Systems Biology of Personalized Nutrition: Feature Article

Feature Article
Systems biology of personalized nutrition
Ben van Ommen, Tim van den Broek, Iris de Hoogh, Marjan van Erk, Eugene van Someren,
Tanja Rouhani-Rankouhi, Joshua C. Anthony, Koen Hogenelst, Wilrike Pasman, André Boorsma,
and Suzan Wopereis
Downloaded from https://academic.oup.com/nutritionreviews/article-abstract/75/8/579/4056663 by guest on 29 June 2019

Personalized nutrition is fast becoming a reality due to a number of technological,
scientific, and societal developments that complement and extend current public
health nutrition recommendations. Personalized nutrition tailors dietary recommen-
dations to specific biological requirements on the basis of a person’s health status
and goals. The biology underpinning these recommendations is complex, and thus
any recommendations must account for multiple biological processes and subpro-
cesses occurring in various tissues and must be formed with an appreciation for
how these processes interact with dietary nutrients and environmental factors.
Therefore, a systems biology–based approach that considers the most relevant
interacting biological mechanisms is necessary to formulate the best recommenda-
tions to help people meet their wellness goals. Here, the concept of “systems
flexibility” is introduced to personalized nutrition biology. Systems flexibility allows
the real-time evaluation of metabolism and other processes that maintain homeo-
stasis following an environmental challenge, thereby enabling the formulation of
personalized recommendations. Examples in the area of macro- and micronutrients
are reviewed. Genetic variations and performance goals are integrated into this sys-
tems approach to provide a strategy for a balanced evaluation and an introduction
to personalized nutrition. Finally, modeling approaches that combine personalized
diagnosis and nutritional intervention into practice are reviewed.
INTRODUCTION etc), various medical associations have established dietary

guidelines for patient subgroups. Health-related societies
Nutrition and health are intimately related, and the sci- and nutrition expert groups have also published dietary
ence underpinning this relationship is the basis for global guidelines for specific healthy populations, such as chil-
public health dietary recommendations. Recognizing that dren, the elderly, pregnant women, and athletes.
food and nutrition play a role in numerous medical condi- Customized nutrition strategies have been added to patient
tions (hypercholesteremia, hyperglycemia, hypertension, treatment plans for many inborn errors of metabolism that
Affiliations: B. van Ommen, T. van den Broek, I. de Hoogh, M. van Erk, E. van Someren, T. Rouhani-Rankouhi, K. Hogenelst, W. Pasman,
A. Boorsma, and S. Wopereis are with TNO (The Netherlands Organization for Applied Scientific Research), Zeist, the Netherlands.
J.C. Anthony is with Habit LLC, Oakland, California, USA.
Correspondence: B. van Ommen, TNO, Utrechtseweg 48, Postbox 360, 3700 AJ Zeist, the Netherlands. Email: ben.vanommen@tno.nl.
Key words: flexibility, nutrigenetics, nutrigenomics, personalized nutrition, systems biology.
C The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute.
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://
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doi: 10.1093/nutrit/nux029
Nutrition ReviewsV Vol. 75(8):579–599
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Table 1 Examples of personal goals in relation to personal nutrition
Goal Definition
Weight management Maintaining (or attaining) an ideal body weight and/or body shaping that ties into heart, muscle, brain, and
metabolic health
Metabolic health Keeping metabolism healthy today and tomorrow
Cholesterol Reducing and optimizing the balance between high-density lipoprotein and low-density lipoprotein choles-
terol in individuals in whom this is disturbed
Blood pressure Reducing blood pressure in individuals who have elevated blood pressure
Heart health Keeping the heart healthy today and tomorrow
Muscle Having muscle mass and muscle functional abilities. This is the physiological basis or underpinning of the
consumer goal of “strength”
Endurance Sustaining energy to meet the challenges of the day (eg, energy to do that report at work, energy to play
soccer with your children after work)

Strength Feeling strong within yourself, avoiding muscle fatigue
Memory Maintaining and attaining an optimal short-term and/or working memory
Attention Maintaining and attaining optimal focused and sustained attention (ie, being “in the moment” and being
able to utilize information from that “moment”)
have a specific nutrition component. Only recently, sci- Finally, this review demonstrates that macronutrient,
entific evidence has shown that advances in analytical micronutrient, and non-nutrient recommendations can
technologies, data science, molecular physiology, and be optimized at the individual level, depending on a
nutritional knowledge may allow the subgrouping of person’s biological characteristics and specific goals.
populations to be refined to a more personal level. This
has resulted in the definition and scientific substantia- PERSONALIZED NUTRITION IN THE ERA OF
tion of a range of personalized health and performance LARGE-SCALE BIOLOGY
goals. Often, these goals extend beyond prevention
and/or mitigation of chronic disease and include multi- Public health recommendations for nutrition and diet
ple aspects of well-being, such as mood, attention, en- are based on averages of population data. However,
durance, and weight maintenance, as well as well-being individuals who adhere to these recommendations will
equivalents of medical conditions (maintenance of glu- differ in their response because of the inherent varia-
cose control, normal blood pressure, healthy levels of tions in and complexity of individual genetic makeups
serum lipids and low-density lipoprotein [LDL] and that interact with a host of environmental stimuli.
high-density lipoprotein [HDL] cholesterols, etc). Overall, the so-called omics revolution provides a solid
Indeed, with respect to nutrition, the boundaries be- framework for a systems-based approach to personal-
tween medical treatments, illness prevention strategies, ized nutrition research. There are, however, limitations
and strategies to achieve optimal health have become to the application of the current framework of evidence
artificial and are a legal hindrance to best nutritional based on randomized controlled trials, which are
practice. For example, the mechanisms of glycemic designed to minimize variation across study population
control and the nutritional approaches to optimize groups, to these new opportunities. In contrast, an ap-
metabolic health and cure type 2 diabetes are almost proach to personalized research requires that individual
identical, yet nutritional interventions are underused variation be embraced, thus necessitating a different ex-
in medical practice. Already in 2002, the Diabetes perimental approach. Indeed, enough inter-individual
Prevention Program established by the US National variation is available and can be quantified to fine-tune
Institute of Diabetes and Digestive and Kidney the genome–exome–phenome relationships. Until re-
Diseases provided evidence that a multiyear lifestyle cently, this biological variation, now exposed by exten-
modification program was more effective than metfor- sive and accurate phenotyping, was ignored (dismissed
min treatment in reducing the incidence of diabetes in as confounders) or avoided (minimized through stratifi-
high-risk persons.1,2 cation). Tools to translate these genotypic and pheno-
This article describes biological mechanisms from a typic variations into personalized recommendations
systems perspective and outlines how the biology of using alternative research approaches, such as n ¼ 1 re-
personalized nutrition can be translated into recom- search paradigms, are now available.3
mendations for achieving specific health and perfor- Over the past 2 decades, various technological revo-
mance goals for individuals (Table 1). The concept of lutions have provided the building blocks for a systems
“systems flexibility” is introduced as an overarching physiology approach. The time is approaching when
biological mechanism, and a number of relevant exam- personal genomes, thousands of plasma proteins and
ples are examined in the context of metabolic health. metabolites can be scrutinized affordably, and detailed
580 Nutrition ReviewsV Vol. 75(8):579–599

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whole-body magnetic resonance imaging scans will be- assisted by a range of fine-tuning mechanisms that gov-
come widely available. Methods to store, share, evaluate, ern biological processes and organ functions.
integrate and interpret this staggering amount of per- Maintenance of homeostasis under continually
sonal health data are lagging behind, but several devel- changing conditions is referred to as phenotypic flexi-
opments are promising and are worth mentioning here. bility or systems flexibility. Under continued energy
Changes in plasma biomarkers can reveal broad net- overload, the maintenance of homeostasis comes at a
works of related cellular processes, as described previ- cost of adaptation: excess energy is stored as lipid in ad-
ously for micronutrients.4 Metabolomics technologies ipose tissue. Once storage exceeds normal physiological
have been developed to elucidate the relationships be- boundaries, insulin resistance and complications start
tween different cellular processes and micronutrient to develop, which potentially leads to pathologies that
status.5 Further, network biology applications based on include adipose deposits in and around major organs,

correlation matrices of multiple omics databases allow rising plasma glucose concentrations causing oxidative
the relationship between micronutrients and human bi- damage to microvasculature, and persistent low-grade
ology to be examined at a systems level.6 Similar inflammation triggered by macrophage infiltration in
approaches, combined with data from large cohorts, adipose tissue. In a human intervention study, a 4-week
connect genetic variations with biomarker responses in overfeeding regimen kept the 3 core processes (glucose
plasma7 and urine.8 The integration of multiple human metabolism, lipid metabolism, and inflammation) sta-
nutrigenomics studies with multiple omics knowledge ble, whereas most metabolic, inflammatory, and endo-
bases enables the creation of combined theoretical– crine processes regulating these core processes were
observation networks that provide a systems view of changed. These regulatory processes contribute to sys-
specific types of nutritional interventions to promote tems flexibility and illustrate the major molecular physi-
health and well-being.9 For this type of approach, a ological efforts to maintain homeostasis.12
standardized open-access depository of nutrigenomics An advantage of considering regulatory processes
studies is essential and available.10 in a systems-based approach is that it provides a means
to identify changes in regulation before the onset of dis-
ease, and thus enables the application of proactive strat-
ROLE OF SYSTEMS FLEXIBILITY IN ACHIEVING egies to optimize health.
OPTIMAL HEALTH Different macronutrients act differently on overlap-
ping regulatory processes involved in phenotypic flexi-
The complexity of personalized nutrition requires a sys- bility (Figure 1). For example, carbohydrates directly
tems solution, not only from a (homeo)static viewpoint trigger an insulin response through rising glucose levels
but also in the dynamic response to an environmental in circulation. Triglycerides and fatty acids, on the other
challenge. Because the relationship between nutrition hand, do not induce an insulin response, but their me-
and health is a continuously changing interaction be- tabolism is governed largely by insulin-dependent regu-
tween environment and physiology, it is important to latory processes. Dietary protein consumed with
understand how biological systems work together to carbohydrates can potentiate the insulin response, and
maintain homeostasis. A key component is the ability individual amino acids can act as insulin secreta-
of the physiological system to continuously adapt to the gogues.13 Insulin-dependent pathways also regulate
variety and amount of foods consumed as well as to the protein turnover, which consists of protein biosynthesis
timing of food consumption. Humans eat food as meals (accomplished in part via the mechanistic target of
and thus continuously switch from net anabolic to net rapamycin [mTOR] pathway)14 and amino acid degra-
catabolic conditions. This repeated switching both dation, both of which provide energy. These processes
requires and trains systems flexibility,11 although this are described in detail in numerous reviews and text-
advantage may become lost by the modern habit of reg- books. For the purpose of this review, it is important to
ular snacking. An important aspect of the relationship stress that multiple, overlapping, tightly regulated pro-
between human nutrition and health is the manage- cesses control energy metabolism. This regulation pre-
ment of energy supply and substrate metabolism. vents the formation of excess concentrations of
Energy is provided primarily by carbohydrates, lipids, metabolic constituents by maintaining a complex ma-
and proteins. A tightly regulated control network chinery of metabolic flexibility that is distributed over
ensures that energy is properly distributed, utilized, and many organs and processes. Redundant mechanisms
stored and that plasma concentrations of essential ensure that this tight regulation is maintained. As noted
metabolites, such as glucose, are kept in homeostasis. above, the lack of phenotypic flexibility can lead to pa-
Peaks in plasma concentrations are corrected by master thologies or to suboptimal health. However, pathology
regulators (such as insulin and glucagon), which are does not necessarily develop during the process or

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personalized
Lipid flexibility blood pressure
Weight
cholesterol Glucose flexibility nutrition based
management
consumer goals
muscle adipose
vasculature
gut
organs
liver pancreas

Insulin sensitivity
Inflammation control Satiety flexibility processes
Fatty acid oxidation
and sub-processes
Lipid distribution Insulin production
triglycerides
folate B12 choline
K
dairy leafy Meat fish
carnine nutrients
fruit vegetables egg (connected in diets)
carbs Grains Mg
protein
&nuts
fiber legumes
Figure 1 A systems biology view on personalized nutrition. Four interacting layers are used to demonstrate the connection between
personal nutrition–based consumer goals (top layer) and nutrients (bottom layer). The 2 middle layers (the organ and process layers)
connect nutrients to goals and represent the detailing of the biological processes involved. These 2 layers are extended in Figure 2.
Abbreviations: K, potassium; Mg, magnesium.
within the organ where loss of flexibility occurs. For ex- flexibility is impaired in obese individuals with type 2
ample, the failure of peripheral adipose tissue to ade- diabetes24 and likely contributes to the selective accu-
quately absorb glucose or convert it into fatty acids may mulation of saturated fatty acids.25 Figure 2 summarizes
lead to the accumulation of hepatic lipids.15,16 the major processes within and between liver, muscle,
Subsequently, other organs (muscle, liver) may also be- pancreas, and adipose tissue involved in the mainte-
come insulin resistant. Several factors can cause insulin nance of plasma glucose homeostasis. It shows several
resistance, including nutrition (overnutrition or, in examples of mechanisms related to the loss of metabolic
some cases, micronutritional inadequacies) and disease. flexibility, which can result in liver steatosis and other
Genetics may also contribute to the development of dis- metabolic impairments. Thus, many processes are con-
ease.17–20 Insulin resistance can also cause increased ac- nected to form a metabolic system in which all parts
cumulation of hepatic triglycerides, ultimately resulting must function optimally and in which malfunctioning
in hepatic steatosis and fatty liver disease.21 (loss of flexibility) of one of the processes may become
Accumulation of hepatic triglycerides can be caused by manifest in other processes or organs. Furthermore, dif-
adipose tissue malfunctioning; it can also be caused by a ferent mechanisms may be impaired in different indi-
shortage of choline resulting from genetic disorders, in- viduals with the same disease. Changes in strategies for
cluding those affecting phosphatidylethanolamine N- handling energy open avenues for personalized
methyltransferase (PEMT) —an enzyme involved in the “systems interventions,” either by modifying the quan-
hepatic biosynthesis of phosphatidylcholine.22 tity, timing, and source of energy consumed, or by opti-
Alternatively, low dietary intake of carnitine, which is mizing the processes involved, through the
essential for shuttling fatty acids into the mitochondria, manipulation of nutrients or other lifestyle components.
may contribute to fatty liver as a result of poor fatty In other words, although impaired phenotypic flexibil-
acid oxidation.23 ity may contribute to morbidities, the opposite is also
Both adipose tissue insulin resistance and hepatic true: regaining or optimizing phenotypic flexibility is
insulin resistance affect systemic triglyceride handling the basis of prevention and cure of metabolic diseases.
and metabolic flexibility (the capacity to switch from Interestingly, the concept of systems flexibility may be
glucose to fatty acids as fuel) in muscle. Metabolic valid for both the health/disease trajectory and the aging

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Figure 2 Major processes in and between liver (blue), muscle (light green), pancreas (brown), brain (dark green), kidney (pink), gut
(mustard), and adipose tissue (purple) involved in maintenance of plasma glucose homeostasis, each of them demonstrating
aspects of glucose flexibility. This biological network presents the middle part of the 4-layer scheme of Figure 1 (see insert top right).
Abbreviations: FA, fatty acid; GLP-1, glucagon-like peptide-1.
trajectory. Many processes involved in aging and in- glucose tolerance test is used clinically to quantify the
creased frailty (energy/glucose/insulin homeostasis, plasma glucose response upon absorption of 75 g of glu-
protein homeostasis, redox homeostasis, mitochondrial cose and provides quantitative information on various
homeostasis, stress resistance, inflammation control) aspects of insulin sensitivity and glucose handling. This
are part of the systems flexibility concept.26,27 concept was extended by adding more analytical param-
In summary, systems flexibility is centrally posi- eters (levels of insulin, inflammatory markers, fatty
tioned in health, disease, and, possibly, aging, and inter- acids, triglycerides, etc) and other stressors (various
individual variations may have multiple causes and lipid/carbohydrate/protein formulations). The science,
consequences. Systems flexibility is a combination of all technology, and applicability of these stress response
of the interacting systems, each of which may have a ge- biomarkers in nutrition research has been extensively
nome component, and a response to environmental fac- reviewed by Stroeve et al.28
tors. Often, single parameters of flexibility, such as The application of both an oral glucose tolerance test
glucose flexibility, are composites of many underlying and a standardized mixed-meal challenge test to compare
processes, each possibly having individual characteris- processes between healthy and metabolically impaired
tics. It is, therefore, important to observe, quantify, and individuals (ie, those with type 2 diabetes) revealed a large
intervene on a systems level and not only on the basis number of biological processes that were different between
of single parameters. the 2 groups (S.W., unpublished data, 2017). The same 2
challenge tests accurately quantified health differences
QUANTIFICATION OF SYSTEMS FLEXIBILITY: within a cohort of 100 healthy individuals ranging in age
BIOMARKERS OF STRESS RESPONSE and fat percentage, substantiating the claim that these bio-
markers can indeed be used to quantify health. This study
Traditionally, plasma biomarkers are measured under used stress response biomarker panels comprising 120
homeostatic (overnight fasting) conditions. If system measured markers that could quantify all relevant systems
flexibility is indeed important to health, the quantifica- flexibility processes. A growing number of nutritional in-
tion of flexibility and its use as a biomarker is relevant. tervention studies, including challenge tests, are being per-
Flexibility can be quantified by using tolerance, chal- formed. A database that focuses on nutritional
lenge, or stress tests. Further, there should be a clear intervention studies of systems flexibility has been estab-
distinction between how markers behave in response to lished, the Nutritional Phenotype Database (http://www.
a challenge under conditions of health versus condi- dbnp.org/). Eventually, the use of a challenge test that
tions of disease. A number of relevant biomarkers exist quantifies systems flexibility could become standard pro-
and are used in tolerance tests. For example, the oral cedure in health diagnostics.29

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•
Lipid flexibility
Adipose insulin sensivity
• Adipokine producon
• Lipoprotein producon
• Muscle insulin sensivity
• Ketogenesis ** **
• beta-oxidaon ******* ** • gluconeogenesis
• Lipolysis
Carnine, choline • insulin sensivity
• incren producon
• bile producon
• insulin sensivity
• Disposion index
• Metabolic flexibility
* *
* ******** *** *
***** * *** * *

• Gut mediated
inflammaon * **** **** *** * * Carbohydrate flexibility
• Oxidave stress * * * * *
• Nitrosave stress
• Chronic low grade * * ***
inflammaon Fiber, vitK, ** * *
• NO formaon *
Mg
*** ** ** * *
*
DHA, EPA, Se, Vit E
Figure 3 The “health space” concept to visualize aspects of systems flexibility, the involvement of specific biological processes, and
the effect of personalized nutritional interventions on these processes. The 3-dimensional space is created by 3 distinct axes, on pur-
pose defined to represent biologically relevant processes (this is in contrast with normal multivariate statistical approaches such as principle
component analysis, where the axes are purely defined on statistical grounds). Each of the axes is constructed from the systems flexibility re-
sponse biomarker profiles connected to the processes mentioned with each axis (see Stroeve et al28 for a detailed explanation of the relation-
ship between biomarkers and biological processes). The multivariate statistical approach is explained in Bouwman et al.30 The effect of
hypothetical nutritional intervention studies is demonstrated by the arrows. Abbreviations: DHA, docosahexaenoic acid; EPA, eicosapentaenoic
acid; Mg, magnesium; Se, selenium; Vit E, vitamin E; Vit K, vitamin K.
A key question, then, is how to define and measure of biomarker panels. Until recently, these large bio-
the state of optimal systems flexibility. This could be marker panels have been too costly to be used outside
achieved in part by using single-parameter methods like of research projects. However, the cost of both geno-
the oral glucose tolerance test, which can be used to de- typic and phenotypic biomarker panels is decreasing
termine a curve derived from optimal homeostatic (fast- rapidly, and it is now possible to assess large research
ing) plasma glucose concentration, optimal plasma cohorts, patient populations, and even consumer
glucose peak concentration and time, optimal time to groups on a routine basis, allowing new disruptive
return to homeostasis, etc. This method can be used if developments in healthcare, as described elsewhere.29,31
sufficient data from a range of health, disease, and age Nevertheless, many questions remain: (1) Is “optimal
conditions are available to establish the comparison be- systems flexibility” equal for all? (2) Are individual data
tween the measured outcome and the desired health points needed? If so, what determines individual differ-
outcome. However, this method, underestimates the ences, and how can this be quantified? and (3) Is
complexity of a systems-based approach because it dis- “optimal systems flexibility” itself flexible (ie, how
regards so many other processes involved in systems should the bandwidth of optimal systems flexibility be
flexibility. To address this complexity, an emerging con- defined)? For example, does the definition of “optimal”
cept to visualize optimal systems flexibility is the “health vary, depending on an individual’s life stage, health
space.”30 Essentially, a 3-dimensional space is created goals, or priorities?
by using predefined axes that represent biological pro-
cesses relevant to different aspects of systems flexibility, SYSTEMS FLEXIBILITY AND NUTRITION: OPTIMIZING
each constructed from multiple biomarkers using mul- EACH PROCESS INVOLVED IN SYSTEMS FLEXIBILITY
tivariate statistical methods. The axes can be tailored to
the scope of the intervention. Figure 328,30 provides an ex- Because multiple biological processes distributed over
ample, tailored to the topic of this review, with the 3 axes various organs, each of which might function subopti-
constructed as carbohydrate flexibility, lipid flexibility, and mally, are involved in systems flexibility, interventions
inflammatory stress. To support the advancement of new that optimize these individual processes need to be
health space models, detailed information about organ designed. Different interventions targeting the same
and process flexibility can be obtained through a number outcome are possible. Upon detailed analysis, results

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from dietary interventions are often specific to respond- mixture of science, medicine, and economics drove
ers or nonresponders. For example, caloric restriction32 these recommendations.37 Despite the decrease in die-
and physical activity33 that lead to weight loss improve tary fat consumption that occurred as a result of these
health by reversing insulin resistance and thus restoring recommendations, the incidence of obesity and type 2
multiple aspects of systems flexibility. However, the ca- diabetes increased.38 Although multiple factors led to
loric restriction that successfully resulted in weight loss the increased incidence of obesity and diabetes, some
for all individuals after 6 months resulted in improved individuals adopted an extreme counter-current “sugar
b-cell functioning in only part of the sample (respond- is toxic” message in response. Recent meta-analyses of
ers).34 Also, in the CordioPrev cohort, in which 642 the effect of macronutrients on important biomarkers
participants maintained their body weight over 3 years like cholesterol, lipoproteins, and serum lipid39 and on
of reporting on a dietary intervention (low-fat diet vs glucose control40 have provided a more balanced view

Mediterranean diet), individuals with a specific muscle- than the “fat is bad” and “sugar is toxic” extremes, and
based insulin resistance were more likely to benefit the scientific opinion on fat is gradually changing.39-41
from the Mediterranean diet, whereas individuals with Another example is that of high-protein diets, like
specific liver-based insulin resistance were more likely Atkins and Paleo, which are popular because of the sati-
to benefit from the low-fat diet.35 Interestingly, the ating and muscle-promoting effects of protein, but these
effects were determined by using the insulin and glu- diets may have adverse effects (eg, on calcium homeo-
cose time course following an oral glucose tolerance test stasis and renal function).42,43 Instead of generalized
as described in the previous paragraph. In another ex- public health recommendations, recommendations
ample, individuals with type 2 diabetes required signifi- based on personal health status and goals may be more
cantly less insulin when a 43% carbohydrate diet was effective for optimizing nutrition and improving health
isocalorically (1800 kcal to maintain weight) substituted outcomes.
with a 70% carbohydrate diet with carbohydrates exclu- The first consideration when personalizing macro-
sively from whole-grain products, vegetables, fruits, and nutrient ratios is the optimization of systems flexibility.
dairy.36 The exact drivers of the changes in insulin sen- From a systems perspective, many organs are important
sitivity that occurred when individuals consumed the for the insulin control of glucose homeostasis: liver,
nutrient-dense, 70% carbohydrate diet are unknown muscle, pancreas, intestines, brain, adipose tissue, and
but may include changes in fiber levels and other chem- vasculature (Figure 1). This section focuses on 3 key
ical components in the whole grains and vegetables. organs in systems flexibility: liver, muscle, and pancreas.
Regardless, organ insulin sensitivity strongly increased As described previously, the contribution of each of
when individuals with diabetes consumed a nutrient- these organs can be easily quantified with an oral glu-
dense, low-glycemic-index diet, which demonstrates the cose tolerance test, which provides insight into im-
power of dietary changes independent of weight loss. paired glucose tolerance (emphasizing the contribution
These studies, in which individuals responded differ- of muscle in glucose uptake), impaired fasting glucose
ently to the diets based on their physiology, demon- (emphasizing the contribution of liver, which produces
strate the potential of personalized nutrition programs glucose through gluconeogenesis), and disposition in-
to optimize health. dex (focusing on acute insulin secretion by the pancreas
corrected for the level of systemic insulin sensitivity).44
PERSONALIZATION OF MACRONUTRIENTS IN THE For each of these phenotypes, specific macronutrient
AREA OF METABOLIC HEALTH BIOLOGY recommendations are available. The CordioPrev study
demonstrated that 2 diets that differed in macronutrient
People can utilize energy from all 3 macronutrient sour- composition had differential effects on liver and muscle
ces (carbohydrate, protein, lipid), and can cope with ex- insulin resistance.35 Individuals with an impaired glu-
treme changes in ratios between the three. Yet, cose tolerance phenotype (with insulin resistance fo-
abundance and reduction of macronutrients have their cused in muscle) require relatively low amounts of
pros and cons depending on an individual’s health state rapidly absorbed carbohydrates from the diet45 and
and/or goals.; however, dietary recommendations are thus should consume a diet low in carbohydrates, and
often generalized, which may lead to individuals receiv- with a low glycemic index. In contrast, individuals with
ing health advice or changing their diet in ways that are impaired fasting glucose (with insulin resistance fo-
counterproductive to personal and overall public health cused in liver) have no need for a low-carbohydrate diet
goals. For example, in the 1960s, concern about the sup- in terms of energy percentage. For these individuals, the
posed effect of saturated fat and cholesterol on cardio- “quality” of the carbohydrates matters, and they should
vascular health led to dietary recommendations to get their carbohydrates mainly from high fiber46 or
reduce intake of fat and saturated fat. An interesting whole-grain products.47 If, as a result of compromised

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normal energy percentage from carbohydrates, mainly
from fiber and whole-grain products, and a high energy
percentage from protein (Figure 4).
Personalized macronutrient recommendations can
also be used for other phenotypes, such as hypertension
or prehypertension phenotypes. A high-protein diet can
improve blood pressure levels55 and reduce the risk of
hypertension.56 In terms of total fat intake, evidence is
conflicting. The Dietary Approaches to Stop
Hypertension (DASH) diet, which is designed to lower
hypertension, restricts total fat to approximately 27 E%.

Figure 4 Personalized macronutrient recommendations related However, evidence suggests that not only the total
to impaired insulin-dependent systems flexibility. The same amount of fat but also the type and source of fat are im-
phenotype (glucose imbalance) may be caused by 3 different pro- portant.57 Hypertensive individuals may benefit not
cesses/organs, which can easily be determined in response to a only from a diet relatively low in total fat but also from
challenge test, and the 3 subphenotypes require different macro- a diet high in polyunsaturated fatty acids, especially
nutrient strategies. Other factors can be involved but are not visu-
eicosapentaenoic acid and docosahexaenoic acid.58 Of
alized in order to demonstrate the concept.
course, total fat restriction is not the only feature of the
DASH diet in relation to blood pressure and glucose
insulin sensitivity caused by either impaired glucose tol- control; the DASH diet is also high in fiber and potas-
erance or impaired fasting glucose, b-cell function is sium and rich in many other nutrients from fruits, veg-
also decreased, individuals may also benefit from a etables, and low-fat dairy products.59
high-protein diet because the ingestion of protein hy- For those whose phenotypes involve abnormal lipo-
drolysate increases insulin secretion.48–50 protein or postprandial triglyceride levels, focusing on
Similarly, individual amino acids have been shown the composition rather than the quantity of macronu-
to regulate insulin secretion.51 Leucine, as a supple- trients can be beneficial. High-fiber diets, especially
mented amino acid, has been shown to modulate glu- those high in pectin and b-glucans, and high intakes of
cose homeostasis through various means. In animals, monounsaturated fatty acids are associated with re-
leucine improves glucose control and partially prevents duced LDL cholesterol levels.60–62 Thus, the amount
diet-induced insulin resistance by targeting the pan- and the type of macronutrients need to be considered
creas. In humans, acute supplementation with protein when optimizing the health status of people with differ-
has been shown to be insulinotropic.48,49,52 It has been ent phenotype. The consumption of eicosapentaenoic
suggested that the insulinotropic effect of leucine is me- acid and docosahexaenoic acid may be beneficial not
diated by stimulation of protein synthesis in pancreatic only for lowering blood pressure but also for reducing
b cells by the mTOR signaling pathway.53 This pathway triglyceride levels.58
mediates insulin resistance by phosphorylation of IRS-1
by S6K1. Overstimulation of this pathway through PERSONALIZATION OF MICRO- AND PHYTONUTRIENTS
hyperinsulinemia may contribute to insulin resistance in IN METABOLIC HEALTH BIOLOGY
insulin-sensitive tissues. Insulin resistance in liver and
muscle following hyperinsulinemia may be prevented by Micronutrients play an essential role in many processes
blocking this pathway. Furthermore, leucine may influ- involved in systems flexibility. Metabolism and related
ence glucose homeostasis by increasing insulin sensitiv- oxidative stress and inflammation are major overarch-
ity and decreasing gluconeogenesis in insulin-sensitive ing processes in the area of metabolic health.4 A loss of
tissues, such as skeletal muscle or liver.54 In summary, it flexibility in these processes contributes to the develop-
is advisable for individuals with decreased b-cell func- ment of many chronic lifestyle-related disorders.
tion to consume a diet low in carbohydrates and high in Oxidative stress usually occurs when metabolic flexibil-
protein. To avoid problems with renal function, person- ity is impaired and peak concentrations of oxidative
alized advice for high protein intake should not exceed metabolites become too high. For example, oxidative
the higher end of the acceptable macronutrient distribu- microvascular damage related to insulin resistance is
tion range. Individuals who have both impaired glucose caused by formation of advanced glycation end prod-
tolerance and decreased b-cell function should consume ucts, activation of the protein kinase C pathways, and
a diet low in carbohydrates and high in protein, whereas reduction of nicotinamide adenine dinucleotide phos-
individuals who have impaired fasting glucose and de- phate by the polyol pathway.63 Personalized micronutri-
creased b-cell function should consume a diet with a ent interventions mechanistically target the impaired

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Personalized (Micro)nutrient Recommendaons with vitamin K, supplementation with vitamin D has
related to systems flexibility been shown to improve insulin secretion and to improve
systemic insulin sensitivity, albeit inconsistently. It has
low grade been suggested that vitamin D acts through peripheral
Liver inflammaon mechanisms (eg, increasing glucose uptake through
Choline, carnine GLUT4) or on pancreatic b cells, thereby increasing in-
vitD, VitE, Mg,
Catechins? ω-3 fay acid, flavonoids,
sulin secretion.70–72 Zinc is part of the insulin complex
curcuminoids and has been shown to have a mechanistic connection
to the activity of insulin on its target tissues.73 Plasma
zinc levels in individuals with type 2 diabetes are altered
when compared with levels in healthy individuals.74–78

Vasculature Pancreas Zinc thus appears to be a prime candidate for use as a
vitC, K, cocoa flavanols, Leucine, vitK, vitD, Mg supplement in individuals with type 2 diabetes.
NO-producing nutrients,
However, although some studies have reported a posi-
lycopene
tive effect of zinc supplementation on glucose homeosta-
Figure 5 Examples of nutrients involved in optimizing specific sis, a systematic review of randomized controlled trials
organ-related processes involved in maintaining systems flex- failed to demonstrate a benefit of zinc supplementation
ibility. Nutrients involved in maintaining inflammatory control are on insulin resistance, as measured by HOMA-IR.79
grouped under adipose tissue. Depending on the quantification of
Oxidative stress is an important factor in the etiology of
specific processes, personalized nutrition can focus on optimizing
these with specific nutrients. Abbreviations: K, potassium; Mg, mag-
diabetic complications, and zinc supplementation has
nesium; NO, nitric oxide; Vit D, vitamin D; Vit E, vitamin E; Vit K, beneficial effects on oxidative stress in the presence of
vitamin K. type 2 diabetes.80,81 The mechanism behind these effects
of zinc has not yet been adequately elucidated, and fur-
processes, either by optimizing specific aspects of glu- ther studies may help explain some of the inconsisten-
cose metabolism with the micronutrients involved (eg, cies observed. Finally, magnesium intake improves
vitamin D, magnesium) or increasing the oxidative insulin resistance, as measured by HOMA-IR, in both
stress capacity with the micronutrients involved (eg, vi- individuals with diabetes and those without.82–84 The
tamin E).63 Broadening the oxidative stress example to beneficial effect of magnesium intake is strongest in
the metabolic disease spectrum, several additional individuals who have impaired glucose tolerance in con-
aspects pertaining to the metabolic syndrome become cert with magnesium deficiency.82,85 Although the exact
apparent. Metabolic syndrome is defined as the pres- mechanism of action remains to be elucidated, it appears
ence of at least 3 of the following parameters: obesity, that magnesium is important for the maintenance of pe-
hypertriglyceridemia, low HDL cholesterol levels, hy- ripheral glucose uptake, which is mediated by GLUT4.
pertension, and increased fasting glucose levels. From a Many non-nutritive dietary components have been
systems flexibility perspective, these risk factors are shown to positively contribute to different aspects of
mechanistically connected (Figure 529,64), and, to be ef- glucose homeostasis. Several classes of polyphenolic
fective, nutritional interventions should target one or compounds have been reported to improve dysregu-
more of these factors and their underlying processes. lated glucose homeostasis and other aspects of systems
flexibility. Catechins (including epigallocatechin gallate)
Metabolism from tea have been shown to improve insulin sensitiv-
ity, as measured by HOMA-IR,86 and may alter post-
Glucose homeostasis plays an important role in the met- prandial glucose response. These compounds are
abolic shock absorption system and many micronu- thought to act on glucose homeostasis through multiple
trients play a role in maintaining glucose homeostasis. mechanisms, such as inhibition of intestinal digestive
Vitamin K intake has been shown to improve glucose enzymes (a-amylase, a-glucosidase, sucrase) and carbo-
metabolism in healthy individuals by affecting insulin hydrate absorption, decrease in gluconeogenesis, and
secretion of pancreatic b cells (Figure 5); it has thus enhancement of insulin sensitivity in adipocytes.87–90
been suggested that recommendations for vitamin K in- Isoflavones improved glucose homeostasis, as measured
take are too low.65–68 It is posited that vitamin K acts on by HOMA-IR. Soy isoflavone intake correlated with im-
b-cell function via the carboxylation of osteocalcin.69 proved impaired fasting glucose in postmenopausal
Furthermore, plasma vitamin D is inversely associated women, although nonobese individuals (body mass in-
with 10-year risk of increase in postprandial 2-hour dex [BMI] <30 kg/m2) were less affected,91–93 which
glucose and homeostatic model assessment–insulin re- illustrates that the efficacy of soy isoflavones and other
sistance (HOMA-IR; a measure of insulin resistance). As compounds in the optimization of glucose homeostasis

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587
Worrying Fear
Sleep disturbance Cognion Mobilizing
Chronic Stress
Disrupon
circadian rhythm High corsol
Physical inactivity Gut
Inflammatory Caloric excess
Endorphins Sweet & fat acvity
response
Quercetin, Se, Zn, … Visceral foods
dyslipidemia
adipose adiposity Adrenalin
inflammaon Muscle metabolic
inflexibility
Omega3-fatty acids ectopic Challenge
Carnitine, choline
lipid overload Adipose IR stress
systemic Hurrying
inflammation Fay liver
Low glycemic index

Lipids, alcohol, fructose Hepac IR Sympathec
Hepac
anthocyanins arousal
inflammaon High cholesterol
Stannols, fibre systemic
High glucose
parasympathec fibrosis Insulin resistance
tone Soy α-amylase
LDL elevated epicathechins
endothelial
inflammaon Glucose toxicity β-cell failure
Heart rate
Heart rate
Atherosclerosis
variability Microvascular
Hypertension Reflexes
damage
Renopathy
Stroke
Nephropathy
gut
IBD Brain
inflammaon
disorders
β-cell Pathology
Cardiac Heart Myocardial
dysfuncon failure infacons gluc Risk factor
Figure 6 A systems flexibility view in the context of personalized nutrition. The inner part of the figure represents the metabolic inflam-
matory part (yellow boxes) connected to risk factors of the metabolic syndrome (red boxes), which is termed phenotypic flexibility (Van
Ommen et al29,64). Imbalance or loss of flexibility leads to one or more pathologies (blue boxes). This system is connected to the outer circle
of neurohormonal processes, which impact the system flexibility (green boxes). A number of nutrients are shown where they interfere with
this flexibility scheme. Abbreviations: gluc, glucose; IBD, inflammatory bowel disease; IR, insulin resistance; LDL, low-density lipoprotein; Se, se-
lenium; Zn, zinc.
depends on the physiological context. To translate the inflammation, decreases with intake of both vitamins E
above information into personalized dietary recom- and D.97,98 Vitamin D has been shown to inhibit nu-
mendations, it may be useful to determine the specific clear factor kappa B (NF-jB) pathway–dependent tran-
insulin-dependent systems flexibility subtype of an indi- scriptional activation through activation of IjB-a,
vidual (as depicted in Figure 3) together with the indi- which may explain changes in CRP production.99
vidual’s vitamin D, magnesium, and vitamin K levels. Vitamin E decreases inflammation in several ways, in-
Individuals with decreased b-cell function may be ad- cluding through activating protein kinase C a and sub-
vised to take (a higher dose of) vitamin K, vitamin D, sequently inhibiting NF-jB and through inhibiting the
and magnesium. Individuals with the muscle insulin re- release of interleukin 1b (IL-1b) from monocytes.100,101
sistance phenotype may benefit from extra vitamin D, Meta-analyses have suggested an inverse relationship
magnesium, and epigallocatechin gallate, whereas non- between magnesium intake and chronic inflammation.
obese, postmenopausal female individuals with liver in- Magnesium deficiency might contribute to elevated
sulin resistance may benefit from soy isoflavones. CRP concentrations by activating macrophages via the
N-methyl-D-aspartate receptor and subsequently releas-
Inflammation ing interleukin 6 (IL-6) and tumor necrosis factor a
(TNF-a).102,103 Furthermore, a large cross-sectional
Chronic low-grade inflammation is involved in many study in the United States showed that flavonoid intake
pathologies,94 its modulation can be quantified by vari- is inversely related to CRP levels in adults.104
ous types of markers,95 and many dietary components The ability of long-chain n-3 fatty acids derived
can alter it.96 C-reactive protein (CRP), a biomarker of from the essential fatty acid alpha-linolenic acid to

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modulate inflammation has been extensively studied. vasculature and acts through several mechanisms, in-
Administration of n-3 fatty acids has been correlated cluding increasing flow-mediated vasodilation, improv-
with reductions in a number of inflammatory markers, ing endothelial dysfunction, and preventing uncoupling
including CRP, IL-6, and TNF-a. Meta-analysis shows of endothelial nitric oxide synthase.57,118
that the ingestion of these compounds is most effective
in individuals with BMI <30 kg/m2. The n-3 polyunsatu- Personalization
rated fatty acids are a minor component of the diet and
are thought to optimize inflammatory control through Dietary advice based on nutrient intake or status
the balancing and antagonistic effects of their metabo- markers provides a basic level of personalization; how-
lites (among others oxylipins, resolvins, and protectins) ever, this advice is based on (epidemiological) associa-
on the prostaglandin and related pathways.105,106 tion rather than the physiological function of the

Flavonoids and flavonoid-rich foods have been nutrient. Recommendations for nutrients based on
found to reduce inflammation and associated bio- their status should be augmented with information
markers, including circulating concentrations of IL-1b, grounded more firmly in the physiology of metabolic
IL-6, TNF-a, and CRP.107,108 Isoflavones from soy show health. The role of key organs in an individual’s glucose
benefits similar to cocoa flavonols on flow-mediated di- homeostasis can be determined by parameters derived
lation in the vascular system in postmenopausal from an oral glucose tolerance test, and hsCRP assays
women. Isoflavones have been shown to reduce inflam- can provide information on inflammatory status.
mation, as measured through plasma CRP, with a Ideally, status-based micronutrient personalization
greater response to the anti-inflammatory actions of should be fine-tuned based on target site active com-
isoflavones seen in postmenopausal women with high pound concentration because this represents the out-
sensitive CRP levels >2.2 mg/L.91 Curcuminoids are come of the sum of process variation. Vitamin D
thought to mainly affect IL-6 and IL-1b, and, possibly, provides a good example because genetic variation
CRP, even though the compounds have very low modulates absorption, metabolism, efficacy, and excre-
bioavailability.109 tion.119 Because phytonutrients are not considered es-
sential nutrients and deficiency and dietary reference
Vascular health intakes are mostly undefined, recommendations for
their intake are based on their effects and not on status
Different mechanisms may contribute to hypertension, markers. Thus, phytonutrients can be selected to ad-
including endothelial dysfunction, malfunctioning of the dress issues (eg, glucose metabolism or inflammation)
renin-angiotensin-aldosterone system, or disturbance of based on an individual’s physiology. The European
the folate/homocysteine pathways.110 It has been sug- Food Safety Authority (EFSA) has sanctioned health
gested that vitamin C improves endothelial function and claims for some phytonutrients, and South Korea has
therefore health status.57 Vitamin C supplementation identified 55 non-nutrients with health benefits
was shown to improve endothelial function in patients through a similar process. Dietary recommendations,
with diabetes, atherosclerosis, and heart failure, but no including phenotype-based personalized recommenda-
effect was observed in healthy volunteers.111 Diets with tions, will benefit from further consensus as to the
both salt restriction and increased potassium are benefi- health benefits of various phytonutrients.120 All of the
cial in preventing or controlling hypertension.57,112,113 non-nutrients regulated by EFSA and South Korea and
The European Food Safety Authority has authorized a mentioned herein, are attainable from the diet but,
health claim for the benefits of cocoa flavanols and wal- depending on personal taste and preferences, are not nec-
nuts in the maintenance or even improvement of nor- essarily consumed in the quantities recommended.
mal endothelium-dependent vasodilation, as measured Opportunities thus exist for new product development,
by flow-mediated dilation.114–116 Positive action on vas- fortification, and supplementation.
cular flexibility through the enhancement of nitric oxide The examples above illustrate that recommenda-
production by endothelial nitric oxide synthase is tions for the intake of micro- and phytonutrients can
thought to be the most probable mechanism by which vary considerably according to the individual and can be
cocoa flavanols and walnuts act.114 In a randomized based on many personal factors (eg, genetics, health sta-
control trial, lycopene supplementation improved endo- tus and biomarkers, environmental factors). Because
thelial function in patients with cardiovascular disease, multiple nutrients may act on a similar phenotype (ie,
but not in healthy volunteers,117 indicating that, similar each has a unique and complementary role in complex
to vitamin C, the beneficial effects of lycopene supple- physiological processes; the immune system is a good ex-
mentation on endothelial function may relate to health ample121), it is important to understand the mechanisms
status. Resveratrol also has beneficial effects on the involved and ideally incorporate these into a systems

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approach. This approach was extensively discussed in that influence the lactase gene are responsible for lactase
another review.4 Knowledge of the mechanisms under- persistence in Europe.126,127 Yet, for both variants, there
pinning specific aspects of systems flexibility can be used is no absolute correlation with dairy consumption or
to connect evidence (both mechanistic and observa- with occurrence of intolerance related to extended or
tional) from nutritional intervention studies of specific abundant lactose consumption because many factors
nutrients to personalized dietary advice aimed at opti- are involved in lactose intolerance, including other ge-
mizing system flexibility. This is illustrated in Figures 1, netic factors (gene–gene interactions), changes in pro-
2, and 5. Figure 6 illustrates how different compounds af- tein expression, and dietary factors (amount of lactose
fect different aspects of physiology. in dairy products, method of preparation, etc).
The health space in Figure 3 presents a simple A more complex example of gene–nutrient inter-
method to visualize the various macro- and micronutri- action is the physiological (disease-related) outcome of

ent interventions in relation to a personalized systems mutations in the gene MTHFR and its interaction with
flexibility profile. A tailored intervention dependent on various nutrients. MTHFR is translated into the en-
the individual’s position in this health space can be zyme methylenetetrahydrofolate reductase, which plays
designed to optimize all relevant flexibility processes a key role in 1-carbon metabolism and is required for
and return optimal systems flexibility. An example of DNA and RNA biosynthesis, amino-acid metabolism,
this approach was elaborated on in a systems biology– and methylation reactions. A common variant of the
based nutritional intervention study using mostly ho- MTHFR gene is the SNP rs1801133 (677TT), which in
meostatic biomarker values.30 homozygotes leads to (1) a 30% reduction in enzyme
activity, (2) a possible lowering of folate bioavailability,
NUTRIGENETICS: CONTRIBUTION OF GENETIC and (3) elevated homocysteine levels, a risk factor for
VARIATION TO PERSONALIZED NUTRITION cardiovascular disease. Low folate bioavailability is as-
sociated with, and mechanistically related to, neural
Personalized nutrition is often directly associated with tube defects. Yet, despite the many studies performed
genetic variation or “nutrigenetics.” Indeed, the human on folate, health effects, and related genetics, no
genome is packed with genetic variants, many of which genetics-based dietary advice on folate intake during
have been identified in genome-wide association stud- pregnancy exists.128 Interestingly, recent work shows a
ies, that are involved in energy metabolism, satiety and clear association between the MTHFR 677TT variant
appetite, growth, nutrient absorption, and many other and high blood pressure. Supplementation with ribo-
nutrition-related processes, some of which are not yet flavin (vitamin B2), which serves as a cofactor in the
understood. Translation from genetic variation to phe- form of flavin adenine dinucleotide for MTHFR activ-
notypic expression is not straightforward, which high- ity, was shown to lower blood pressure, specifically in
lights the importance of using a systems approach to hypertensive individuals with the MTHFR 677TT vari-
create robust personalized recommendations. ant.129 Although the exact mechanism by which
For a number of rare diseases, rigid dietary control MTHFR 677TT interacts with riboflavin and affects
can help control the disease. The metabolic disease phe- blood pressure is not known, there are associations
nylketonuria is caused by a loss-of-function mutation in with the deregulation of nitric oxide, which is known
the phenylalanine hydroxylase gene (PAH). This muta- to affect blood pressure by regulating vasodilatation.
tion results in accumulation of phenylalanine, which can Also, higher concentrations of flavin adenine dinucleo-
cause mental retardation, organ damage, and neurobeha- tide and folate cofactors stabilize MTHFR.130
vioral abnormalities. If the disease is detected early, tight An ultimate example of genetic adaptation to nu-
control of dietary phenylalanine intake and provision of tritional intake is found in Inuit, a group of indigenous
sufficient tyrosine allow for normal growth and develop- people inhabiting the Arctic regions of Greenland.
ment.122,123 Although the gene–nutrient interaction of Inuit have lived for a long time in extreme conditions
phenylketonuria is relatively straightforward, phenylala- and on an extreme diet that is low in carbohydrates,
nine tolerance may vary from patient to patient depend- high in protein and fats, and low in vegetables and
ing on residual PAH activity, among other things.124 fruits. Importantly, the diets are particularly high in
Lactose intolerance also has a genetic component. polyunsaturated fatty acids. Despite high fat intake,
The majority of the world population undergoes a ge- (traditional) Inuit show low levels of cardiovascular
netically programmed decrease in lactase biosynthesis disease. A recent study131 found several variants in the
with age.125 Interestingly, in large parts of Europe, the fatty acids desaturase (FADS) genes that were present
population has regained the ability to express lactase in in almost all Inuit selected for the study; in contrast,
adulthood. Variants in the MCM6 gene (single nucleo- these variants were seen in only 2% of Europeans. The
tide polymorphisms [SNPs] rs4988235 and rs182549) variants lower the production of n-6 and n-3 fatty

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acids, probably counteracting the already high intake of adipocytes to energy-storing white adipocytes. For this
these fatty acids from the diet. Interestingly, these particular variant, weight gain might not necessarily be a
mutations lower LDL cholesterol levels and have a pro- result of higher energy intake but instead be related to
found effect on height and weight. Other variants reduced levels of energy-dissipating beige adipocytes,
found in the Inuit population were associated with which is in line with the findings that this FTO variant is
TBX15 and have roles in the differentiation of brown part of a gene–exercise interaction on obesity risk.137
and white adipocytes. This differentiation may be asso- When formulating diet interventions, it is thus impor-
ciated with adaption to cold in Inuit populations. A tant to know the exact mechanism of action related to a
variant in FN3KRP is associated with protection from genetic variant associated with a health condition be-
increased oxidative stress that could be caused by high cause different genetic variants may require different
intake of polyunsaturated fatty acids. Health effects of interventions. At this stage, the FTO case is so complex

the Inuit diet are closely related to the population’s spe- that responders and nonresponders have not yet been
cific genetic makeup and thus might not directly be identified. Additionally, despite the FTO variant contrib-
translated to other populations.127 uting the most to obesity risk of all known variants, its
The above examples show the complexity of formu- contribution to obesity risk is still very small.
lating dietary advice if the genetic variation occurs The complexity of such multifactorial phenotypes
within one specific biochemical pathway. In many can partly be addressed by constructing a genetic sus-
cases, the complexity is even higher because the path- ceptibility score or genetic risk score (GRS) which pro-
way is one of many that work in concert to regulate an vides an overview of the cumulative theoretical
overarching process. A good example is satiety, which contribution of genetics to a condition, such as obesity,
involves multiple signaling pathways that monitor both for a given set of genetic variants.138 This score is still
acute and chronic needs for energy. Within this com- based on average numbers obtained from large study
plexity, some master regulators can overrule the subtle- cohorts and, thus, does not provide an ideal solution for
ties of the network, and rare mutations may lead to personalized nutrition because it does not pinpoint the
morbid obesity.132 The common variants of the gene mechanism and, thereby, the specific intervention
FTO, which, among all the identified common genetic needed. Fine-tuning a risk score into contributing
variants in obesity, contribute the most to the risk of aspects or traits (for the case of obesity: BMI, fat mass,
obesity, provide an example of such an interaction. waist-to-hip-ratio, extreme phenotypes, waist circum-
Speliotes et al133 found a cluster of several SNPs ference138) does not help if actionable mechanisms are
that impact adiposity by affecting expression of either not addressed. Genetic risk scores for insulin resistance
FTO or its neighboring genes. In addition, Loos and and type 2 diabetes may become more useful as the un-
Yeo134 calculated that each individual risk allele of this derlying processes are more clearly identified and sepa-
cluster was associated with a 0.39 kg/m2 increase in rated. This has been done for drug targets of specific
BMI and a 1.20-fold increase in risk of obesity. FTO is type 2 diabetes processes, where process-based risk
thought to have a role in appetite regulation, and SNPs scores were defined based on genes associated with
associated with FTO are thought to cause decreased ap- drug classes.139 A very similar approach could be used
petite control, which leads to weight gain in individuals to construct process-based GRSs for mechanisms un-
with these mutations. Most studies assume a higher to- derpinning phenotypic flexibility. Because no processes
tal energy intake for carriers of the FTO risk alleles. A are completely independent, genetic variants might be
meta-analysis of weight-loss studies that included 7700 part of more than one GRS, and the process-based GRS
individuals demonstrated that the TA and AA geno- would serve to match the phenotypic quantification of
types of the FTO variant rs9939609 together contrib- the same process rather than being a mathematical frac-
uted to an average 0.20-kg additional weight loss as tion of the total GRS. Finally, existing dedicated catalogs
compared to the TT genotype.135 For personalized nu- of gene–diet and gene–environment interactions, of
trition, however, it is irrelevant that 7700 individuals ex- which the CardioGxE catalog is a good example,140 will
perienced an average additional weight loss of 0.20 kg; be of increasing importance for the construction of
what matters is what specific dietary (or coaching) ad- such process-based GRSs.
vice should be given to an individual and whether that
one individual loses 3.1 kg or gains 0.7 kg. THE MASTERS OF SYSTEMS FLEXIBILITY:
Interestingly, Claussnitzer et al136 showed that the NEUROBIOLOGY OF PERSONALIZED NUTRITION
rs1421085 T-to-C variant of FTO influences expression
of the nearby genes IRX3 and IRX5, which repress mito- The brain acts as the master regulator of metabolism
chondrial thermogenesis in adipocyte precursor cells, by utilizing multiple nutrient-sensing mechanisms
resulting in a shift from energy-dissipating beige and neuronal feedback control systems for metabolic

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regulation. This has been reviewed by others.141 Three dietary fibers (more satiating food components), espe-
important areas of this master regulation (satiety, chro- cially when they also have the FTO risk allele.
nobiology, intermittent fasting and motivation) are spe-
cifically related to nutrition, including personalization Chronobiology
of nutrition. The importance of these areas of master
regulation is apparent when looking at genetic varia- The circadian clock system organizes multiple physiolog-
tions in these systems. For example, mutations in the ical functions, including digestion, absorption of food,
neural melanocortin receptors are responsible for the and metabolism. It also influences energy expenditure,
most common forms of monogenic obesity.142 activity, and sleep.150,151 The central internal clock sys-
tem resides in the anterior hypothalamic suprachiasmatic
Satiety nucleus. In normal physiological conditions, the supra-

chiasmatic nucleus synchronizes rhythms with peripheral
Caloric intake depends on food quantity and quality tissues through a series of neural and hormonal path-
(type of macronutrient), and satiation is one of the ma- ways.152,153 In addition, peripheral rhythms are entrained
jor regulators of quantity. Satiety is tightly controlled by by various other factors, among which feeding/fasting is
a network of neuronal, hormonal, and metabolic sen- the most important.154 Knowledge of the circadian
sors, acting both short term (postprandial; triggered by rhythms in the digestive system and metabolic activity
volume, density, content) and long term (connected to can be used to devise strategies for the optimal timing of
set-point regulation). Signal hormones such as grehlin food intake to preserve or improve health.150 For exam-
and leptin induce feelings of hunger and satiety, respec- ple, sensitivity to elevated glucose concentration is high-
tively, from the periphery to the hypothalamus.143 Well- est in the early morning and declines over the course of
known satiety hormones such as cholecystokinine, the day.155 Therefore, people with reduced insulin sensi-
glucagon-like peptide-1, and peptide YY increase after tivity may be best advised to eat evening meals low in
food intake, acting as signals for individuals to reduce carbohydrates or carbohydrates with a low glycemic in-
food intake.144 The satiety cascade145 illustrates the differ- dex. Further, there is considerable interindividual varia-
ent systems involved in appetite control, including sen- tion in circadian patterns. These may derive from
sory, cognitive, postingestive, and postabsorptive external factors relating to behavior and personal prefer-
processes, which act acutely on satiation (the process that ences, as well as from genetic influences such as the
brings food intake to an end) and, after food consump- CLOCK gene.154,156 A person’s circadian preference or so
tion, on satiety, affecting the time between food intake. called chronotype can be determined using the
Different macronutrients have different satiating morningness–eveningness questionnaire developed by
€ 157
properties, and thus changing the ratios of macronu- Horne and Ostberg.
trients can modulate feelings of satiety. The satiating ef- Eveningness, as compared with morningness, has
fect of macronutrients has been studied in multiple been linked with unhealthy eating, increased BMI, re-
populations, including lean and obese persons, men duced HDL cholesterol,158 and metabolic syndrome.159
and women, and restrained and unrestrained eaters, Those with evening chronotypes, as compared with
with varied responses. Diets high in protein (up to those with morning chronotypes, tend to eat later in the
30 E%) may reduce appetite and support body-weight day (ie, after 8 PM), which has been suggested to increase
management compared with diets low in protein146,147; the risk of obesity.150 This may be especially true for
this may be due in part to a greater satiating effect of late sleepers160 and those who get insufficient sleep
protein relative to other macronutrients. A high-protein (ie, 5 h).161 Thus, those with morning chronotypes
diet has been shown to result in less ad libitum caloric may be advised to consume the standard macronutrient
intake, resulting in significant weight loss.148 The in- compositions throughout the day, and those with eve-
creased energy expenditure reported with high-protein ning chronotypes may be advised to eat more frequently
diets supports the negative energy balance theory for during the day. Further, those with evening chrono-
enabling weight loss and/weight maintenance.147 Obese types may be advised to consume evening meals that
individuals show a clearer satiety response to fiber in- are higher in protein and rich in fiber to promote satia-
take, especially when on a very low-energy diet.149 tion and thereby lower the individual’s risk of overeat-
Body-weight characteristics such as BMI and waist cir- ing in the evening/night.
cumference, as well as FTO SNP allele status, can help
determine the possible effects of macronutrients, espe- Intermittent fasting
cially protein and dietary fibers, on an individual’s sati-
ety. People with a high BMI and a large waist may, for Evidence is accumulating that intermittent fasting (ie,
example, be advised to eat more protein and more fasting periods of 16 h), during which a complete

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catabolic metabolism, including fatty acid oxidation, alternative research approaches, such as n ¼ 1 para-
glycogen depletion, and ketone production, is activated, digms, must also be considered for the creation of effec-
benefits insulin sensitivity and optimizes brain bioener- tive recommendations. At this time, variations of the
getics and inflammatory control. Finally, implications evidence pyramid169 are commonly used by regulatory
for longevity have been reported, at least in model agencies and advisory boards, including the European
organisms.11 Although intermittent fasting is not a Food Safety Authority. As an example, the recommen-
usual dietary habit, it may be promising for individuals dation for increased folate intake for pregnant women
with insulin resistance and is a proven method for is now broadly accepted; however, the MTHFR 677TT
regaining insulin sensitivity in individuals with type 2 genetic variation, which reduces the catalytic activity of
diabetes and obese persons.162,163 a key enzyme in folate bioavailability,170 has been the
subject of more than 100 studies, but knowledge from

Motivation these studies has not been used by public health agen-
cies to modulate folate intake recommendations.128 A
The motivation to eat has physiological and nonphysio- global consortium of nutrigenetics experts currently
logical origins and shows interindividual variation. oversees the consensus evaluation of nutrient–gene
First, motivation to eat is based on the feeling of satiety. interactions, providing an initial guidance frame-
Second, brain reward circuits may influence the salience work171 (Grimaldi, in press), and this methodology is
of food and, thereby, the drive to eat.151 Sleep restriction brought into practice by evaluations published in a
leads to increased activation of brain areas that are sensi- growing and regularly updated library of nutrient gene
tive to food stimuli164 and increased neural responses to cards in the online journal Genes and Nutrition.
unhealthy foods in nonobese individuals.165 Thus, indi- For nutritional experts to keep track of the enor-
viduals who are sleep deprived may be more prone to mous complexity of nutrient—health relationships and
eating nutritionally poor food (eg, simple sugars and quickly retrieve all relevant information, the use of ap-
high-fat foods). Counseling individuals to choose tasty propriate knowledge management systems is impera-
and healthy alternatives at the right time may improve tive. Systems should use a multilevel organization of
health. Third, because eating is rewarding and comfort- knowledge—that is, they should capture information on
ing, people may (over)eat to alleviate their negative mood biological concepts at the intervention level (food, nu-
or emotional distress.166 Alternatively, eating may lift trient, compound, supplement, lifestyle, SNP), the inter-
mood directly by affecting mood-regulating neurocircuits mediate molecular/biological level (marker, pathway,
via a serotonergic mechanism.167 Because there are con- process, organ), and the phenotypic level (health, dis-
siderable differences in mood and subjective well-being ease) (Figures 1 and 5). For each concept, information
between individuals, both temporarily and over the long on known values/thresholds (eg, a dietary reference in-
term,168 it is important to consider mood and well-being take for vitamin D) and intervals (eg, lower and upper
when devising a personalized nutritional plan. With ap- boundaries defining normal cholesterol levels) should
propriate timing, overeating due to negative mood may be stored. In addition, information concerning the rela-
be attenuated by providing satiating foods high in pro- tionships between biological concepts should be cap-
tein and fiber. Finally, there may be other external moti- tured by the system. A relationship between 2 concepts
vators to eat (eg, the desire to stay awake for nightshift can be represented by a “triple” (a combination of
workers). subject, predicate, and object) or nanopublication. An
example of a nanopublication is “angiotensin II” –
INTEGRATING KNOWLEDGE INTO PRACTICE: “increases” – “lipogenesis.” Each triple needs to be ac-
PERSONALIZED SYSTEMS APPROACHES companied by information concerning the source of
information (eg, a reference), the level of scientific evi-
The value of adding personalized nutrition and dietary dence, and the conditions in which this relationship
advice to generic public health recommendations is applies (eg, sex, age, ethnicity).
supported by a large body of knowledge on biological Based on this information, experts can design deci-
mechanisms, observational studies, and nutritional and sion trees that define which recommendations to follow
dietary interventions. The complexity of personalized in a given personal situation. For example, IF “marker
nutrition is enormous, however, and it is practically X” is “low” and “SNP Y” has “allele Z” AND “sex” is
impossible to perform randomized controlled trials “male,” THEN the advice for “nutrient A” should be
for each genome–phenome–exome combination. “low.” Complexity can be added by combining and in-
Established evaluation procedures have been tried but tegrating multiple decision trees into personalized die-
have mostly resulted in inconclusive results, as de- tary advice. A major benefit of the use of expert-derived
scribed herein with regard to nutrigenetics. The use of decision trees is the transparency of the advice given.

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593
Each piece of advice can be traced back to a particular consume an average of 6000 kcal daily.176 The extreme
decision point, and each decision point is based on endurance performance that these cyclists deliver over a
established concepts and values. period of 3 weeks requires a well-adapted intestinal sys-
Modeling methods help to provide personalized die- tem that enables substrate uptake during activity.
tary advice based on personal health status and personal Personalizing nutrition for physical performance may
health and performance goals. For example, in the area of involve specific nutrients for specific types of perfor-
weight control, these modeling methods can range from mance, as well as specific timing of nutrient intake.
simple logic (“I want to lose weight, so I will consume less For endurance sports, simple carbohydrates are the
calories”) to multiparameter mathematical models.172 If main substrate used during activity, with a mean uptake
mechanisms are not known or only partly known, models of approximately 1 g of carbohydrates per minute.175,177
may be descriptive, data fitting, and reliant on trainer- Optimization of intake of carbohydrates before, during,

tester dataset validation. In these cases, it is essential that and after activity has been shown to enhance perfor-
the modeling approach be open access and peer reviewed mance and endurance over time.175,177 Duration of the
instead of “black-boxed.”173 Complex models are usually exercise activity (<1 h, 1–2 h, 2–3 h, >3 h), the amount
probabilistic (ie, all rules or assumptions contain uncer- of carbohydrate needed (small amounts, 30 g/h, 60 g/h,
tainty) and, if they are to be used practical advice, need to 90 g/h), the recommended type of carbohydrate (single
be carefully documented and ultimately validated. and/or multiple transportable carbohydrates), and con-
Personalized dietary advice based on scientifically vali- sumption connected to this training have been studied
dated rules according to set criteria become decision trees for endurance sports.177 For the well-trained runner, for
(ie, a relatively straightforward series of science-based example, carbohydrate intake should be 10–12 g/kg/d
choices or decisions that in essence narrow down the for 2–3 days before a marathon.178 Training should in-
general population into specific subsets). As new trees are clude consumption of carbohydrates at the increased
validated, progressively more personalized recommenda- levels so endurance athletes can adjust to the digestion
tions can be realized. Early models of these decision trees of these quantities of carbohydrates and learn to manage
were successfully designed and applied in the Food4Me any intestinal discomfort. After exercise, sufficient and
research project on personalized nutrition.174 fast carbohydrate intake (ie, 1.2–1.5 g/kg within 4 hours)
Applying science-based personalized dietary advice is recommended to replenish the glycogen stores in liver
not only at the time of initial phenotyping or goal set- and muscle.179 Endurance athletes mostly consume a
ting but also in response to iterative diagnostics, with high-carbohydrate diet (60–70 E%). Interestingly, there
the advice optimized after each measurement to achieve is debate about whether a high-carbohydrate diet is es-
the desired goal, is the next step in personalized nutri- sential for well-trained people because they also show
tion. The energy intake in the simple example above increased fat oxidation. This has recently resulted in an
(“I want to lose weight, so I will consume fewer calo- opposite theory—that a high-fat diet should be the diet of
ries”) is easily optimized if connected to regular body- choice for elite athletes.180 Essentially, this debate stresses
weight checks. Even in complex decision trees, iterative the importance of metabolic flexibility (ie, the capacity of
fine tuning of personalized dietary advice based on a muscles to use both glucose and fatty acids as substrate)
timeline of (a series of) biomarkers improves the quality and suggests that at optimal flexibility the choice of en-
of the advice. Mathematical applications such as ergy source is less relevant. Figure 7 summarizes this rea-
Bayesian modeling can further improve this modeling soning and selections in a decision tree scheme.
process, especially if a large dataset of personal diet In addition to an increased need for (simple) carbo-
health records becomes available. This would be the real hydrates, endurance athletes have an increased need for
strength of a data democracy–driven health system. protein because of its role in muscle damage and repair
processes. For well-trained athletes, a level of 1.2–1.7 g of
PHYSICAL ACTIVITY AS PERSONALIZED protein per kilogram of body weight is advised175 instead
NUTRITION GOAL of the 0.8–1.2 g of protein per kilogram of body weight
recommended for people with average activity levels.
For normal daily activities the average recommenda- Caffeine intake (3 mg/kg) before exercise (<1 h)
tions for daily food intake and the mean macronutrient may improve endurance performance.181 Several stud-
composition of approximately 50–55 E% carbohydrates, ies indicate that consuming approximately 500 mg of
30–35 E% fat, and 10–15 E% protein are adequate.174 nitrate from beetroot juice or an equivalent food source
For people seriously participating in sport activities, en- may benefit endurance performance.182 In particular, it
durance training, or strength training for multiple is believed that low to moderately trained individuals
hours a day, increased energy needs are required.175 For benefit from extra nitrate in their diet. In professional
instance, cyclists in the Tour de France need to athletes, the effects of extra nitrate are inconsistent.182

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Physical components of this flexibility machinery are subject to
Acvity nutritional modulation and relate directly to health out-
comes. This article presents many examples of these
Muscle strength Endurance nutrient–flexibility–health relationships and the ways in
which they can be personalized. Further expansion and
exercise type
(duraon, frequency,
maturation of personalized nutrition biology requires a
intensity) systems flexibility approach, spanning increased mecha-
Consumpon ming nistic knowledge, modeling technologies, knowledge
(prior, during, post)
infrastructures, and alternatives to randomized con-
trolled trials. This is a prerequisite for the professional
and credible expansion of personalized nutrition in a

healthy society and its food supply.
Protein Carbohydrate
recommendaon recommendaon
Figure 7 Simplified decision tree of personalized nutrition in Acknowledgments

relation to physical activity. The various components that pro-
vide evidence-based fine-tuning of dietary advice are visualized. Funding/support. This review was written as part of
the collaboration between TNO (The Netherlands
The American College of Sports Medicine has spe- Organization for Applied Scientific Research),
cial position papers on the maintenance of fluid balance Campbell Soup Company, and Habit LLC to establish
to enable optimal endurance performance and well- the biology of a personalized nutritional advice system.
being. Performance deteriorates when individuals lose It was funded by Habit LLC.
body water equivalent to 2%–3% of body weight, result-
ing in decreased temperature regulation and an in- Declaration of interest. The authors have no relevant
creased risk of heat stroke. Fluid loss during exercise interests to declare.
due to sweating should be compensated for by drinking
isotonic before, during, and after exercise to prevent de-
hydration and hyponatremia. The amount of electro- REFERENCES
lytes, sugars, and water volume needed depend on
1. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of
environmental conditions, training status, and exercise type 2 diabetes with lifestyle intervention or metformin. N Engl J Med.
performance (type, time, and intensity) and is mostly 2002;346:393–403.
2. Diabetes Prevention Program Research Group. The Diabetes Prevention
advised per kilogram of body weight.183 Program (DPP): description of lifestyle intervention. Diabetes Care.
2002;25:2165–2171.
3. van der Greef J, Hankemeier T, McBurney RN. Metabolomics-based systems biol-
CONCLUSION ogy and personalized medicine: moving towards n ¼ 1 clinical trials?
Pharmacogenomics. 2006;7:1087–1094.
4. van Ommen B, Fairweather-Tait S, Freidig A, et al. A network biology model of
Personalized nutrition is here to stay, and more infor- micronutrient related health. Br J Nutr. 2008;99(suppl 3):S72–S80.
mation on metabolic processes in the areas of nutrition 5. Bayle M-L, Wopereis S, Bouwman J, et al. Semi-targeted metabolomic
approaches to validate potential markers of health for micronutrients: analytical
and health is becoming available for use in personalized perspectives. Metabolomics. 2012;8:1114–1129.
nutrition. Also, major opportunities exist to optimize 6. Scott-Boyer MP, Lacroix S, Scotti M, et al. A network analysis of cofactor-protein
interactions for analyzing associations between human nutrition and diseases.
nutrition recommendations for individuals with dis- Sci Rep. 2016;6:19633. doi:10.1038/srep19633.
ease. Mechanistically, health and disease are tightly con- 7. Shin S-Y, Fauman EB, Petersen A-K, et al. An atlas of genetic influences on human
nected in the concept of systems flexibility, and blood metabolites. Nat Genet. 2014;46:543–540.
8. Suhre K, Wallaschofski H, Raffler J, et al. A genome-wide association study of
nutrition plays a role in both optimizing and impairing metabolic traits in human urine. Nat Genet. 2011;43:565–569.
flexibility processes. From a nutritional perspective, sys- 9. Kelder T, Summer G, Caspers M, et al. White adipose tissue reference network: a
knowledge resource for exploring health-relevant relations. Genes Nutr.
tems flexibility starts with the control of metabolic flexi- 2015;10:439. doi:10.1007/s12263-014-0439-x.
bility but extends to neurohormonal control of many 10. Van Ommen B, Bouwman J, Dragsted LO, et al. Challenges of molecular nutrition
research 6: the nutritional phenotype database to store, share and evaluate nu-
processes involved in maintaining homeostasis. tritional systems biology studies. Genes Nutr. 2010;5:189–203.
Essentially, a large part of the biochemical regulatory 11. Mattson MP, Allison DB, Fontana L, et al. Meal frequency and timing in health
and disease. Proc Natl Acad Sci U S A. 2014;111:16647–16653.
system is geared toward continuous adaptation to exter- 12. Kardinaal AFM, van Erk MJ, Dutman A E, et al. Quantifying phenotypic flexibility
nal challenges, and nutrition is a major component of as the response to a high-fat challenge test in different states of metabolic
health. FASEB J. 2015:29;4600–4613.
this process. To understand the unique, integrated, and 13. Regazzi R, Rodriguez-Trejo A, Jacovetti C. Insulin secretion in health and disease:
functional relationship of nutrition and health, one nutrients dictate the pace. Proc Nutr Soc. 2016;75:19–29.
14. Anthony JC, Yoshizawa F, Anthony TG, et al. Leucine stimulates translation initia-
must have knowledge of the connected mechanisms tion in skeletal muscle of postabsorptive rats via a rapamycin-sensitive pathway
that govern systems flexibility because many 1. J Nutr. 2000;130:2413–2419.

R
595
15. Virtue S, Vidal-Puig A. Adipose tissue expandability, lipotoxicity and the metabolic 45. European Food Safety Authority. Scientific opinion on the substantiation of
syndrome—an allostatic perspective. Biochim Biophys Acta. 2010;1801:338–349. health claims related to beta-glucans from oats and barley and maintenance of
16. Frayn K. Adipose tissue as a buffer for daily lipid flux. Diabetologia. normal blood LDL-cholesterol concentrations (ID 1236, 1299), increase in satiety
2002;45:1201–1210. leading to a reduction in energy intake (ID 851), reduction of post-prandial gly-
17. Vangipurapu J, Stancakova A, Pihlajam€aki J, et al. Association of indices of liver caemic responses (ID 821, 824), and “digestive function” (ID 850) pursuant to ar-
and adipocyte insulin resistance with 19 confirmed susceptibility loci for type 2 ticle 13(1) of regulation (EC) no 1924/2006. EFSA J. 2011;9:2207. doi:10.2903/
diabetes in 6,733 non-diabetic Finnish men. Diabetologia. 2011;54:563–571. j.efsa.2011.2207.
18. Wang J, Ban MR, Zou GY, et al. Polygenic determinants of severe hypertriglyceri- 46. Silva FM, Kramer CK, de Almeida JC, et al. Fiber intake and glycemic control in
demia. Hum Mol Genet. 2008;17:2894–2899. patients with type 2 diabetes mellitus: a systematic review with meta-analysis of
19. De Castro-Oros I, Cenarro A, Tejedor MT, et al. Common genetic variants contrib- randomized controlled trials. Nutr Rev. 2013;71:790–801.
ute to primary hypertriglyceridemia without differences between familial com- 47. Nettleton JA, McKeown NM, Kanoni S, et al. Interactions of dietary whole-grain
bined hyperlipidemia and isolated hypertriglyceridemia. Circ Cardiovasc Genet. intake with fasting glucose- and insulin-related genetic loci in individuals of
2014;7:814–821. European descent: a meta-analysis of 14 cohort studies. Diabetes Care.
20. Hegele RA. Monogenic dyslipidemias: window on determinants of plasma lipo- 2010;33:2684–2691.
protein metabolism. Am J Hum Genet. 2001;69:1161–1177. 48. Manders RJF, Wagenmakers AJM, Koopman R, et al. Co-ingestion of a protein hy-
21. Ress C, Kaser S. Mechanisms of intrahepatic triglyceride accumulation. World J drolysate and amino acid mixture with carbohydrate improves plasma glucose

Gastroenterol. 2016;22:1664. doi:10.3748/wjg.v22.i4.1664. disposal in patients with type 2 diabetes. Am J Clin Nutr. 2005;82:76–83.
22. Macaluso FS, Maida M, Petta S. Genetic background in nonalcoholic fatty liver 49. Manders RJF, Hansen D, Zorenc AHG, et al. Protein co-ingestion strongly
disease: a comprehensive review. World J Gastroenterol. 2015;21:11088–11111. increases postprandial insulin secretion in type 2 diabetes patients. J Med Food.
23. Malaguarnera M, Gargante MP, Russo C, et al. L-carnitine supplementation to 2014;17:758–763.
diet: a new tool in treatment of nonalcoholic steatohepatitis–a randomized and 50. Heer M, Egert S. Nutrients other than carbohydrates: their effects on glucose ho-
controlled clinical trial. Am J Gastroenterol. 2010;105:1338–1345. meostasis in humans. Diabetes Metab Res Rev. 2015;31:14–35.
24. Corpeleijn E, Saris WHM, Blaak EE. Metabolic flexibility in the development of insu- 51. Newsholme P, Bender K, Kiely A, et al. Amino acid metabolism, insulin secretion
lin resistance and type 2 diabetes: effects of lifestyle. Obes Rev. 2009;10:178–193. and diabetes. Biochem Soc Trans. 2007;35(pt 5):1180–1186.
25. Goossens GH, Moors CCM, Jocken JWE, et al. Altered skeletal muscle fatty acid 52. van Loon LJ, Kruijshoop M, Menheere PP, et al. Amino acid ingestion strongly
handling in subjects with impaired glucose tolerance as compared to impaired enhances insulin secretion in patients with long-term type 2 diabetes. Diabetes
fasting glucose. Nutrients. 2016;8:164. doi:10.3390/nu8030164. Care. 2003;26:625–630.
26. Lopez-Otın C, Galluzzi L, Freije JMP, et al. Metabolic control of longevity. Cell. 53. Xu G, Kwon G, Cruz WS, et al. Metabolic regulation by leucine of translation initi-
2016;166:802–821. ation through the mTOR-signaling pathway by pancreatic b-cells. Diabetes.
27. Furman D, Chang J, Lartigue L, et al. Expression of specific inflammasome gene 2001;50:353–360.
modules stratifies older individuals into two extreme clinical and immunological 54. Pedroso JAB, Zampieri TT, Donato J. Reviewing the effects of L-leucine supple-
states. Nat Med. 2017;23:174–184. mentation in the regulation of food intake, energy balance, and glucose homeo-
28. Stroeve JHM, van Wietmarschen H, Kremer BHA, et al. Phenotypic flexibility as a stasis. Nutrients. 2015;7:3914–3937.
measure of health: the optimal nutritional stress response test. Genes Nutr. 55. Rebholz CM, Friedman EE, Powers LJ, et al. Dietary protein intake and blood
2015;10:459. doi:10.1007/s12263-015-0459-1. pressure: a meta-analysis of randomized controlled trials. Am J Epidemiol.
29. Van Ommen B, Wopereis S. Next-generation biomarkers of health. Nestle Nutr 2012;176(suppl 7):S27–S43.
Inst Workshop Ser. 2016;84:25–34. 56. Buendia JR, Bradlee ML, Singer MR, et al. Diets higher in protein predict lower
30. Bouwman J, Vogels JT, Wopereis S, et al. Visualization and identification of health high blood pressure risk in Framingham Offspring Study adults. Am J Hypertens.
space, based on personalized molecular phenotype and treatment response to 2015;28:372–379.
relevant underlying biological processes. BMC Med Genomics. 2012;5:1. 57. Houston M. The role of nutrition and nutraceutical supplements in the treatment
doi:10.1186/1755-8794-5-1. of hypertension. World J Cardiol. 2014;6:38. doi:10.4330/wjc.v6.i2.38.
31. Sagner M, McNeil A, Puska P, et al. The P4 health spectrum—a predictive, pre- 58. European Food Safety Authority. Scientific opinion on the substantiation of
ventive, personalized and participatory continuum for promoting healthspan. health claims related to eicosapentaenoic acid (EPA), docosahexaenoic acid
Prog Cardiovasc Dis. 2016;59:506–521. (DHA), docosapentaenoic acid (DPA) and maintenance of normal cardiac func-
32. Lim EL, Hollingsworth KG, Aribisala BS, et al. Reversal of type 2 diabetes: normal- tion (ID 504, 506, 516, 527, 538, 703, 1128, 1317, 1324, 1325), maintenance of
isation of beta cell function in association with decreased pancreas and liver tria- normal blood glucose concentrations (ID 566), maintenance of normal blood
cylglycerol. Diabetologia. 2011;54:2506–2514. pressure (ID 506, 516, 703, 1317, 1324), maintenance of normal blood HDL-
33. Asano RY, Sales MM, Browne R, et al. Acute effects of physical exercise in type 2 cholesterol concentrations (ID 506), maintenance of normal (fasting) blood con-
diabetes: a review. World J Diabetes. 2014;5:659–665. centrations of triglycerides (ID 506, 527, 538, 1317, 1324, 1325), maintenance of
34. Steven S, Hollingsworth KG, Al-Mrabeh A, et al. Very-low-calorie diet and 6 normal blood LDL-cholesterol concentrations (ID 527, 538, 1317, 1325, 4689),
months of weight stability in type 2 diabetes: pathophysiologic changes in res- protection of the skin from photo-oxidative (UV-induced) damage (ID 530), im-
ponders and nonresponders. Diabetes Care. 2016:39;808–815. proved absorption of EPA and DHA (ID 522, 523), contribution to the normal
35. Blanco-Rojo R, Alcala-Diaz JF, Wopereis S, et al. The insulin resistance phenotype function of the immune system by decreasing the levels of eicosanoids, arachi-
(muscle or liver) interacts with the type of diet to determine changes in disposi- donic acid-derived mediators and pro-inflammatory cytokines (ID 520, 2914),
tion index after 2 years of intervention: the CORDIOPREV-DIAB randomised clini- and “immunomodulating agent” (4690) pursuant to article 13(1) of regulation
cal trial. Diabetologia. 2016;59:67–76. (EC) no 1924/2006. EFSA J. 2010;8:1796. doi:10.2903/j.efsa.2010.1796.
36. Anderson JW, Ward K. High-carbohydrate hig-fiber diets for insulin-treated men 59. Hinderliter AL, Babyak MA, Sherwood A, Blumenthal J. The DASH diet and insulin
with diabetes mellitus. Am J Clin Nutr. 1979;32:2312–2321. sensitivity. Curr Hypertens Rep. 2011;13:67–73.
37. Kearns CE, Schmidt LA, Glantz SA. Sugar industry and coronary heart disease re- 60. European Food Safety Authority. Scientific opinion on the substantiation of
search. JAMA Intern Med. 2016;176:1680–1685. health claims related to pectins and reduction of post-prandial glycaemic
38. Burke JP, Williams K, Gaskill SP, et al. Rapid rise in the incidence of type 2 diabe- responses (ID 786), maintenance of normal blood cholesterol concentrations (ID
tes from 1987 to 1996: results from the San Antonio Heart Study. Arch Intern 818) and increase in satiety leading to a reduction in energy intake (ID 4692) pur-
Med. 1999;159:1450–1456. suant to article 13(1) of regulation (EC) no 1924/2006. EFSA J. 2010;8:1747.
39. Mensink RP. Effects of saturated fatty acids on serum lipids and lipoproteins: a doi:10.2903/j.efsa.2010.1747.
systematic review and regression analysis. Geneva, Switzerland: WHO; 2016. 61. European Food Safety Authority. Scientific opinion on the substantiation of a
40. Imamura F, Micha R, Wu JHY, et al. Effects of saturated fat, polyunsaturated fat, health claim related to oat beta-glucan and lowering blood cholesterol and re-
monounsaturated fat, and carbohydrate on glucose-insulin homeostasis: a sys- duced risk of (coronary) heart disease pursuant to article 14 of regulation (EC) no
tematic review and meta-analysis of randomised controlled feeding trials. PLOS 1924/2006. EFSA J. 2010;8:1885. doi:10.2903/j.efsa.2010.1885.
Med. 2016;13:e1002087. doi:10.1371/journal.pmed.1002087. 62. Whitehead A, Beck EJ, Tosh S, et al. Cholesterol-lowering effects of oat b-glucan:
41. Ludwig DS. Lowering the bar on the low-fat diet. JAMA. 2016;2115:5–6. a meta-analysis of randomized controlled trials. Am J Clin Nutr.
42. Cuenca-Sanchez M, Navas-Carrillo D, Orenes-Pinero E. Controversies surrounding 2014;100:1413–1421.
high-protein diet intake: satiating effect and kidney and bone health. Adv Nutr 63. Bartlett HE, Eperjesi F. Nutritional supplementation for type 2 diabetes: a system-
An Int Rev J. 2015;6:260–266. atic review. Ophthalmic Physiol Opt. 2008;28:503–523.
43. Delimaris I. Adverse effects associated with protein intake above the recom- 64. van Ommen B, van der Greef J, Ordovas JM, et al. Phenotypic flexibility as key
mended dietary allowance for adults. ISRN Nutr. 2013;2013:126929. doi:10.5402/ factor in the human nutrition and health relationship. Genes Nutr. 2014;9:423.
2013/126929. doi:10.1007/s12263-014-0423-5.
44. Bacha F, Lee S, Gungor N, Arslanian SA. From pre-diabetes to type 2 diabetes in 65. Sakamoto N, Nishiike T, Iguchi H, et al. Relationship between acute insulin re-
obese youth: pathophysiological characteristics along the spectrum of glucose sponse and vitamin K intake in healthy young male volunteers. Diabetes Nutr
dysregulation. Diabetes Care. 2010;33:2225–2231. Metab. 1999;12:37–41.

R
66. Yoshida M, Jacques PF, Meigs JB, et al. Effect of vitamin K supplementation on in- 92. Dong J-Y, Wang P, He K, et al. Effect of soy isoflavones on circulating C-reactive
sulin resistance in older men and women. Diabetes Care. 2008;31:2092–2096. protein in postmenopausal women: meta-analysis of randomized controlled tri-
67. Choi HJ, Yu J, Choi H, et al. Vitamin K2 supplementation improves insulin sensi- als. Menopause. 2011;18:1256–1262.
tivity via osteocalcin metabolism: a placebo-controlled trial. Diabetes Care. 93. Fang K, Dong H, Wang D, et al. Soy isoflavones and glucose metabolism in men-
2011;34:e147. doi:10.2337/dc11-0551. opausal women: a systematic review and meta-analysis of randomized con-
68. Sakamoto N, Nishiike T, Iguchi H, et al. Possible effects of one week vitamin K trolled trials. Mol Nutr Food Res. 2016;60:1602–1614.
(menaquinone-4) tablets intake on glucose tolerance in healthy young male vol- 94. Calder PC, Albers R, Antoine J-M, et al. Inflammatory disease processes and inter-
unteers with different descarboxy prothrombin levels. Clin Nutr. actions with nutrition. Br J Nutr. 2009;101(suppl):S1–S45.
2000;19:259–263. 95. Albers R, Bourdet-Sicard R, Braun D, et al. Monitoring immune modulation by
69. Manna P, Kalita J. Beneficial role of vitamin K supplementation on insulin sensi- nutrition in the general population: identifying and substantiating effects on hu-
tivity, glucose metabolism, and the reduced risk of type 2 diabetes: a review. man health. Br J Nutr. 2013;110(suppl):S1–S30.
Nutrition. 2016;32:732–739. 96. Minihane AM, Vinoy S, Russell WR, et al. Low-grade inflammation, diet composi-
70. Harris SS, Pittas AG, Palermo NJ. A randomized, placebo-controlled trial of vita- tion and health: current research evidence and its translation. Br J Nutr.
min D supplementation to improve glycaemia in overweight and obese African 2015;114:999–1012.
Americans. Diabetes Obes Metab. 2012;14:789–794. 97. Chen N, Wan Z, Han S-F, et al. Effect of vitamin D supplementation on the level
71. von Hurst PR, Stonehouse W, Coad J, et al. Vitamin D supplementation reduces of circulating high-sensitivity C-reactive protein: a meta-analysis of randomized

insulin resistance in South Asian women living in New Zealand who are insulin controlled trials. Nutrients. 2014;6:2206–2216.
resistant and vitamin D deficient—a randomised, placebo-controlled trial. Br J 98. Saboori S, Shab-Bidar S, Speakman JR, et al. Effect of vitamin E supplementation
Nutr. 2010;103:549–555. on serum C-reactive protein level: a meta-analysis of randomized controlled tri-
72. Mitri J, Dawson-Hughes B, Hu FB, et al. Effects of vitamin D and calcium supple- als. Eur J Clin Nutr. 2015;69:867–873.
mentation on pancreatic b cell function, insulin sensitivity, and glycemia in 99. Cohen-Lahav M, Shany S, Tobvin D, et al. Vitamin D decreases NF B activity by in-
adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus creasing I B levels. Nephrol Dial Transplant. 2005;21:889–897.
(CaDDM) randomized controlled trial. Am J Clin Nutr. 2011;94:486–494. 100. Devaraj S, Jialal I. The effects of alpha-tocopherol on critical cells in atherogene-
73. Jansen J, Karges W, Rink L. Zinc and diabetes—clinical links and molecular mech- sis. Curr Opin Lipidol. 1998;9:11–15.
anisms. J Nutr Biochem. 2009;20:399–417. 101. Nakamura T, Goto M, Matsumoto A, et al. Inhibition of NF-kappa B transcriptional
74. Aguilar MV, Saavedra P, Arrieta FJ, et al. Plasma mineral content in type-2 dia- activity by alpha-tocopheryl succinate. Biofactors. 1998;7:21–30.
betic patients and their association with the metabolic syndrome. Ann Nutr 102. Dibaba DT, Xun P, He K. Dietary magnesium intake is inversely associated with
Metab. 2007;51:402–406. serum C-reactive protein levels: meta-analysis and systematic review. Eur J Clin
75. Quilliot D, Dousset B, Guerci B, et al. Evidence that diabetes mellitus favors im- Nutr. 2014;68:510–516.
paired metabolism of zinc, copper, and selenium in chronic pancreatitis. 103. Chacko SA, Song Y, Nathan L, et al. Relations of dietary magnesium intake to bio-
Pancreas. 2001;22:299–306. markers of inflammation and endothelial dysfunction in an ethnically diverse co-
76. Pai LH, Prasad AS. Cellular zinc in patients with diabetes mellitus. Nutr Res. hort of postmenopausal women. Diabetes Care. 2010;33:304–310.
1988;8:889–897. 104. Chun OK, Chung S-J, Claycombe KJ, et al. Serum C-reactive protein concentra-
77. Kinlaw WB, Levine AS, Morley JE, et al. Abnormal zinc metabolism in type II dia- tions are inversely associated with dietary flavonoid intake in U.S. adults. J Nutr.
betes mellitus. Am J Med. 1983;75:273–277. 2008;138:753–760.
78. Al-Maroof RA, Al-Sharbatti SS. Serum zinc levels in diabetic patients and effect of 105. Li K, Huang T, Zheng J, et al. Effect of marine-derived n-3 polyunsaturated fatty
zinc supplementation on glycemic control of type 2 diabetics. Saudi Med J. acids on C-reactive protein, interleukin 6 and tumor necrosis factor a: a meta-
2006;27:344–350. analysis. PLoS One. 2014;9:e88103. doi:10.1371/journal.pone.0088103.
79. El Dib R, Gameiro OL, Ogata MS, et al. Zinc supplementation for the prevention 106. Gabbs M, Leng S, Devassy JG, et al. Advances in our understanding of oxylipins
of type 2 diabetes mellitus in adults with insulin resistance. Cochrane Database derived from dietary PUFAs. Adv Nutr. 2015;6:513–540.
Syst Rev. 2015;5:CD005525. doi:10.1002/14651858.CD005525.pub3. 107. Peluso I, Raguzzini A, Serafini M. Effect of flavonoids on circulating levels of TNF-
80. Roussel A-M, Kerkeni A, Zouari N, et al. Antioxidant effects of zinc a and IL-6 in humans: a systematic review and meta-analysis. Mol Nutr Food Res.
supplementation in Tunisians with type 2 diabetes mellitus. J Am Coll Nutr. 2013;57:784–801.
2003;22:316–321. 108. Rangel-Huerta OD, Pastor-Villaescusa B, Aguilera CM, et al. A systematic review
81. Anderson RA, Roussel AM, Zouari N, et al. Potential antioxidant effects of zinc of the efficacy of bioactive compounds in cardiovascular disease: phenolic
and chromium supplementation in people with type 2 diabetes mellitus. J Am compounds.
Coll Nutr. 2001;20:212–218. 109. Sahebkar A. Are curcuminoids effective C-reactive protein-lowering agents in
82. Mooren FC, Kruger K, Volker K, et al. Oral magnesium supplementation reduces clinical practice? Evidence from a meta-analysis. Phytother Res.
insulin resistance in non-diabetic subjects—a double-blind, placebo-controlled, 2014;28:633–642.
randomized trial. Diabetes Obes Metab. 2011;13:281–284. 110. Pilic L, Pedlar CR, Mavrommatis Y, et al. Salt-sensitive hypertension: mechanisms
83. Rumawas ME, McKeown NM, Rogers G, et al. Magnesium intake is related to im- and effects of dietary and other lifestyle factors. Nutr Rev. 2016;360:1903–1913.
proved insulin homeostasis in the framingham offspring cohort. J Am Coll Nutr. 111. Ashor AW, Siervo M, Lara J, et al. Effect of vitamin C and vitamin E supplementa-
2006;25:486–492. tion on endothelial function: a systematic review and meta-analysis of rando-
84. Veronese N, Watutantrige SF, Luchini C, et al. Effect of magnesium supplementa- mised controlled trials. Br J Nutr. 2015;113:1182–1194.
tion on glucose metabolism in people with or at risk of diabetes: a systematic re- 112. Aaron KJ, Sanders PW, Aaron, Kristal J. Role of dietary salt and potassium intake
view and meta-analysis of double-blind randomized controlled trials. Eur J Clin in cardiovascular health and disease: a review of the evidence. Mayo Clin Proc.
Nutr. 2016:70;1354–1359. 2013;88:987–995.
85. Song Y, He K, Levitan EB, et al. Effects of oral magnesium supplementation on 113. Aburto NJ, Hanson S, Gutierrez H, et al. Effect of increased potassium intake on
glycaemic control in type 2 diabetes: a meta-analysis of randomized double- cardiovascular risk factors and disease: systematic review and meta-analyses.
blind controlled trials. Diabet Med. 2006;23:1050–1056. BMJ. 2013;346:F1378–F1378.
86. Zheng X-X, Xu Y-L, Li S-H, et al. Effects of green tea catechins with or without caf- 114. European Food Safety Authority. Scientific opinion on the substantiation of
feine on glycemic control in adults: a meta-analysis of randomized controlled tri- health claims related to walnuts and maintenance of normal blood LDL-
als. Am J Clin Nutr. 2013;97:750–762. cholesterol concentrations (ID 1156, 1158) and improvement of endothelium-
87. Roghani M, Baluchnejadmojarad T. Hypoglycemic and hypolipidemic effect and dependent vasodilation (ID 1155, 1157) pursuant to article 13(1) of regulation
antioxidant activity of chronic epigallocatechin-gallate in streptozotocin-diabetic (EC) no 1924/2006. EFSA J. 2011;9:2074. doi:10.2903/j.efsa.2011.2074.
rats. Pathophysiology. 2010;17:55–59. 115. European Food Safety Authority. Scientific opinion on the substantiation of a
88. Sakurai N, Mochizuki K, Kameji H, et al. (-)-Epigallocatechin gallate enhances the health claim related to cocoa flavanols and maintenance of normal
expression of genes related to insulin sensitivity and adipocyte differentiation in endothelium-dependent vasodilation pursuant to article 13(5) of regulation (EC)
3T3-L1 adipocytes at an early stage of differentiation. Nutrition. no 1924/2006. EFSA J. 2012;10:2809. doi:10.2903/j.efsa.2012.2809.
2009;25:1047–1056. 116. European Food Safety Authority. Scientific opinion on the modification of the
89. Collins QF, Liu H-Y, Pi J, et al. Epigallocatechin-3-gallate (EGCG), a green tea poly- authorisation of a health claim related to cocoa flavanols and maintenance
phenol, suppresses hepatic gluconeogenesis through 5’-AMP-activated protein of normal endothelium-dependent vasodilation pursuant to article 13 (5) of
kinase. J Biol Chem. 2007;282:30143–30149. regulation (EC) no 1924 / 2006 1 following a request in accordance with arti-
90. Broadhurst CL, Polansky MM, Anderson RA. Insulin-like biological activity of culi- cle 19 of regulation (EC) no 1924/2006. EFSA J. 2014;12;3654. doi:10.2903/
nary and medicinal plant aqueous extracts in vitro. J Agric Food Chem. j.efsa.2014.3654.
2000;48:849–852. 117. Gajendragadkar PR, Hubsch A, M€aki-Pet€aj€a KM, et al. Effects of oral lycopene
91. Li S-H, Liu X-X, Bai Y-Y, et al. Effect of oral isoflavone supplementation on vascu- supplementation on vascular function in patients with cardiovascular disease
lar endothelial function in postmenopausal women: a meta-analysis of random- and healthy volunteers: a randomised controlled trial. PLoS One. 2014;9:e99070.
ized placebo-controlled trials. Am J Clin Nutr. 2010;91:480–486. doi:10.1371/journal.pone.0099070.

R
597
118. Kelly-Spratt KS, Pitteri SJ, Gurley KE, et al. Plasma proteome profiles associated compensatory changes in diurnal plasma leptin and ghrelin concentrations. Am
with inflammation, angiogenesis, and cancer. PLoS One. 2011;6:e19721. J Clin Nutr. 2005;82:41–48.
doi:10.1371/journal.pone.0019721. 149. Pasman WJ, Saris WH, Wauters MA, et al. Effect of one week of fibre supplemen-
119. Mokry LE, Ross S, Ahmad OS, et al. Vitamin D and risk of multiple sclerosis: a tation on hunger and satiety ratings and energy intake. Appetite. 1997;29:77–87.
Mendelian randomization study. PLOS Med. 2015;12:e1001866. doi:10.1371/ 150. Tahara Y, Shibata S. Chronobiology and nutrition. Neuroscience. 2013;253:78–88.
journal.pmed.1001866. 151. Chaput J-P, McCarthy S. Sleep patterns, diet quality and energy balance. Physiol
120. Lupton JR, Atkinson S a, Chang N, et al. Exploring the benefits and challenges of Behav. 2014;134:86–91.
establishing a DRI-like process for bioactives. Eur J Nutr. 2014;53(suppl 1):1–9. 152. Bass J, Takahashi JS. Circadian integration of metabolism and energetics.
121. Larbi A, Franceschi C, Mazzatti D, et al. Aging of the immune system as a prog- Science. 2010;330:1349–1354.
nostic factor for human longevity. Physiology (Bethesda). 2008;23:64–74. 153. Johnston JD. Physiological responses to food intake throughout the day. Nutr
122. Scriver CR. The PAH gene, phenylketonuria, and a paradigm shift. Hum Mutat. Res Rev. 2014;27:107–118.
2007;28:831–845. 154. Oosterman JE, Kalsbeek A, la Fleur SE, et al. Impact of nutrients on circadian
123. Singh RH, Cunningham AC, Mofidi S, et al. Updated, web-based nutrition man- rhythmicity. Am J Physiol—Regul Integr Comp Physiol. 2015;308:R337–R350.
agement guideline for PKU: an evidence and consensus based approach. Mol 155. Van Cauter E, Polonsky KS, Scheen AJ. Roles of circadian rhythmicity and sleep in
Genet Metab. 2016;118:72–83. human glucose regulation. Endocr Rev. 1997;18:716–738.
124. de Baulny HO, Abadie V, Feillet F, et al. Management of phenylketonuria and 156. Ruiz-Lozano T, Vidal J, de Hollanda A, et al. Evening-chronotype associates with

hyperphenylalaninemia. J Nutr. 2007;137(suppl 1):1561S–1563S; discussion obesity in severe obese subjects: interaction with CLOCK 3111T/C. Int J Obes
1573S–1575S. (London). 2016;40;1550–1557.
125. Deng Y, Misselwitz B, Dai N, et al. Lactose intolerance in adults: biological mecha- 157. Horne JA, Ostberg O. A self-assessment questionnaire to determine morningness-
nism and dietary management. Nutrients. 2015;7:8020–8035. eveningness in human circadian rhythms. Int J Chronobiol. 1976;4:97–110.
126. Enattah NS, Sahi T, Savilahti E, et al. Identification of a variant associated with 158. Lucassen EA, Zhao X, Rother KI, et al. Evening chronotype is associated with
adult-type hypolactasia. Nat Genet. 2002;30:233–237. changes in eating behavior, more sleep apnea, and increased stress hormones in
127. Mathieson I, Lazaridis I, Rohland N, et al. Genome-wide patterns of selection in short sleeping obese individuals. PLoS One. 2013;8:e56519. doi:10.1371/
230 ancient Eurasians. Nature. 2015;528:499–503. journal.pone.0056519.
128. Levin BL, Varga E. MTHFR: addressing genetic counseling dilemmas using 159. Yu JH, Yun CH, Ahn JH, et al. Evening chronotype is associated with metabolic
evidence-based literature. J Genet Couns. 2016;25:901–911. disorders and body composition in middle-aged adults. J Clin Endocrinol Metab.
129. Wilson CP, McNulty H, Ward M, et al. Blood pressure in treated hypertensive indi- 2015;100:1494–1502.
viduals with the MTHFR 677TT genotype is responsive to intervention with ribo- 160. Baron KG, Reid KJ, Kern AS, et al. Role of sleep timing in caloric intake and BMI.
flavin: findings of a targeted randomized trial. Hypertension. Obesity (Silver Spring). 2011;19:1374–1381.
2013;61:1302–1308. 161. Markwald RR, Melanson EL, Smith MR, et al. Impact of insufficient sleep on total
130. Lienhart WD, Gudipati V, MacHeroux P. The human flavoproteome. Arch daily energy expenditure, food intake and weight gain. Proc Natl Acad Sci U S A.
Biochem Biophys. 2013;535:150–162. 2013;110:5695–5700.
131. Fumagalli M, Moltke I, Grarup N, et al. Greenlandic Inuit show genetic signatures 162. Barnosky AR, Hoddy KK, Unterman TG, et al. Intermittent fasting vs daily calorie
of diet and climate adaptation. Science. 2015;349:1343–1347. restriction for type 2 diabetes prevention: a review of human findings. Transl
132. Xia Q, Grant SFA. The genetics of human obesity. Ann N Y Acad Sci. Res. 2014;164:302–311.
2013;1281:178–190. 163. Antoni R, Johnston KL, Collins AL, Robertson MD. Investigation into the acute
133. Speliotes EK, Willer CJ, Berndt SI, et al. Association analyses of 249,796 individu- effects of total and partial energy restriction on postprandial metabolism among
als reveal 18 new loci associated with body mass index. Nat Genet. overweight/obese participants. Br J Nutr. 2016;115:951–959.
2010;42:937–948. 164. Benedict C, Brooks SJ, O’Daly OG, et al. Acute sleep deprivation enhances the
134. Loos RJF, Yeo GSH. The bigger picture of FTO: the first GWAS-identified obesity brain’s response to hedonic food stimuli: an fMRI study. J Clin Endocrinol Metab.
gene. Nat Rev Endocrinol. 2014;10:51–61. 2012;97:443–447.
135. Xiang L, Wu H, Pan A, et al. FTO genotype and weight loss in diet and lifestyle 165. St-Onge M-P, Wolfe S, Sy M, et al. Sleep restriction increases the neuronal re-
interventions: a systematic review and meta-analysis. Am J Clin Nutr. sponse to unhealthy food in normal-weight individuals. Int J Obes (London).
2016;103:1162–1170. 2014;38:411–416.
136. Claussnitzer M, Dankel SN, Kim K-H, et al. FTO obesity variant circuitry and adipo- 166. Adam TC, Epel ES. Stress, eating and the reward system. Physiol Behav.
cyte browning in humans. N Engl J Med. 2015;373:895–907. 2007;91:449–458.
137. Young AI, Wauthier F, Donnelly P. Multiple novel gene-by-environment interac- 167. Kroes MCW, van Wingen GA, Wittwer J, et al. Food can lift mood by affecting
tions modify the effect of FTO variants on body mass index. Nat Commun. mood-regulating neurocircuits via a serotonergic mechanism. Neuroimage.
2016;7:12724. doi:10.1038/ncomms12724. 2014;84:825–832.
138. Fall T, Ingelsson E. Genome-wide association studies of obesity and metabolic 168. National Research Council. Subjective Well-Being Measuring Happiness,
syndrome. Mol Cell Endocrinol. 2014;382:740–757. Suffering, and Other Dimensions of Experience. Washington, DC: The National
139. Segrè AV, Wei N, Altshuler D, et al. Pathways targeted by antidiabetes drugs are Academies Press; 2013.
enriched for multiple genes associated with type 2 diabetes risk. Diabetes. 169. Pandis N. The evidence pyramid and introduction to randomized controlled tri-
2015;64:1470–1483. als. Am J Orthod Dentofac Orthop. 2011;140:446–447.
140. Parnell LD, Blokker B, Dashti HS, et al. CardioGxE, a catalog of gene-environment 170. Molloy AM. Genetic aspects of folate metabolism. Subcell Biochem.
interactions for cardiometabolic traits. BioData Min. 2014;7:21. doi:10.1186/1756- 2012;56:105–130.
0381-7-21. 171. Grimaldi K, Van Ommen B, Ordovas JA, et al Proposed guidelines to evaluate sci-
141. Roh E, Song DK, Kim M-S. Emerging role of the brain in the homeostatic regula- entific validity and evidence for genotype-based dietary advice. Genes and
tion of energy and glucose metabolism. Exp Mol Med. 2016;48:e216. Nutrition. In press.
doi:10.1038/emm.2016.4. 172. Hall KDD, Bemis T, Brychta R, et al. Calorie for calorie, dietary fat restriction
142. Tao YX. Molecular mechanisms of the neural melanocortin receptor dysfunction results in more body fat loss than carbohydrate restriction in people with obe-
in severe early onset obesity. Mol Cell Endocrinol. 2005;239:1–14. sity. Cell Metab. 2015;22:427–436.
143. Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in the regula- 173. Zeevi D, Korem T, Zmora N, et al. Personalized nutrition by prediction of glyce-
tion of food intake and body weight in humans: a review. Obes Rev. mic responses. Cell. 2015;163:1079–1094.
2007;8:21–34. 174. Forster H, Walsh MC, O’Donovan CB, et al. A dietary feedback system for the de-
144. De Graaf C, Blom WAM, Smeets PAM, et al. Biomarkers of satiation and satiety. livery of consistent personalized dietary advice in the web-based multicenter
Am J Clin Nutr. 2004;79:946–961. Food4Me Study. J Med Internet Res. 2016;18:e150. doi:10.2196/jmir.5620.
145. Blundell JE, Hill AJ, Rogers PJ. Hunger and the satiety cascade—their importance 175. American Dietetic Association, Dietitians of Canada, American College of Sports
for food acceptance in the late 20th century. In: Thomson DMH, ed. Food Medicine, et al. American College of Sports Medicine position stand. Nutrition
Acceptability. London, UK: Elsevier; 1988:230–250. and athletic performance. Med Sci Sport Exerc. 2009;41:709–731.
146. Leidy HJ, Clifton PM, Astrup A, et al. The role of protein in weight loss and main- 176. Saris WH, van Erp-Baart MA, Brouns F, et al. Study on food intake and energy ex-
tenance. Am J Clin Nutr. 2015;101:1320–1329. penditure during extreme sustained exercise: the Tour de France. Int J Sports
147. Westerterp-Plantenga MS, Lemmens SG, Westerterp KR. Dietary protein—its Med. 1989;10(suppl 1):S26–S31.
role in satiety, energetics, weight loss and health. Br J Nutr. 2012;108(suppl 177. Jeukendrup A. A step towards personalized sports nutrition: carbohydrate intake
2):S105–S112. during exercise. Sport Med. 2014;44(suppl 1):25–33.
148. Weigle DS, Breen PA, Matthys CC, et al. A high-protein diet induces sustained 178. Burke LM. Nutrition strategies for the marathon: fuel for training and racing.
reductions in appetite, ad libitum caloric intake, and body weight despite Sports Med. 2007;37:344–347.

R
179. Stellingwerff T, Maughan RJ, Burke LM. Nutrition for power sports: middle- reduction in the rated perceived exertion/effort during exercise (ID 1488, 1490)
distance running, track cycling, rowing, canoeing/kayaking, and swimming. J pursuant to article 13(1) of regulation (EC) no 1924/2006. EFSA J. 2011;9:2053.
Sports Sci. 2011;29(supp1):S79–S89. doi:10.2903/j.efsa.2011.2053.
180. Volek JS, Noakes T, Phinney SD. Rethinking fat as a fuel for endurance exercise. 182. Bescos R, Sureda A, Tur JA, et al. The effect of nitric-oxide-related supplements
Eur J Sport Sci. 2015;15:13–20. on human performance. Sport Med. 2012;42:99–117.
181. European Food Safety Authority. Scientific opinion on the substantiation of 183. American College of Sports Medicine, Sawka MN, Burke LM, et al. American
health claims related to caffeine and increase in physical performance during College of Sports Medicine position stand. Exercise and fluid replacement. Med
short-term high-intensity exercise (ID 737, 1486, 1489), increase in endurance Sci Sports Exerc. 2007;39:377–390.
performance (ID 737, 1486), increase in endurance capacity (ID 1488) and

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Feature Article

Systems biology of personalized nutrition

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INTRODUCTION etc), various medical associations have established dietary

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Lipid distribution Insulin production

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Figure 7 Simplified decision tree of personalized nutrition in Acknowledgments

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