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PN-22-002; Total nos of Pages: 3;
PN-22-002
Perspective
OPEN
Precision nutrition: concept, evolution, and future
vision
1 2,∗
Benjamin P. Xu , Hanping Shi
1Department of Epidemiology, Nutritional Epidemiology Concentration, Harvard T. H. Chan School of Public Health, Boston, MA, USA,
2Department of GI Surgery and Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.
∗ Corresponding author. Address: Hanping Shi, Department of GI Surgery and Department of Clinical Nutrition, Beijing Shijitan Hospital, Capital
Medical University, Beijing 100038, China. E-mail address: shihp@ccmu.edu.cn (H. Shi).
The concept of precision nutrition has received significant Asaconcept,precisionnutrition beganfermenting overadecade
attention in recent years.[1–3] However, given the novel nature of ago.Atthattime,researchersstudiedtheeffectsofdifferentdoses
the field, a clear definition and scope of ‘precision nutrition’ has ofvitaminsupplementationondisease.Thefullstoryofprecision
yet to be established. nutrition, however, begins even further back. The United States
has a long history of implementing food fortification to combat
An important distinction to make is between the terms specific diseases due to micronutrient deficiency. Examples range
“personalized nutrition” and “precision nutrition.” While they from iodized salt in 1924, to enriched flour containing thiamin,
werepreviouslyinterchangeable,theformerisnowconsideredan niacin, riboflavin, andironin1940,tomorerecentlytheaddition
outdatedtermbytheNationalResearchCouncil,duetopotential of folic acid to all grain products in 1998.[4] The mandatory folic
misinterpretation of “personalized” as meaning development of acid fortification of grain products marks an important step in
recommendations for specific individuals. Rather, precision combating neural tube defects (devastating yet preventable birth
nutrition aims to provide the most effective nutrition recom- defects) through nutritional supplementation. This has proven to
mendations based on a person’s biology, environment, and be a major public health success story.[5,6] However, like its
lifestyle. predecessors, the folic acid fortification policy is still a “one size
fits all” solution. According to the US National Health and
Precision nutrition thus contrasts with the traditional approach NutritionExaminationSurveys,whiletheaveragefolatelevelhas
to nutrition, which tends to be “one-size-fits-all,” for example, risen significantly, and the national rate of neural tube defect has
through fixed-dose supplementation. indeed decreased, there are clear limitations. Among a nationally
representative sample, the population folate levels following the
We reviewed existing literature and extracted the five big 1998 folic acid fortification program showed a huge level of
questions that precision nutrition seeks to answer. variation,rangingfrominsufficienttopotentiallyexcessivelyhigh
folate levels.[7] A similar degree of variation was also shown in a
1. What should we eat? cohort of US minority mothers.[8] Unfortunately, a uniform
2. What is the health effect of nutrition across our lifespan? fortification strategy can fall short on an individual level. For
3. What are the roles of food and nutrients as medicine? example, there is no ability to distinguish between those with
4. How can we apply nutritional science to prevent and treat sufficient folate (for whom fortification could even be harmful),
disease? and those with more extreme deficiency (for whom standard
5. Howcanweleverageadvancedtechnologies,suchasartificial fortification may be inadequate).
intelligence(AI),omics,bigdata,andwearablestoadvancethe
field? This brings us to the next chapter of folic acid supplementation.
Huge controversy remained regarding the role of folic acid
Precision nutrition is a transdisciplinary field ripe with supplementationinpreventingchronicdiseases.[9]Resultsranged
opportunities for collaboration, application of cutting-edge from inconclusive, to protective, to downright harmful.[10] In
science and technology, discovery, and translation. In both the 2015, the “China Stroke Primary Prevention Trial,” or CSPPT
US and China, even globally, precision nutrition has been brought new insight.[11] The trial’s goal was to compare the
recognizedasakeyfocusforthenexttenyearsofhealthresearch. effectsofenalaprilaloneversusenalaprilwith0.8mgfolicacidon
first stroke risk over five years of follow-up. The results
Editor: n/a definitively showed that, in a low-folate population, 0.8mg folic
Copyright © 2022 Reproductive and Developmental Medicine, Published by acid daily could significantly reduce the risk of first stroke by
Wolters Kluwer Health, Inc. 21%beyond the base benefit of the enalapril anti-hypertensive.
This is an open access article distributed under the terms of the Creative There were two major advantages that gave this study the edge
Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC- overitspredecessors:considerationofunderlyingnutritionstatus
ND), where it is permissible to download and share the work provided it is in the population, and genetic risk profiling on an individual
properly cited. The work cannot be changed in any way or used commercially [12]
without permission from the journal. level. Study participants were stratified by MTHFR C677T
Precision Nutrition (2022) 1(1):e00002 genotype before randomization. The MTHFR gene encodes an
Received: 3 January 2022, Revised: 21 January 2022, Accepted: 22 January importantrate-limitingenzymeinhomocysteinemetabolism,and
2022 position 677 is one of the most-studied single nucleotide
doi: 10.1097/PN9.0000000000000002 polymorphism for the gene. The researchers found that
Xu and Shi 1(1), 1-3, month XX, 2022 1
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individuals with the mutant genotype (TT) had a higher risk of health are dependent on its forms as well as its interactions with
stroke overall and may particularly benefit from folic acid the other elements in one-carbon metabolism.
supplementation. Thus, the study is an excellent example of the
precision nutrition principles we hope to see more of in the Moststudies so far used biomarker of total folate to reflect body
coming years. status and did not distinguish its different forms. Folate and folic
acidareoftenusedinterchangeably,buttheydifferinmanyways.
While the CSPPT was an early foray during the infancy of Folate is the naturally occurring form, while folic acid is a
precision nutrition, it highlights some key elements of precision synthetic form used in supplementation and fortification because
nutrition: of its improved stability and shelf-life over natural folate.
1. Target the right disease: CSPPT targets stroke, which is not However,adownsideoffolicacidisthatitmustfirstbeconverted
only the leading cause of death in China and the world but to the active form 5-methyltetrahydrofolate in the liver or other
may benefit from folic acid supplementation. tissues before it can be utilized by the body. This process can be
2. Identify the right population: CSPPT was conducted in a high- slow and inefficient for some individuals, leading to increased
levels of unmetabolizedfolicacid(UMFA)inthebloodstream.[14]
risk Chinese population with hypertension, who had wide- Agrowing body of research suggests that high levels of UMFA
spread folate insufficiency and associated elevated homocys- mayindeed pose health risks, including increased risk of certain
teine, an important modifiable nutritional factor to address cancers, aberrant DNA methylation, increased risk of cardiovas-
underlying pathology of stroke in low folate population. [15,16]
3. Designtherightinterventiontomitigatepathogenicpathways: cular disease and diabetes, and others. Thus, in supple-
CSPPT combined folate with angiotensin converting enzyme menting folic acid, we must also consider potential downside of
inhibitor to simultaneously lower blood pressure and Hcy, a UMFA. However, UMFA is understudied compared to total
synergistic risk reduction. folate.
4. Integratenutritionalandgeneticbiomarkerstoenhancecausal Furthermore, folate is one of the elements of and interacts with
inference and generate the strongest evidence. otherelementsinonecarbonmetabolism.Forexample,folateisa
5. Translatediscoverytoclinicalandcommunitysettingsbeyond key player within the folate cycle and B12 is a key player within
the original CSPPT, demonstrating the potential to save the methionine cycle (important for DNA synthesis and
millions of people from stroke in real world settings. methylation), and both of which are integral parts of one carbon
metabolism and thus should not be studied independent-
Most importantly, the CSPPT has demonstrated a promising [13,17,18]
ly. AnaddedcomplexityisthatB12alsoexistinmultiple
pipeline for precision nutrition, from discovery to translation, forms and each form functions very different. Methylcobalamin
that can be a useful framework for developing more advanced is biologically active form. Adenosylcobalamin is part of a
precision nutrition initiatives today and tomorrow. completely different pathway that takes place within the
mitochondrion and is involved in energy production via the
Previous studies have largely focused on single or a few nutrients citric acid cycle, as well as myelin synthesis. Cyanocobalaminand
orgenotypes.However,humanbodysystemsareinter-connected hydroxocobalaminaremanufacturedformsofvitaminB12used
and involve complex interactions between many biological in supplementation, which must be converted to the aforemen-
systems and micronutrients and their metabolic processes. With tioned biologically active forms. To date, almost all studies used
the advent of multi-omics, we now have the capacity to the biomarker of total B12, a mixture of different forms of B12.
understand the complex interactions by expanding from one
genotype to genome-wide scale; and from single nutrient to a Ideally, when we consider supplementation, such as of folic acid,
largepanelofnutrients.Ametabolomicsapproachcanprovideus weshouldevaluateitsdifferentformsandtheirimpactonhealth,
withapowerfultooltocomprehensivelyevaluateanindividual’s notjust onasingleendpointlikehomocysteine,butonthewhole
nutritional status cross-sectionally and longitudinally. By body and all the potential metabolic pathways and associated
systematically studying metabolic responses to nutritional nutrients that can be impacted. Through this type of comprehen-
intervention, we unlock the potential to provide nutritional sive analysis, we will be able to better understand the health
intervention more precisely and more efficiently. effects of nutrient supplementation. Suchtypeofstudiesmayalso
help us understand variable individual responses to supplemen-
As an example of the complexity but also the potential of tation and inconsistent findings across studies.
systematic approach for precision nutrition, we need look no
furtherthanone-carbonmetabolism.[13]One-carbonmetabolism Analytically,asthenumberofnutrientsinconsiderationincreases,
is a group of biochemical reactions mediated by the folate new methodologies for analysis will be required to handle the
cofactor along with many other cofactors including B2, B6, and addeddimensionality.Machinelearningalgorithmsprovideaway
B12, and plays an important role in four major biological to simultaneously consider the myriad factors involved in a
processes, including: metabolomics study. For example, Bayesian kernel machine
1. DNA synthesis and repair, regression is a method for modelling many exposure variables,
2. amino acid homeostasis (glycine, serine, and methionine), andexcelswithcomplexexposure-responsefunctions,especiallyin
[19]
3. DNA methylation, and the presence of non-linear or non-additive relations.
4. inhibiting the production of reactive oxygen species. While our discussion has thus far focused mainly on micro-
nutrients, macronutrients are no less important and relevant. On
One-carbonmetabolismiscentral to maintaining the integrity of a broader scale, precision nutrition will also incorporate
human health and resilience and folate is an important methyl recommendations for intake of carbohydrates, lipids, and
donor to one-carbon metabolism. Folate’s effects on our bodily proteins.
2 Xu and Shi 1(1), 1-3, month XX, 2022
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It is important to note some of the current limitations of precision [4] Dietary reference intakes: guiding principles for nutrition labeling
nutrition. These limitations include: the acquisition and storage and fortification. Nutr Rev 2004;62(2):73–79. doi: 10.1111/j.1753-
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combination of epidemiological, clinical, nutritional, and total homocysteine concentrations in the United States: analysis of data
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3. A longitudinal and dynamic process: individuals will be of the Boston Birth Cohort, sample of a US urban low-income
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[20] What are some of the challenges facing precision medicine and the
Conflicts of Interest Precision Medicine Initiative? 2021. Available from: https://medlineplus.
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January 16, 2022]
[21] Precision Nutrition; 2021. Available from: https://www.hsph.harvard.
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