell division. As a consequence of its biologic
interest, it is the most well characterized epigenetic mark and the
most extensively measured in epidemiologic research.
In mammals, DNA methylation occurs primarily on cytosines
within a CpG dinucleotide, of whom approximately 70e80% are
methylated [38]. Besides, stretches of CpG-rich sequences with low
levels of DNA methylation, also called CpG islands (CGIs), exist
[11,39]. CpG islands are defined as sequences with a G þC content
above 60% and a ratio of CpG to GpC of at least 0.6 [40]. They
frequently are highly enriched at gene promoters (about 60% of all
mammalian gene promoters are CpG-rich). Unmethylated CpG
islands are usually open regions of DNA with low nucleosome oc-
cupancy (euchromatin), promoting relaxed chromatin structure
that facilitates accessibility to the transcription start site of RNA
polymerase II and other components of the basal transcription
machinery [41,42]. On the other hand, DNA methylation is
frequently related to gene repression [43,44]. Many targets of de
novo DNA methylation are promoters of stem cell- and germline-
specific genes during differentiation, repetitive DNA sequences,
such as those within the chromosomes centromeric and pericen-
tromeric regions or in the endogenous transposable elements (i.e.
long interspersed nuclear elements (LINEs), short interspersed
nuclear elements (SINEs) and long terminal repeat (LTR)-contain-
ing endogenous retroviruses) [43,45]. Moreover, DNA methylation
recruits methyl-CpG-binding proteins which interacts with pro-
teins that can play a role in the repression of genes with CpG islands
(i.e. Methyl CpG binding protein 1, MeCP1) or, on the other hand,
can add silencing modifications to neighboring histones (i.e.
MeCP2) [46]. This harmonization between DNA methylation and
silencing histone marks determines the compaction of chromatin
and gene repression. However, DNA methylation is also found
within the bodies of genes, where higher levels of intragenic
methylation correlate with higher levels of gene expression. Thus,
the functional significance of gene body methylation is less clear,
and regulation of alternative transcription initiation sites or regu-
lation of splicing are two potential role hypothesized to explain this
phenomenon [47e50].
Despite it was originally retained that DNA methylation was a
stabile mark which once established was then maintained
throughout the life course of the organism (because of its ther-
modynamic stability and the initial incertitude of a biochemical
mechanism that could directly remove the methyl group from
5 mC), it is now clear that DNA methylation can be dynamically
regulated [49]. Recent discoveries showed that, together with
DNMTs-mediated methylation processes, passive or enzymatically-
directed DNA demethylation also occur. Several DNA demethylases
such as Ten-Eleven Translocation (TET) proteins, Methyl Binding
Domain protein, DNA repair endonucleases XPG and a G/T
mismatch repair DNA glycosylase has been identified. They do not
act by directly removing the methyl group, but through a multistep
process linked either to DNA repair mechanisms or through further
modification of 5 mC such as 5-hydroxymethylcytosine (5hmC), 5-
formylcytosine (5 fC) and 5-carboxylcytosine (5caC). TET proteins
can oxidize 5 mC to 5hmC but also to 5 fC and/or 5caC, which are
subsequently excised by thymine DNA glycosylase, or deaminated
by activation-induced deaminase, whose deamination product (5-
hydroxymethyluracil), activates base-excision repair pathway
leading to demethylation [51e56]. Among these other DNA modi-
fications, 5hmC acquired growing importance, specifically in
certain cell types, not just as an intermediate of demethylation
processes, but as an epigenetic mark itself. High levels of 5hmC are
found in embryonic stem cells, in multipotent adult stem cells and
progenitor cells. During differentiation, levels decrease in most of
cells, except that in Purkinje neurons and other neural subtypes,
where high levels can be still measured [57]. Like 5 mC, 5hmC is not
uniformly distributed though the genome. 5hmC are enriched
within gene bodies and at transcription start sites and promoters
associated with gene expression, supporting the premise that
5hmC is associated with gene activation [58e60]. Interestingly,
DNA hydroxymethylation has been demonstrated to be affected in
response to environmental stress through redox system alterations
and, in particular, TET proteins activation [61,62]. Which are the
connections between 5 mC, 5hmC and gene expression regulation
is still to be completely elucidated.
Together with DNA modifications, epigenetic gene regulation
also includes modifications in histones that make up the nucleo-
somes. Nucleosomes are the basic unit of chromatin in eukaryotic
organisms, composed by the DNA wrapped around a core of eight
histone proteins (H2A, H2B, H3 and H4), essential to reduce its
size. Beside this fundamental function, it is now clear that histones
are not only important for DNA packaging, but also exert pivotal
roles in gene expression regulation, in conjunction with DNA
methylation [63]. Histone proteins contain a globular domain and
an amino tail domain. The amino tail domains protrude out of the
nucleosomes and are rich in positively charged amino acids, that
interact with the negatively charged DNA. These tails are subject to
a large number of post-translational modifications, among which
the most frequent are acetylation, methylation, ubiquitination,
sumoylation, and phosphorylation, raising up to thousands of
potential combinations of modifications within a single nucleo-
some [64]. Thus, whereas DNA can primarily be methylated, his-
tones are capable of carrying a wide array of post-translational
modifications, with different role in gene expression regulation
processes [65,66]. They are dynamic, and several enzymes
involved in their modulations have been identified [67]. Recur-
rently, specific histone variants are found at definite locations
within the chromatin or are used to demarcate heterochromatic
and euchromatic regions. Histone modifications can directly in-
fluence interactions between histone and DNA or between
different histones, or they can be targeted by protein effectors also
called histone-binding domains. To define proteins that deposit,
remove and recognize histones post-translational modifications,
respectively, the terms ‘writer’,‘eraser’and ‘reader’were coined
[68,69]. They can act in cooperation, and it is the peculiar
arrangement of histone modifications at a specific site that
habitually defines which protein complexes are recruited to
L. Bordoni, R. Gabbianelli / Biochimie 160 (2019) 156e171 159
activate or repress transcription, catalyze further histone modifi-
cations or recruit other histone-modifying proteins [70], regu-
lating various DNA-dependent processes, including DNA
replication, transcription and repair. The collection of the “post
translational modifications of specific amino acid residues within
the histones that leads to the binding of effector proteins that, in
turn, bring about specific cellular processes”is defined as histone
code [71,72]. While mechanisms of transmission of DNA
methylation has been recognized, it is still debated how histone
modifications are transmitted during cell replication [73,74].
Furthermore, more recent evidence suggests that local and three-
dimensional chromatin architecture provide additional levels of
gene regulation in pluripotent stem cells. Local chromatin archi-
tecture defines the position and density of nucleosomes as well as
the presence of histone variants [75,76]. However, its roles in
cellular reprogramming has not been completely elucidated yet.
Ongoing projects are producing cell-specific reference data sets
that offer a basis for defining the complex interaction between
epigenomic processes and the transcriptome: ENCODE (Encyclo-
pedia of DNA Elements) project and the International Human
Epigenome Consortium [77] intended to classify the regulatory
elements in human cells and to investigate the epigenomic sig-
natures of cell cultures; the Roadmap Epigenomics Project (from
US National Institutes of Health) extends the ENCODE project and
is devoted to clarify in what way epigenetics contribute to human
biology and disease [78,79]. Providing reference epigenomes for
numerous human tissues and cell-types, research provided the
basis to understand how epigenomic are linked to the corre-
sponding genetic information. The final goal would be to clarify
the complete landscape of epigenomic elements which controls
gene expression in the human body [80].
1.5. Interaction between genetics and epigenetics
Epigenetic mechanisms may be considered complementary to
genetic functions in the regulation of gene expression and can be
saw as the way by which a specific cell or tissue interprets the
genome information [81]. At the same time, primary DNA sequence
is a strong determinant of the epigenetic state. This can be
evidently inferred by noting that the distribution of epigenetic
marks across the genome is, at least in part, determined by CpG
density and G:C content in the sequence [82,83]. Additionally,
proximity to repetitive elements such as Alu and LINE, nuclear ar-
chitecture and binding sequences for transacting proteins repre-
sent further genetic influences. Furthermore, some evidences
suggested that genetic polymorphisms can affect epigenetic state
[34]. In fact, mutations in genes encoding epigenetic modifiers
(such as DNMTs, chromatin remodeling proteins or histone modi-
fying enzymes) can contribute to epigenetic changes, and have
been well documented in several diseases [34]. Aberrant epigenetic
modifications can directly modulate regulation of target genes or
can interact with specific genetic variants predisposing to them
[34]. Furthermore, studies that investigated both genetic variations
and DNA methylation demonstrated that alleles specificDNA
methylation, related to polymorphic nucleotides situated nearby
the DNA methylation site, can extensively occur through the
genome [84].
Given the complexity of the genome and the notable intricacyof
epigenetic changes, that take account of dozens of different post-
translational histone modifications and more than 50 million
sites of potential DNA methylation in a diploid human genome, it
appears that no two human cells would have identical epigenomes,
which, additionally, change over time in response to develop-
mental and pathological progressions, as well as consequentially to
environmental exposures and random drift [34].
1.6. Epigenetics as a bridge between the environment and the
genome
In accordance with the World Health Organization (WHO), more
than 13 million deceases per annum are caused by environmental
issues and so far as 24% of disease is due to exposures which could
be prevented [85]. A conspicuous amount of lifestyle and envi-
ronmental factors have been revealed to affect numerous diseases;
however, not all of them have been characterized as genotoxic
agents, able to promote DNA sequence mutation [86]. Thus,
genome-environment interactions have been discussed exten-
sively, and the role of epigenetics has been progressively more
acknowledged as a mechanism of interface between them [87].
Indeed, multiple differences in gene expression have been recog-
nized in numerous tissues already from newborn identical twins
(presumably reflecting intrauterine epigenetic differences), sug-
gesting that not just differences in the genome, but also different
exposure to environment, can affect the epigenome [88]. Consid-
ering that several epigenetic events have been identified as tissue-
specific and reversible, epigenetics is particularly compelling to
explain differential susceptibilities in the exposed population and
why exposures affect precise organs.
Since a lot of epigenetic modifications can be modulated by both
external and internal factors and can change gene expressions,
epigenetics is considered a key mechanism through which ge-
nomes interact with environmental exposures, providing a novel
approach in the exploration of etiological factors in numerous
environment related pathologies [89]. As these epigenetic marks
are potentially cumulative and could take place over time, to
identify the cause-effect associations among epigenetic changes,
environmental factors and diseases represents a big goal. However,
even if mechanisms of action of some of these agents remains to be
completely elucidated, some others has been well characterized
[34,89,90].
The epigenome appears more susceptible to environmental
factors during periods of extensive epigenetic reprogramming in
early life, particularly during the prenatal, neonatal and pubertal
periods, when the epigenome is being established and environ-
mental insults may interfere with processes that regulates its
reprogramming. However, somatic changes to epigenetic marks
might also ensue from environmental exposures in adults, as it has
been observed in aging and numerous disease processes (i.e. can-
cer, neurodegenerative and metabolic diseases among others)
[34,89,90].
Furthermore, numerous environmental factors, from nutrition
to toxicants, have been shown to induce an epigenetic trans-
generational inheritance [91], which is described as the germline
transmission of epigenetic information between generations
without direct exposure [92]. Several different model of epigenetic
inheritance of disease and phenotypic variation has been proposed
to be linked to environmental exposure. Drake and Lui [93e95]
outline three possible mechanisms that could be responsible of
multigenerational observations: a) persistent environmental ex-
posures (i.e. generation after generation) during early develop-
ment; b) a single “maternal environment”exposure that can yet
induce a multigenerational phenotype; and c) epigenetic effects
which can be transmitted across the germline. Transgenerational
epigenetic inheritance induced by environmental agents has been
mainly studied performing exposure to environmental insult dur-
ing pregnancy, which can affect a mother (F0 generation), the
developing fetus (F1 generation) but also the fetus germ cells which
will go on to form the F2 generation. Nutrition [96], temperature
[97], stress [91], and toxicants [91] can all induce epigenetic
transgenerational inheritance of phenotypic variation [98]. This
evidence has been demonstrated in plants, fish, insects, pigs,
L. Bordoni, R. Gabbianelli / Biochimie 160 (2019) 156e171160
rodents, and humans [91]. The altered transgenerational pheno-
types have been observed for generations in mammals [91], and for
hundreds of generations in plants [99]. The capacity of environ-
ment to modify phenotype and phenotypic variation through
epigenetic mechanism is suggested to be important for evolution.
Environmentally induced epigenetic inheritance can bring a pop-
ulation closer to an increased fitness in a faster way than genetic
changes; then, genetic variations may ultimately follow (if the new
environment is stable), likewise the genetic fixation of initially
induced phenotypes occurs. Furthermore, the selection can act
upon randomly induced metastable epialleles, thus contributing to
adaptation in a similar way than genetics [10 0].
Indeed, environmental epigenetics and epigenetic trans-
generational inheritance represent the molecular mechanism able
to support the neo-Lamarckian theory, which assert that environ-
mental factors directly alter phenotypes. Although aspects of the
original Lamarckian evolution theory, such as having “directed”
phenotypes within a generation, were not accurate [101e103], the
notion that environment can impact phenotype is reinforced by
environmental and transgenerational epigenetic studies. These
findings do not contrast the Darwinian theories, but rather overlap
with them, suggesting that a new integrated theory should be hy-
pothesized. Specifically, the well-established aspect of Darwinian
evolution is the ability of environment through natural selection to
act on phenotypic variation, with genetic mutations and variation
considered the main molecular mechanism involved in generating
the phenotypic variation. Nevertheless, being the environment able
to impact epigenetic programming through generations, environ-
mentally induced epigenetic changes can be considered as another
source of phenotypic variation. Guerrero-Bosagna and colleagues
reports an example of how developmental effects of environmental
exposures can influence adult characters in mammals also poten-
tially having evolutionary consequences [104]. They demonstrated
that a high consumption of isoflavones can alter both epigenetic
and morphometric characters or sexual maturation, which are
characters that might play relevant roles from an evolutionary
perspective. All in all, the unified evolutionary theory sustains that
both environmental epigenetics (impacting on phenotypic varia-
tion) and the capacity of environment to intercede in natural se-
lection will be equally important for evolution [105]. Another
relevant aspect is the ability of epigenetic processes to endorse
genetic mutations [106], in particular CG to TG transitions [107];
thus, environmental epigenetics might not merely provide
increased phenotypic variation, but could drive genetic change and
directly increase genotypic variation likewise.
Being both genetic and environment pivotal phenotypic de-
terminants, genetic X epigenetic X environmental interactions has
to be taken into account [108], in order to carefully define intricate
biological interactions and, as ultimate goal, ascertain susceptible
subpopulations. Beyond implication of evolutionary prospectives, it
is intuitive that epigenetics has considerable potential for identi-
fying new biomarkers to predict which exposures would increase
the risk in exposed subjects and which individuals are particularly
vulnerable to develop disease.
1.7. The role of environment as a strong determinant of health
There has been a growing awareness of environmental effects on
human health, and that neither purely environmental factors, nor
purely genetic factors can entirelyexplain the observed estimates of
disease incidence and progression. Furthermore, the balance be-
tween genetic and epigenetic contributions in the development of
pathologies appears to change during life. While, for instance, the
majority of childhood tumors are connected to an inherited genetic
or epigenetic (for example, imprinted) problem, this equilibrium
shifts in favor of acquired epigenetic and genetic burden in tumors in
adult or elderly age [109]. Many epidemiologic studies investigated
the effects of exposure to chemical, social or physical factors in
relation to several pathologies, such as cardiovascular disease, dia-
betes and canceramong others. These kind of studies are starting to
incorporate gene-environment interactions and epigenetic modifi-
cations to better investigate the multidisciplinary nature of indi-
vidual, in order to have a better estimate of the complexity of
exposure biology and the smalleffects that are easily disturbed[110].
Numerous environmental factors have been suggested to be able
to influence the epigenome, resulting in long-term changes in gene
expression and metabolism: air pollution, tobacco smoke, oxidative
stress, organic chemicals, endocrine disruptors, metals and, last but
not least, nutrient intake and social environments [34,109]. The
totality of our exposures from conception onward has been defined
by Christopher Wild with the new coined term “exposome”. Expo-
sures come from our external environment and lifestyle, but are also
the outcome of our internal biological processes and metabolism;
given this more complete view of the exposome, the concept was
redefined by Miller and Jones as “the cumulative measure of envi-
ronmental influences and associated biological responses
throughout the lifespan.”Current scientific opinion sustains that the
study of the exposome could be helpful to clarify the interaction
between genetic and environmental factors that contribute to dis-
ease, with the potential to revolutionize biomedical science, espe-
cially in term of prevention of late onset chronic disease that
represent the main burden in the modern society [111].
Several different models have been hypothesized to explain the
role of epigenetics on the late onset disease. Barker hypothesized
that adult diseases are consequences of fetal adverse conditions
due to the fetus adaptation to a certain environment to which it was
exposed in early life [112 ]. Adaptive responses, which can be either
in the form of metabolic changes or sensitivity of the target organs
to hormones, will not induce immediate consequences in the
newborn but could lead to physiologic and metabolic disturbances
in later life. Gluckman and Hanson suggested that fetal exposure to
adverse conditions makes immediate changes which are reversible,
except in the case that stress conditions persist [113 ]; in that case
fetus undergoes to irreversible changes that will persist throughout
life, influencing (positively or negatively) the adulthood [114]. They
coined term predictive adaptive response (PAR) for the phenome-
non. Another hypothesis is represented by the DOHaD (Develop-
mental origin of health and disease) model, which postulate that
not merely embryonic development but also the period of devel-
opment during infancy is responsible for late life risk of diseases.
Another theory, which represents the evolution of the previously
listed, is the LEARn (Latent early life associated regulation) model.
This concept sustains that environmental agents such as nutrition,
metal exposure, head trauma and lifestyle are “hits”that are related
to the cause and progression of common late onset diseases. LEARn
is based on the idea that latent epigenetic changes induced in early
life do not result in any disease symptom immediately, but create a
perturbation in the genome. It is just later in life, after a latency
period (which finish when a second triggering agent manifest), that
the epigenetic perturbation will result in manifested consequences.
Genes that respond late in relation to early life responses are called
LEARned genes, while others which don't are called unLEARNed.
The responses to the early life environmental triggers after the la-
tency period is defined as LEARning [115 ].
2. Nutrigenetics
2.1. Introduction to nutrigenetics
The notion that interactions between genetics and nutrition are
L. Bordoni, R. Gabbianelli / Biochimie 160 (2019) 156e171 161
responsible for the final phenotype was recognized by Archibald E.
Garrod in 1902, when he published in The Lancet a milestone paper
in which he depicted his observations of people with black urine or
black bone disease, also known as alkaptonuria (AKU) [116]. AKU is
a rare disorder of autosomal inheritance. It is caused by a mutation
in the homogentisate 1,2 dioxygenase gene, resulting in the accu-
mulation of homogentisic acid. It was one of the first disorders
found to conform with the principles of Mendelian recessive in-
heritance in humans, and was primarily described as an example of
genetic disruption of food metabolism. The increasing in
biochemical knowledge gradually started to support fruitful
nutritional intervention for handling some of these metabolic pa-
thologies. In 1934, Asbjørn Følling discovered that another defec-
tive metabolism of a dietary amino acid (phenylalanine) could
induce severe mental deficiency in subjects affected by a metabolic
defect called phenylketonuria (PKU). Later, in 1953, Horst Bickel
demonstrated that nutritional treatment can be effective in treating
this condition, helping to prevent devastating consequences just
starting a specific nutritional treatment few days after birth. The
same happened with other untreatable inherited diseases (maple
syrup urine disease, biotinidase deficiency and others), for which
early nutritional intervention resulted to be effective [117].
In 1960, Dr JA Roper explained the links between genetics and
nutrition with a paper entitled ‘Genetic determination of nutri-
tional requirements’[118]. There was quite slight progress in un-
derstanding interactions between genotypes and nutrition in
humans until the Human Genome Project was completed; few time
later, ‘nutrigenomics’, i.e. the study of the gene-nutrients in-
teractions, was predicted would be the future of nutrition [119 ,120].
Nutritional genomics (or nutrigenomics) has been described as the
branch of science investigating all types of interactions between
nutrition and the genome by high-throughput genomic tools [121].
Nutritional genetics (or nutrigenetics) is described as a sub-set of
nutrigenomics, which aims to understand how genomic variants
interact with dietary factors and which implications derive from
such interactions (Fig. 1 A).
2.2. The role of genetic variants in nutrition
Nutrigenetics examines inherited differences in nutrient meta-
bolism and investigates how to use individual genetic information
to tailor better nutrition plans [117 ]. Several different types of
genomic structural variation emerged from the investigation of
human genome [122]. SNP, inverted gene sequences, gene deletion,
segmental duplication and CNV has been almost all associated to
some nutritional-related phenotype or showed to be able to modify
individual's response to diet.
While the ‘simple’Mendelian genetics is responsible for inborn
errors of metabolism such as alkaptonuria or phenylketonuria,
multifactorial diseases, such as diet-related diseases and obesity,
are seldom due to single genetic variants. For example, at least
ninety-seven variants resulted to be associated with body fatness,
and together these explain <3% of the variance in BMI [123,124].
Numerous pathways affecting the central nervous system (i.e.
satiety regulations or food intake) or metabolic features, such as
lipid metabolism and adipogenesis, are regulated by the involved
genes. Additionally, genetic variants involved in various cell
biology, cell signaling and in RNA binding processing has been
related with adiposity risk as well [123]. This is just an example
intended to underline the complexity of nutrigenetics, which aim
to study complex polygenic traits, related to numerous different
physiological pathways.
Fig. 1. Graphical representation of interactions between diet and the genome. (A) Nutrigenetics: genetic polymorphisms can induce differential gene expression. As a result, different
metabotypes, which show different responses to diet, different nutrient requirement and potential food intolerance, exist. Of note, the location of the SNPs can also affect epigenetic
modifications. (B-C-D) Nutrigenomics: methyl donors availability, bioactivity of dietary compound and xenobiotics (B) can affect the one-carbon cycle and other pathways thus,
consequentially, affect DNA methylation and histone modifications (C). Not just parental molecules (B) but also derived compounds and metabolic products of microbial activity (D)
can affect these pathways (C).
L. Bordoni, R. Gabbianelli / Biochimie 160 (2019) 156e171162
Genetic variants able to modulate the effects of certain dietary
factors or to affect food preferences can be investigated through
different experimental approaches. The candidate gene approach is
based on the selection of a gene because of its putative function or
for other specific knowledges about it. In dependence on the
number of SNPs in the gene and their potential functional effects,
assessments can be conducted using single SNPs or combinations of
them, such as haplotypes. More recently, genome-wide approach
started to be applied in modern studies. This method is based on
the identification of previously unknown genetic variants which
can modify response to diet scanning the entire genome. Whether a
candidate gene approach is preferential if few genetic variance
(selected a priori following a certain hypothesis) want to be tested
with a high power, GWAS has the advantage to be hypothesis-free
and can be useful for exploratory analysis, testing large number of
variants at the same time. At the same time, very large populations
are required for GWA studies to have a good power. Other strate-
gies, such as meta-analysis of GWAS or calculation of genetic risk
score, can be helpful to increase the analyzed population or take
into account different genetic model, respectively.
Recognizing relevant diet-gene interactions will not only be
useful for individual personalized dietary advices, but will improve
public health recommendations (supported by scientific evidences
connecting specific dietary compounds to different health out-
comes) and scientific research as well. In fact, studying people re-
sponses to a nutrient assuming that they are all metabolically
similar, often results in the identification responders and non-
responders to the intervention, and this observed variation in the
outcome is frequently attributed to weaknesses in the scientific
design of the study, making obtained results difficult to publish ad
difficult to use to improve human health. Thus, the usage in study
projecting of modern genetic methods, through which is possible to
predict who are the responders, could strongly help to improve
results and optimize resources [117].
2.3. Genetic determinants of responsiveness to dietary interventions
Diet represents a key modifiable risk factor for human health.
However, benefits we currently gain are significantly reduced
comparing to the full potential of its protective effects. Several
reasons can be at the basis of this phenomenon, including indi-
vidual variability in response to certain nutritional regimen. Taking
into account that genetic variants can create metabolic in-
efficiencies, it is reasonable to hypostesize that such SNPs can in-
fluence dietary requirements. Thus, it is almost evident that taking
into account individual responses is essential to gain the full benefit
of dietary regimes [125].
There are considerable evidences that inter-individual variation
in response to dietary interventions can influence beneficial effect
that certain individuals or population subgroups can obtain, more
than others, from a diet, in dependence on their genotype,
phenotype, and environment [126]. Despite that, dietary reference
values, which are designed for the general population assuming a
unique Gaussian distribution, are not optimized for genetic sub-
groups, which may significantly differ for noteworthy metabolic
aspects (such as for example the activity of metabolic enzyme
requiring micronutrients as cofactors and/or micronutrient trans-
port proteins) because of their genetics [126]. Considering that the
“one-size-fits-all”approach applied in nutrition until now resulted
to be unsuccessful, the identification of genetic variants, that
recognize responsive and non-responsive individuals for specific
dietetic intervention, represents one of the most challenging and
potentially useful goal of nutrition research. If the issue is relatively
easy for monogenic characters (such as the genetic determinant of
lactose intolerance), the landscape becomes more intricate for
complex polygenic traits, such as predisposition to hypertension or
diabetes. Despite consistent efforts, it is still to be cleared how to
modulate disease development through consumption of a complex
diet based on different genotypes [125].
2.4. Nutrigenetic tests for personalized nutrition
Precision nutrition can occur at three levels: (1) conventional
nutrition, following general guidelines for population groups by
age, gender and social determinants; (2) individualized nutrition,
that take into account also phenotypic information about current
nutritional status of the subject (such as, among others,
biochemical and metabolic analysis, anthropometry and physical
activity), and (3) genotype-directed nutrition, taking into consid-
eration rare or common gene variation which determine different
responses to certain nutritional plans [127]. The use of genotypic
information in tailoring personalized dietary advice has been a
major objective since the beginning of the modern nutrigenomics
era [128]. Several beneficial effects of providing personalized
nutritional advices, such as supporting disease prevention,
reducing health care costs and improving motivation to change,
has been observed [129,130]. Besides, recent randomized control
trials showed that genotype-based personalized dietary advices
were better understood and increased the adherence to the
nutritional plan than general dietary advice [130,131]. This result is
not irrelevant, considering that compliance and diet adherence has
been identified as one of the most effective parameters in nutri-
tional intervention success [132].
Relevant findings concerning this aspect come from the EU-
funded Food4Me project [133]. It is a multi-center study aimed
to investigate if fully internet delivered personalized nutrition
advice (according to individual phenotype and genotype) could
affect people's lifestyle. Promising data from the Food4Me Euro-
pean randomized controlled trial involving 683 participants shows
greater body weight and weight circumference reductions in risk
carriers than in non-risk carriers of the fat mass and obesity-
associated (FTO) gene, when participants were informed to be
carriers of the FTO risk allele [134]. Further investigations from the
Food4Me study showed that adherence to specific healthy regi-
mens, such as the Mediterranean diet, can have beneficial effects
on anthropometric parameters overcoming an adverse genetic
load [135 ]. Nevertheless, San-Cristobal and colleagues demon-
strated that a higher genetic risk score (calculated by several ge-
netic variants related to metabolic risk features) may reduce
benefits on total cholesterol levels and influences the levels of
plasma carotenoids, indeed suggesting that gene nutrient in-
teractions might contribute to the implementation of practical
accurate nutrigenetic advice. However, despite promising evi-
dences, no univocal demonstration that including phenotypic plus
genotypic information can improve the effectiveness of the
personalized nutritional advice can be inferred from this big study
[136,137].
All in all, nutrigenetics is still involved in an extensive discus-
sion about personal genetics, which started in 2001 with the
presentation of Sciona Ltd. (in the United Kingdom), and persisted
with the subsequent launch of popular companies such as
23andMe, Navigenics and deCode in the following years [13 8]. The
principal query, indeed, concerns the clinical utility of nutritional
genetic tests: can the evidences coming from nutrigenetic studies
be translated into helpful dietary recommendation which would
not be accessible without the use of genetic information? There is
emerging consensus on the idea that each subject's health is
established by interactions between his or her fixed genotype and
nutrition (among other environmental exposures), in addition to
the effects of stochastic events, as hypothesized in the ‘‘health
L. Bordoni, R. Gabbianelli / Biochimie 160 (2019) 156e171 163
pendulum’’ theory. Nevertheless, current knowledge in this area is
fragmentary, and a limited number of dietegeneehealth associa-
tions have been tested for causality in intervention studies on
humans [128]. Filling these gaps will require larger, even better-
designed randomized controlled trials. At the same time, it is
also true that most of nutritional recommendation come from
observational and epidemiological studies. Thus, it is debated why
the level of evidence for genetically influenced nutritional advice
are not evaluated according to the same standards used for
traditional nutritional recommendations [138]. Gorman and col-
laborators also discuss risks and benefits of precautionary princi-
ple, thus ignoring nutrigenetics. For certain nutrigenetic
evidences, such as those regarding methylenetetrahydrofolate
reductase (MTHFR) gene C677T polymorphism, folic acid, and
homocysteine, it is to choose that chronically high homocysteine is
potentially less dangerous than increasing daily folic acid intake, in
individuals who don't benefit of the standard recommended
intake because carriers of the TT genotype. Whether ignore new
scientific evidences can sometimes be synonymous of applying the
precautionary approach, it is probably not always the case of
nutrigenetics. Wildavsky [13 9] claims that in the case of lack of
knowledge, small-risk taking, followed by stepwise evaluation, is a
safer course than avoiding risk. Cautious estimation of the balance
between benefits and risks, together with a step by steps approach
able to progressively increase the benefits and diminish the risks,
would be probably the best way to approach nutrigenetics. This
means that more and more research on this promising field is
required. The inconsistent results produced by the candidate-gene
association studies are actually not associated to the research
quality in general, but rather to the complexity of nutritional ef-
fects in the long term. Technological improvements and the
increasing usage of genotype analysis in randomized control trials
suggest a promising increase of knowledge in this field in the next
years.
Thus, it is clear that nutrigenetics is not a science with easy
answers and it doesn't rely on a standard dietary recommendation
to each genotype. Nutritional factors interactions with the genome
are very complex and need competent nutrition professionals who
can guide patients successfully through this complex landscape
[117]. Furthermore, from a dietetic point of view, there is often not
just one simply solution for a specific problem. On the contrary
many solutions can be designed by dieticians, physician and
nutritionist, depending by other characteristics of each analyzed
subject beyond its genetics. In fact, personalized nutrition is based,
per definition, on the knowledge and integration of the genetic
background with biological and cultural variations, such as food
preferences, intolerances and allergies. This means that the genetic
profile alone is usually not sufficient to provide a personalized di-
etetic plan, while it has to be integrated by expert professionals
with patient anamnesis, anthropometry, food preferences and life-
style. For this reason, another open debate is currently centered on
the legitimacy of direct-to-consumer (DTC) tests [140], which, in a
certain way, bypasses this multifaceted approach, avoiding the
mediation of professionals able to provide a correct interpretation
and usage of genetic data.
Concluding, to understand what can be legitimately used, a
deep knowledge of the topic is essential. In addition, personalized
nutrition needs to be kept in its proper context, that not overlaps
with clinical genetics, disease treatment, or disease prediction. In
fact, nutrigenetics uses genetic information in a different way
than classical genetics; it does not estimate disease risk based on
association studies but provides exact information based on
specific interactions between gene and diet, to identify subgroups
which could maximize the benefit of different nutritional
interventions.
3. Nutrigenomics
3.1. Introduction to nutrigenomics
Nutrition research has gone through a relevant shift in the past
decade, from focusing on physiology and epidemiology to
biochemistry, genetics and molecular biology. Micronutrients and
macronutrients have been clearly recognized as powerful dietary
signals able to affect metabolic programming of cells, with a central
role in the control of body homeostasis [141]. These evidences
make the scientific community to realize that it is not possible to
really understand the impact of nutrition on health and disease
without a deep knowledge of molecular effects of nutrients.
Nutrigenomics, which also includes the study of genes that influ-
ence different predisposition to nutrition-related impairment
(hence nutrigenetics), attempts to study in a broad way the
genome-wide influences of nutrition, with the major goal to apply
this knowledge to prevent diet-related diseases.
3.2. Nutritional factors that can influence the epigenome and the
mechanisms involved
In some ways, nutrigenomics can resemble to pharmacoge-
nomics [142]. However, an important difference between these two
disciplines is that pharmacogenomics concerns with the effects on
the genome of drugs, which are pure compounds, given in exact
doses, while nutrigenomics has to take into account the complexity
and variability of nutrition. This concept is just a tip to have an idea
of the complexity of this research field.
The study of gene expression patterns, protein expression and
production of metabolites in response to certain nutrients have
been the main object of nutrigenomic studies at the beginning of
this new science. From the point of view of nutrigenomics, nutri-
ents are dietary signals which are perceived by the cellular sensor
systems, and which are able to affect gene and protein expression
and, consequently, metabolite production [143].
Recently, among the wide spectrum of activities for which many
nutrients are known in their role on prevention and mitigation of
various diseases, epigenetic effects acquired an emerging impor-
tance. This specific research area, which describes effects of nutri-
ents on human health through epigenetic modifications, has been
referred as nutritional epigenomics, or “nutriepigenomics”[144]
(Fig. 1B and C).
Whether several studies demonstrated that numerous nutrients
and bioactive compounds influence different pathways through
which epigenetics affects gene expression, there are still relatively
few information about the precise mechanisms through which
nutrients modulate epigenetics. Different ways through which
what we eat can influence the expression of our gene through
epigenetics have been suggested. These multiple mechanisms are
mutually compatible and may operate together in time, enriching
the complexity of this regulative pathway [144 ,145]. They can be
clustered in three main groups: 1) food provides substrates
necessary for proper methylation of DNA and histones, cofactors
that modulate enzymatic activity of DNA methyltransferases and
can regulate activity of the enzymes involved in the one-carbon
cycle; 2) bioactive molecules contained in food can directly or
indirectly interact with the epigenome, as well as 3) toxicant con-
tained in food also can (Fig. 1 B).
Most of the understanding concerning the ability of nutritional
factors to modulate gene expression by epigenetic mechanisms
refers to the one-carbon metabolism, a complex network of inter-
related biochemical reactions in which methyl donor nutrients
provide one-carbon units to different biochemical and molecular
reactions. This step is essential for several molecular pathways
L. Bordoni, R. Gabbianelli / Biochimie 160 (2019) 156e171164
including DNA synthesis, purine synthesis, methylation of DNA,
RNA, protein, phospholipids and small molecules [146]. Nutrients
are processed through the folate cycle and the methionine cycle,
serving as methyl sources for the universal methyl donor, S-ade-
nosylmethionine (SAM). A methyl group from SAM can be enzy-
matically transferred to other molecules (i.e. specific cytosines in
the DNA), thus generating S-adenosylhomocysteine (SAH) (which
acts as an inhibitor of methyltransferases themselves) as an end
product. For this reason, nutrients affecting one of the two main
metabolites of the one-carbon metabolism (i.e. SAM or SAH) can
potentially alter the methylation of DNA and histones. DNA
methylation can be affected by four different type of nutrients: 1)
dietary methyl donor nutrients (methionine, choline, betaine,
serine); 2) B vitamins (B12, B6, B2, B9) as coenzymes of one-carbon
metabolism (with folate acting as acceptor or donor of methyl
groups), 3) micronutrients which can affect one-carbon meta-
bolism (zinc, retinoic acid, selenium) and 4) bioactive food com-
pounds that can modulate DNA methyltransferases’activity [81].
Not just specific nutrients play a role in nutrigenomics, but also
bioactive molecules, such as secondary plant metabolites, can
modulate gene expression. Epigallocatechin-3-gallate, genistein,
equol, myricetin, but also butyrate, sulforaphane and curcumin
have been showed to be epigenetically active [144,147], not just
regulating DNMTs functions, but also acting as chromatin remod-
elers through modulation of histone deacetylases (HDAC).
Interestingly, it must be noticed that epigenetic mechanisms are
strongly associated to cellular oxidative stress homeostasis [14 8],
and, finally, they are not just involved in nuclear gene expression
regulation, but also strictly involved in mitochondrial functions
regulation too [149]. These observations further increase the
number of potential indirect effects exerted by nutrigenomics on
health.
Another aspect to consider is that molecules contained in the
food we eat can affect and be affected by the gut microbiome. The
production of metabolites acting as allosteric regulators and critical
cofactors of epigenetic processes, is one of the major mechanisms
linking gut microbiota and control of gene expression. Indeed, the
gut microbiota produce numerous low weight bioactive molecules
which can play a role in epigenetic processes, i.e. folate, butyrate,
biotin, and acetate. In addition, the absorption and excretion of
minerals such as zinc, selenium, iodine, cobalt (indeed, cofactors of
enzymes participating in epigenetic processes) is influenced by the
microbiota, which can also metabolize bioactive compounds con-
tained in food (i.e. ellagic acid and ellagitannins are metabolized in
urolithins) influencing their bioavailability [150,151](Fig. 1 D).
Moreover not just natural food components but also several
classes of pesticides (including persistent organic pollutants,
arsenic, endocrine disruptors, several herbicides and insecticides)
have been shown to modify epigenetic marks [152e154].
Numerous investigations studied the effects of environmental ex-
posures on epigenetic markers, identifying many toxicants able to
modify epigenetic states (in particular in terms of DNA methylation
and histone modifications) similarly to what happens in some
pathological conditions [152,155e157]. Additional investigations
are necessary to clarify if epigenetics can act as a causal link be-
tween exposure to pesticide and health outcomes, or rather be a
sensitive early biomarker of exposure.
3.3. Susceptible period of exposure, epigenetic reprogramming and
transgenerational effects in nutrigenomics
The mechanisms previously described provide convincing evi-
dence that epigenetic marks serve as a memory of exposure to
environmental factors and, among others, inadequate or inappro-
priate nutritional factors. These environmental stimuli can have
different impact depending on the period of life of the exposed
organisms. Considering the epigenetic plasticity of growing and
developing tissue, exposures during early life represent a critical
period [158e160 ]. Not just pre-natal and intrauterine periods, but
also post-natal early life and periods of epigenetic remodeling
characterized by rapid physiological changes (such as puberty and
aging) represent susceptible period of exposure [147,161].
Several examples of late onset disease have been found to take
their origins in early life period, or at least to be influenced by
episodes occurring in the first stages of life. Furthermore, in addi-
tion to prenatal and postnatal nutritional effects, which can result
in stable changes and predispose individuals to disease later in life
(which is referred as “early life programming”), transgenerational
mechanisms must be considered. Transgenerational epigenetic
inheritance can result from several different environmental expo-
sures, even though little is known about the mechanism undergone
to the maintenance of the epigenetic marks suggested to be
involved in this phenomenon. It has been established that factors
like maternal diabetes, behavioral programming (maternal care),
nutritional interventions (carbohydrate-rich or fat-rich diet or
caloric restriction), glucocorticoids and exercise, endocrine dis-
ruptors, stress during gestation and lactation may all cause
imprinting in the following generations [144].
One of the most cited and studied example that clearly shows
the role of nutrigenomics is the Agouti mouse, where coat color
variation and healthy/unhealthy phenotype is established early in
development according to maternal diet [162,163]. Another
example is represented by protein malnutrition in pregnant mice
which resulted to determine significant gene expression changes,
miRNA changes, and different DNA methylation patterns in brains
of the offspring [164]. Studies on humans that corroborate trans-
generational inheritance also exists. One of the first example is the
“the Dutch famine study”, which showed that starvation in one
generation affects the risk for glucose intolerance and metabolic
disorders in its offspring [165]. Another pivotal study has been
conducted on the €
Overkalix population, where overeating by
paternal grandfather or father induced increased risk for cardio-
vascular diseases or diabetes in grandsons, while a reduced food
availability during father adolescence exerted an opposite effect in
the offspring [166 ].
Despite better controlled studies in humans are needed, a hy-
pothesis which could powerfully impact our lives is emerging:
what do we eat, is not just important for us, but may affect future
generations’health as well. Moreover, given that thousands of
nutrients and other compounds are contained in food, but only few
of these have been tested for transgenerational epigenetic effects,
further research in this field is essential in order to promote public
health and set sensible public policy.
3.4. Interactions between nutrigenetics and nutrigenomics
Even if based on different scientific approach, nutrigenetics and
nutrigenomics cannot be considered separately. In fact, if it is true
that certain dietary molecules can potentially modify cellular ho-
meostasis, it is also true that the alteration of the homeostatic
mechanisms especially occurs in individuals with susceptible ge-
notypes [143]. Indeed, not only nutrients, but also the genetic
make-up can surely impact one-carbon metabolism (Fig. 1 A).
Among different combinations of nutrients and genes, folate and
the MTHFR 677 C to T SNP represents a peculiar example of
nutrient gene interactions affecting DNA methylation. In partic-
ular, carriers of the MTHFR 677TT genotype display a reduced
availability of 5-methyl tetrahydrofolate and a consequent higher
folate requirement for the regulation of plasma homocysteine
concentrations. Interestingly, researchers showed that not all
L. Bordoni, R. Gabbianelli / Biochimie 160 (2019) 156e171 165
MTHFR 677 TT carriers had impaired global DNA methylation
levels, but just those who were deficient for folate, suggesting that
MTHFR C677TT SNP affects genomic DNA methylation status
through an interaction with folate status [167].
Similar conditions can occur for other metabolites of the one-
carbon cycle, such as for choline, a methyl donor necessary for
the conversion of homocysteine to methionine [168 ]. Excluding
diet, the only other source of choline is the de novo biosynthesis of
phosphatidylcholine (can be converted to choline) catalyzed by
phosphatidylethanolamine-N-methyltransferase (PEMT) in liver.
Considering that the consume of foods containing choline are often
discouraged because rich in fat and cholesterol (e.g. eggs and liver),
it has been measured that only a small percent of the population
achieves the recommended adequate intake for choline, in partic-
ular man, post-menopausal women and the 44% of pre-
menopausal women. The risk of choline deficiency is reduced in
young woman because PEMT is estrogen-inducible; however, it is
interesting that those women that are more prone to choline
deficiency (even at youngest age) have a SNP in PEMT
(rs12325817); similarly women with the rs2236225 SNP in the
gene MTHFD1 (5,10-methylenetetrahydrofolate dehydrogenase 1)
are 15 times more predisposed to develop signs of choline defi-
ciency in case of low-choline diet respect to wild types [169]. This
example shows how dietetic intake of choline can be particularly
important for a certain subpopulation (pre-menopausal women
carriers of the susceptible gene alleles), not just simply counter-
acting a specific metabolic deficiency, but also protecting from
impairment of epigenetic regulation processes.
Another different interesting example of interaction between
genetic and epigenetics is represented by the lactase persistence. To
date, inter-individual differences in lactase expression in human
adults have been ascribed merely to DNA sequence variation up-
stream of lactase (LCT) gene. Specifically, the rs4988235 SNP (C/T-
13910) has been related to the phenotypes of lactase persistence
and non-persistence in European populations [17 0]. Nevertheless,
it is interesting to notice that in non-Europeans, this SNP does not
fully explain lactase persistence, with certain African individuals
exhibiting lactase in the absence of LCT-associated variants.
Furthermore, the molecular mechanism able to explain the age-
dependent changes of LCT expression (that varies from very high
levels in infancy to significant downregulation in most of adults) is
also unclear. Considering that DNA sequence is steady, more dy-
namic regulatory systems must be dragged in the temporal varia-
tion of lactase non-persistence. Interestingly, recent studies
showed that lactase non-persistence derives from accumulation of
transcriptionally suppressive epigenetic changes on the SNP C-
13910 carriers, while T-13910 carriers escape from epigenetic
inactivation facilitating lactase persistence [171 ].
3.5. Personalized epigenomics
Improvement in personalized epigenetics for the therapy and
management of several specific pathologies is quickly conducting
to an important increase of the tools accessible to clinicians in
preventing and controlling diseases that have an epigenetic base in
their etiology and pathogenesis. An case in point is represented by
chronic pain management, for which an important role of epige-
netics has been highlighted. In this case, assessing the epigenomic
marks in subjects suffering from chronic pain could have sub-
stantial utility in the selection of adequate analgesics which can
give relief to patients affected by chronic pain [172]. Several genes
which are under epigenetic control can also affect the onset of
obesity and related metabolic diseases (for instance diabetes) [173].
Dietary factors are well known to produce epigenetic changes, with
a certain inter-individual variability of the effects. Concerning
obesity, both the quality and the quantity of diet have been
demonstrated to modulate the epigenetic signature of individuals
inducing epigenetic irregularities that could be managed by
personalized therapy [174]. Thus, taking into account personalized
epigenetic approaches would represent a greatimprovement in the
efficacy of obesity management. Furthermore, personalized epi-
genetics can be useful also in prevention, considering that envi-
ronmental factors have central roles in the development of obesity,
and epigenetic modifications can be reversible through changes in
environmental factors (life-style in particular) that lead to such a
disorder [174].
Even if this prospective is quite far from immediate practical
application, interesting evidences about therapeutic applications of
epigenetically active nutrients are available [147]. In fact, as
epigenetic modifications are reversible and tissue-specific, a regu-
lation of these processes through diet or specific nutrients could
also help diseases prevention and health maintenance. Some of the
natural products which showed positive outcomes on particular
human diseases are also being studied in clinical trials. Surrogate
endpoints associated with metabolic syndrome resulted to be
improved by genistein indirectly reducing the risk of developing
diabetes and cardiovascular disease [175 ]; similarly, a reduction of
type II diabetes onset has been observed in pre-diabetic individuals
supplemented with curcumin [176]. Genistein, curcumin, epi-
gallocatechin-3-gallate and resveratrol are some of the phyto-
chemicals that have been demonstrated to trigger the anti-
inflammatory machinery and improve some of the symptoms
associated with metabolic syndrome [177]. These are just few ex-
amples of potential epigenetically active nutrients and their
beneficial effect that has been hypothesized to be exerted through
epigenetic processes [147].
Furthermore, nutrigenomics strongly improves current knowl-
edge in nutrition providing, through the usage of metabolomic and
epigenetic approaches, novel biomarkers of food intake and dietary
patterns which will lead to more objective and robust measures of
dietary exposure [121]. For all these reasons, it is clear that appli-
cation of nutrigenomics research can offer considerable potential to
improve public health [178 ].
4. Conclusions
Nutrition is one of the most important life-long environmental
factors able to impact human wellbeing. Among the mechanisms
involved, genome nutrient interactions have been definitely
demonstrated to play an important role in health maintenance and
disease prevention. The disciplines of nutrigenetics and nutrige-
nomics aim to address how genetics and epigenetics can explain
individual dietary susceptibility and to understand how human
variability in preferences, requirements and responses to diet can
be implemented in a personalized nutrition. Despite a growing
interest of the scientific community for these topics, the body of
research is still to be enlarged to make the actual knowledge able to
provide personalized advices tailored by nutrigenetics and nutri-
genomics [179 ]. Given the high potential of these disciplines,
research on nutrigenetics and nutrigenomics should be promoted
and divulged to a wide-reaching audience [180,181 ], in order to
make both professionals and the general population aware of the
profound effects of nutrition on our health.
Author contributions
L.B. wrote the article, R.G. supervised, revised and proofread the
paper. All the authors approved the final version of the manuscript.
L. Bordoni, R. Gabbianelli / Biochimie 160 (2019) 156e171166
Declaration of interest
Material submitted is original, all authors are in agreement to
have the article published.
Conflict of interest
Authors have neither founding sources nor competing interests
to declare.
Acknowledgements
We thank the artist Irene Saluzzi who give an important
contribution in the drawing of the Fig. 1, helping us to make the
complexity of nutrigenetics and nutrigenomics easier to be un-
derstood and communicated.
This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors.
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