ORIGINAL RESEARCH

published: 22 June 2022

doi: 10.3389/fnut.2022.919882

Personalized Nutrition Intervention

Improves Health Status in
Overweight/Obese Chinese Adults: A
Randomized Controlled Trial
Juntao Kan 1† , Jiayi Ni 2† , Kun Xue 3 , Feijie Wang 1 , Jianheng Zheng 1 , Junrui Cheng 1 ,
Peiying Wu 4 , Matthew K. Runyon 5 , Hongwei Guo 3* and Jun Du 1*
1
Nutrilite Health Institute, Shanghai, China, 2 Research Institute of the McGill University Health Center, Montreal, QC, Canada,
3
School of Public Health, Fudan University, Shanghai, China, 4 Department of Nutrition, Shanghai General Hospital,
Shanghai, China, 5 Nutrilite Health Institute, Ada, MI, United States

Background: Overweight and obesity increase the risk of noncommunicable

Edited by: diseases (NCDs). Personalized nutrition (PN) approaches may provide tailored
Kirsty Pourshahidi, nutritional advice/service by focusing on individual’s unique characteristics to prevent
Ulster University, United Kingdom
against NCDs.
Reviewed by:
Xin Peng, Objective: We aimed to compare the effect of PN intervention with the traditional “one
Zhejiang University, China
size fits all” intervention on health status in overweight/obese Chinese adults.
Yipeng Wang,
Soochow University, China Methods: In this 12-week randomized controlled trial, 400 adults with BMI ≥24 kg/m2
*Correspondence: were randomized to control group (CG, n = 200) and PN group (PNG, n = 200). The CG
Jun Du
Eric.du@amway.com
received conventional health guidance according to the Dietary Guidelines for Chinese
Hongwei Guo Residents and Chinese DRIs Handbook, whereas the PNG experienced PN intervention
hwguo@shmu.edu.cn
that was developed by using decision trees based on the subjects’ anthropometric
† These authors have contributed measurements, blood samples (phenotype), buccal cells (genotype), and dietary and
equally to this work and share first
physical activity (PA) assessments (baseline and updated).
authorship
Results: Compared with the conventional intervention, PN intervention significantly
Specialty section: improved clinical outcomes of anthropometric (e.g., body mass index (BMI), body fat
This article was submitted to
Nutrition and Food Science percentage, waist circumference) and blood biomarkers (e.g., blood lipids, uric acid,
Technology, homocysteine). The improvement in clinical outcomes was achieved through behavior
a section of the journal
change in diet and PA. The subjects in the PNG had higher China dietary guidelines
Frontiers in Nutrition
index values and PA levels. Personalized recommendations of “lose weight,” “increase
Received: 14 April 2022
Accepted: 20 May 2022 fiber” and “take multivitamin/mineral supplements” were the major contributors to the
Published: 22 June 2022 decrease of BMI and improvement of lipid profile.
Citation:
Kan J, Ni J, Xue K, Wang F, Zheng J,
Conclusion: We provided the first evidence that PN intervention was more beneficial
Cheng J, Wu P, Runyon MK, Guo H than conventional nutrition intervention to improve health status in overweight/obese
and Du J (2022) Personalized Nutrition
Chinese adults. This study provides a model of framework for developing personalized
Intervention Improves Health Status in
Overweight/Obese Chinese Adults: A advice in Chinese population.
Randomized Controlled Trial. Chictr.org.cn (ChiCTR1900026226).
Front. Nutr. 9:919882.
doi: 10.3389/fnut.2022.919882 Keywords: personalized nutrition, diet, physical activity, genotype, phenotype, clinical trial

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Kan et al. PN Intervention Improves Health Status

INTRODUCTION diet and PA, anthropometric measurements, blood samples,

buccal cells, and fecal samples were collected at baseline. During
Overweight and obesity increase the risk of non-communicable the intervention, 24-h dietary recall was collected every 2
diseases (NCDs), including diabetes, cardiovascular diseases, weeks, and portable devices were worn every day. At the end
non-alcohol fatty liver disease, and even certain cancers (1, 2). point, the questionnaires, anthropometric measurements, blood,
The rising trends in overweight and obesity have plateaued and fecal samples were collected again from both groups for
in many high-income countries, but have accelerated in most analysis (Figure 2A). The primary outcome was body mass index
Asian countries (1). Effective prevention strategies are required (BMI). The secondary outcomes were other clinical outcomes
to reduce the immense global burden of nutrition-related NCDs, of anthropometrics and blood biomarkers. No changes to trial
especially those primarily related to poor lifestyle choices, outcomes after the trial commenced. Informed consent was
including unhealthy dietary patterns and insufficient physical obtained from all the patients. This trial was approved by the
activity (PA) (3, 4). Most population strategies to reduce the Institutional Review Board (IRB) of the Shanghai Nutrition
burden of NCDs have used conventional ‘one size fits all’ public Society and registered at chictr.org.cn (ChiCTR1900026226).
health recommendations throughout the past decades, but with
limited efficacy (5). Inclusion/Exclusion Criteria
Personalized nutrition (PN) approaches, which provide The inclusion criteria encompassed either of the sexes, age 25 to
nutrition advice, products, and services tailored for an individual 50 years, and overweight/obesity with BMI ≥24 kg/m2 . Subjects
according to his/her unique biological characteristics, may were excluded if they had coronary heart disease, cerebrovascular
provide extra motivations to the individual, and therefore, be disease, liver disease, kidney disease, inflammatory bowel disease,
more efficacious in preventing against NCDs (6). Zeevi et al. or hematologic disease; were pregnant or lactating women; were
created personalized diets using a machine learning algorithm currently taking any drugs or dietary supplements in recent days,
that integrated parameters including dietary habits, PA, and which could interfere with the study product; participated in
gut microbiota, to successfully lower postprandial blood glucose another clinical trial in the past 3 months; or were not willing
and its metabolic consequences (7). Mathers et al. carried to comply with the study procedures.
out the Food4Me randomized controlled trial (RCT) in seven
European countries and showed that decision tree-based PN Intervention
intervention produced larger and more appropriate changes in The subjects in CG received a non-personalized, conventional
dietary behavior compared with the conventional approaches. health guidance on diet, PA, and nutritional supplements
These studies collectively triggered enthusiasm on PN research intake based on Dietary Guidelines for Chinese Residents and
in recent years (5, 8). Chinese DRIs Handbook (Figure 2B). The guidelines embody
PN at the individual level requires not only the comprehensive the recommended proportion of the different food groups
collection of information, including anthropometric data, dietary in the diet, recommendations to drink plenty of water, PA,
intake, PA, blood biomarkers, and genotypes—which is both dietary supplement intake, and dietary recommendations for
costly and demanding—but also models that are capable of specific population groups. A brochure summarizing the health
accurately generating personalized advice for each individual guidance was delivered to each CG subject at baseline. Differed
(9, 10). Food4Me decision trees have been validated in several PN from the conventional nutrition intervention, a personalized
trials (5, 8, 11, 12). In the current study, the principal investigator solution integrating recommendations on diet, PA, and dietary
and registered dietitians certificated by the China Nutrition supplements (Nutrilite, Guangzhou, China) was generated by
Society revised the decision trees and accompanying advice registered dietitians based on decision trees, and was biweekly
messages to keep them in accordance with the Chinese dietary updated according to the dietary recall and PA assessments
habits and technical standards. Using the localized decision trees, during the study (Figure 2C). The interventions to the CG
along with the PN report prepared by the registered dietitians, and PNG were delivered through sending notifications via a
we carried out the first RCT on PN in China (Diet2Me study) to localized messaging and calling application (WeChat) with the
investigate whether PN intervention would show greater benefits same frequency (biweekly) to ensure that both groups underwent
to health status in overweight/obese adults compared with the the same intensity of intervention throughout the study. Neither
conventional intervention. CG nor PNG had actual interactions with dieticians to minimize
bias between the groups. More details on the personalized
METHODS intervention were described in the following sections. The list of
dietary supplements is shown in Supplementary Table 1.
Study Design
This randomized, controlled, multicenter clinical trial was Decision Trees
conducted in Aier Hospital and Songnan Hospital, Shanghai, The decision trees used herein originated from the Food4Me
China. The participants were identified from the hospital study decision trees, which were kindly provided by Prof. John
databases. A total of 400 participants were initially enrolled in C. Mathers (5, 8). Considering the differences in dietary habits
the study at baseline and randomized with a 1:1 ratio into two and technical standards between Western and Eastern countries,
groups: control group (CG) and personalized nutrition group the decision trees and corresponding feedback messages were
(PNG) (Figure 1). For both groups, questionnaires assessing revised by Prof. Hongwei Guo, the principal investigator of

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Kan et al. PN Intervention Improves Health Status

FIGURE 1 | Flowchart of the clinical trial.

the current study, in addition to five other registered dietitians just included the main goals and some follow-up comments on
certificated by the Chinese Nutrition Society. There were 16 the behavior changes regarding to the individual goal.
decision trees in the current study, covering the majority of
macro- and micronutrients. Anthropometric Measurements
Body weight (BW) and body height (BH) were measured using
a standardized digital weight scale (Seca, Hamburg, Germany)
Personalized Nutrition Report and height meter (Seca). BMI is defined as weight in kilograms
The PN report included a summary of the individual’s divided by the square of height in meters (kg/m2 ). Waist
anthropometric, nutrient, blood, and genetic (nutrition-related) circumference (WC) and hip circumference (HC) was measured
profiles, an overall goal established by the registered dietitian, as using a non-stretch tape, and waist-to-hip ratio (WHR) was
well as personalized recommendations on lifestyle modifications. calculated accordingly. Body composition was assessed utilizing
All the PN reports were prepared manually by registered an InBody (Biospace Co., Ltd., Seoul, Korea), in which body
dietitians using the revised decision trees. In brief, the numerical fat percentage (BFP) was recorded. Systolic blood pressure
data collected at baseline (anthropometric characteristics, blood (SBP) and diastolic blood pressure (DBP) were measured by
biomarkers, food intake, PA) were categorized into three levels: an electronic sphygmomanometer (Omron, Kyoto, Japan). All
green (normal), yellow (higher or lower in moderation), and measures were taken twice at least. A third measure was taken
red (severely higher or lower), based on the Chinese standards when substantial discrepancies (difference ≥ 1%) were observed
published by the Chinese Nutrition Society and Chinese Medical in the first two attempts.
Association (13, 14). Then, the categorized parameters were
ranked, and 3–5 targeted goals were identified by registered PA Assessment
dietitians. Specific messages related to each goal were developed Intensity (vigorous, moderate, or walking), frequency, and
according to the decision trees to advise changes in dietary habits duration of PA were recorded using the short version of the
and PA (5, 15). A nutritional supplement was suggested when International Physical Activity Questionnaire (IPAQ) to measure
the calculated intake of a certain nutrient was lower than 80% of the PA level (16). The minutes/week of each PA intensity
the estimated average requirement (EAR). The complete report was calculated. According to the IPAQ scoring protocol, the
was delivered to each subject at baseline. In the follow-up period, metabolic equivalents of task (METs)-min/week were obtained
the subjects received updated report sent by the dietitian every by multiplying the average energy expenditure by min/week for
2 weeks. This updated report was prepared based on the most each PA intensity (8.0 MET for vigorous intensity, 4.0 MET
recently collected 24 h-recall and wearable device recording, and for moderate intensity, and 3.3 MET for walking) (17). Total

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Kan et al. PN Intervention Improves Health Status

FIGURE 2 | Overview of the study design. (A) Questionnaires, anthropometric measurements, blood, and fecal samples were collected at baseline and at end point.
Buccal cells were collected at baseline for genotyping. During the intervention, 24-h recall was collected every 2 weeks, and a portable device was worn every day. (B)
The subjects in the control group (CG) received non-personalized, conventional health guidance on diet, physical activity (PA), and nutritional supplements intake
based on the Dietary Guidelines for Chinese Residents and Chinese DRIs Handbook. A brochure summarizing the health guidance was delivered to each CG subject
at baseline, and follow-up notifications on nutrition education were provided biweekly to these subjects using WeChat. (C) The subjects in the personalized nutrition
group (PNG) received personalized nutrition solution on diet, physical activity (PA), and nutritional supplements intake from the registered dietitians based on the
decision trees. The personalized solution was updated biweekly based on the subjects’ dietary and PA changes.

PA score in MET-min/week was obtained by summing the Blood Biomarkers

results of each intensity of PA. The continuous scores were then Blood samples were collected after over 12-h fasting. The
categorized into three levels (low, moderate, and high) of PA to serum levels of triglycerides (TG), total cholesterol (TC), low-
classify populations. In addition, step count, consumed energy, density lipoprotein (LDL), high-density lipoprotein (HDL),
and sleep condition were recorded by Mi Band (Xiaomi, Beijing, glucose (GLU), uric acid (UA), homocysteine (HCY), aspartate
China), a wearable device, in real time. aminotransferase (AST), and alanine aminotransferase (ALT)
were determined by colorimetry. The levels of vitamin A
Diet Assessment (VA), 25(OH)D3 (VD), docosahexaenoic acid (DHA), and
A semiquantitative food frequency questionnaire (FFQ) eicosapentaenoic acid (EPA) were determined by tandem mass
approved by the Chinese Center for Disease Control and spectrometry. The levels of insulin (INS), vitamin B9 (folic
Prevention was slightly revised in the current study to assess acid, VB9) and vitamin B12 (VB12) were determined by
the dietary intake of the subjects (18). The questionnaire chemiluminescence. The levels of calcium (Ca), magnesium
contained 77 food items grouped into 13 categories: staple (Mg), iron (Fe), zinc (Zn), and copper (Cu) were determined by
food, bean, vegetable, fungi/algae, fruit, dairy, meat, fish, egg, atomic absorption spectrometry.
snack, drink, oil/spices, and smoke/alcohol. For each food item,
the frequency and amount of consumption over the past week Genotyping
were recorded. China dietary guidelines index (CDGI) was Buccal cells were collected with oral swab (DNA Genotek,
calculated accordingly to evaluate the overall diet quality of the Ottawa, ON, Canada). DNA was extracted and analyzed by
subjects. The details on the CDGI calculation were previously WuXi NextCode (Shanghai, China) using an Asian Single
published (19). Nucleotide Polymorphism (SNP) Screening Chip (Illumina, San
The participants also used 24-h dietary recalls to record the Diego, California, USA). The list of nine nutrition-related genes,
name and amount of each food consumed for breakfast, lunch, including BCO1, GC, MTHFR, FTO, APOE, FADS1, TCF7L2,
dinner, and snacks. Food composition analysis was performed CaSR, and TMPRSS6, is shown in Supplementary Table 2. The
using commercially available software (Feihua, Beijing, China). gene variants were selected based on the documented evidence

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Kan et al. PN Intervention Improves Health Status

of gene-diet interactions (20–28). A systematic review of the TABLE 1 | Baseline characteristics of the subjects who completed the study.
rationale for selection of genes will be published separately soon.
CG PNG P-value
N = 152 N = 166
Sample Size Calculation
It was estimated that a total sample size of 286 participants (143 Male (%) 60 (39.5) 71 (42.8) 0.551
per group) would provide 80% power to detect a more than 5% Age (years) 38.1±7.5 38.8±7.5 0.415
change in BMI (29) between the two groups, with a significance 25–34 64 (42.1) 69 (41.6)
level of 0.05. Allowing for a potential dropout rate of 25% during 35–50 88 (57.9) 97 (58.4)
the intervention, we recruited 400 subjects (200 for each group) Education (%) 0.441
at baseline. ≤ 9 years 9 (5.9) 15 (9.0)
9–12 years 15 (9.9) 20 (12.1)
Statistical Analysis >12 years 128 (84.2) 131 (78.9)
Statistical analyses were completed using SAS 9.4 (SAS Institute
Family monthly income (%) 0.572
Inc., Cary, NC, USA). All statistical tests were two-sided and
<20 000 RMB 16 (10.5) 24 (14.5)
performed at the 0.05 significance level. Means and standard
20,000–30,000 RMB 76 (50.0) 79 (47.6)
deviations (SD) were summarized for continuous variables with
≥30 000 RMB 60 (39.5) 63 (38.0)
a normal distribution; medians and quartiles were provided
Weight (kg) 72.7 ± 10.6 73.8 ± 12.0 0.378
for non-normally distributed variables; and frequencies and
Height (cm) 163.1 ± 8.8 164.3 ± 9.1 0.237
percentages were provided for categorical variables. Differences
BMI (kg/m2 ) 27.3 ± 3.4 27.2 ± 2.8 0.834
between the groups at baseline were assessed using analysis of
Body fat percentage (%) 27.2 ± 5.3 27.5 ± 5.1 0.646
variance (ANOVA) for continuous variables, and chi-square test
for nominal categorical variables. Evaluations of the intervention Waist circumference (cm) 92.4 ± 9.9 92.6 ± 9.5 0.863

effect were performed using analysis of covariance (ANCOVA) Waist-to-hip ratio 0.92 ± 0.08 0.92 ± 0.08 0.801

for normally distributed continuous variables, adjusted for Systolic pressure (mm Hg) 125.1 ± 20.4 123.2 ± 17.4 0.368

baseline values. Log transformation was applied to non-normal Diastolic pressure (mm Hg) 84.2 ± 9.7 84.2 ± 11.2 0.995

continuous variables. Wilcoxon–Mann–Whitney test was used Smoking (%) 21 (13.8) 18 (10.8) 0.420
for highly skewed variables. The connections of longitudinal Alcohol (%) 28 (18.4) 26 (15.7) 0.513
correlation network were calculated by Spearman or Point- Data are presented as frequency (%) or mean ± standard deviation (SD).
Biserial and then plotted as a network by Cytoscape 3.8.2 Intergroup differences were evaluated using chi-square test or one-way analysis of
(Cytoscape Consortium, San Diego, CA, USA). variance (ANOVA).
BMI, body mass index; CG, control group; PNG, personalized nutrition group.

RESULTS
Study Design and Baseline Characteristics In addition, PN intervention was more efficient than
A total of 2,718 participants were screened, of whom 400 the conventional intervention in decreasing blood levels
eligible subjects were randomized into two groups: control of TG, TC, LDL, uric acid, and homocysteine (Table 2,
group (CG) and personalized nutrition group (PNG). During Supplementary Table 4).
12-week intervention, 82 subjects withdrew, resulting in a
total dropout rate of 20.5% (Figure 1). The subjects in PNG Effect of PN Intervention on Dietary Intake
received a personalized nutrition solution on diet, PA, and PN intervention significantly improved the overall diet
nutritional supplements intake, which was provided by registered quality of the subjects, as reflected in the CDGI (Table 3).
dietitians using decision trees. The subjects in CG received Compared with the subjects in CG, the subjects receiving
non-personalized, conventional health guidance (Figure 2). The PN intervention consumed more whole grains, vegetables,
baseline characteristics of the subjects, including demographics especially dark green vegetables, fruits, dairy products, and
and anthropometrics, were comparable between the two nuts. Within-intervention comparison showed the improvement
groups (Table 1). of diet quality in both groups, but PNG showed greater
improvement (Supplementary Table 5). Although the energy
Effect of PN Intervention on intake was not signficantly differed, compared with the CG,
Anthropometric Measurements and Blood the PNG had substantially reduced fat consumption and
Biomarkers increased dietary intake of beneficial vitamin and minerals
After 12 weeks of intervention, the subjects in both (Supplementary Table 6). The dietary modification partially
CG and PNG experienced significant improvement in explained why we observed significantly higher circulating
weight, BMI, body fat percentage, waist circumference, EPA, folic acid and calcium levels in the PNG than CG
and waist-to-hip ratio (Supplementary Table 3). The (Table 2). Dietary supplement intake was beneficial in
effects of PN intervention on decreasing BMI, body fat improving blood biomarkers, and Multi-Vitamin and Minerals
percentage, waist circumference, and waist-to-hip ratio were (MVM) was the only supplement that led to significant BMI
significantly more potent than those in CG (Figure 3). decrease (Figure 4).

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Kan et al. PN Intervention Improves Health Status

FIGURE 3 | Changes in anthropometric measurements between CG and PNG. Intergroup differences in changes in anthropometric measurements (A–D) were
evaluated using Wilcoxon–Mann–Whitney test. *P < 0.05, **P < 0.01, ***P < 0.001.

Effect of PN Intervention on PA related to the personalized recommendations of “increase fiber,”

Although both groups expereinced improvement in PA with “lose weight”, and “use MVM supplements,” the increase of
the interventions, the PNG had significantly higher vigorous, moderate MET, and the intake of dietary vitamin B2, B6,
moderate, and total metabolic equivalent of task (MET), as and B12. In addition, TMPRSS6, FTO and MTHFR genotypes
compared to the CG (Table 3, Supplementary Table 7). In mediated the efficacy of nutritional recommendations and
addition, the sitting duration was shortened to a greater extent lifestyle modifications on BMI decrease (Figure 5, sub-network).
in the PNG than the CG, whereas the sleeping duration
change in both groups was similar. The PA was categorized
into three levels (low, moderate, and high); a significantly
DISCUSSION
higher level of PA was observed in PNG after the intervention Health benefits achieved by PN should be measured using
compared with CG (Supplementary Table 8). Subjects with validated clinical outcomes, such as anthropometric parameters
higher PA level after the intervention experienced greater (e.g., BMI, body fat percentage, and waist circumference)
reduction in body weight, BMI, and waist circumference and blood biomarkers (e.g., blood lipids, blood glucose, and
(Supplementary Figure 1). Based on the wearable device, the blood nutrients) (10). Anthropometric measurements and blood
PNG had signficantly more step counts and consumed more biomarkers are suitable for PN assessment and monitoring as
energy than the CG (Supplementary Table 9). they provide real-time information that reflects an individual’s
current metabolic or physiological state (6). More importantly,
Association Between Genotype and PN the information is readily actionable and easily trackable, as
Intervention Effect these parameters change over time in response to diet, PA,
Data collected at the baseline showed significant correlations and other lifestyle factors (6). In this study, we observed
between the risk of MTHFR and blood level of folic acid; the improved clinical outcomes (weight, BMI, body fat percentage,
risk of FTO and the levels of HDL and uric acid; the risk of waist circumference, waist-to-hip ratio, blood TG, TC, LDL,
APOE and the levels of TG, TC and LDL; the risk of FADS1 and uric acid, homocysteine, folic acid, EPA, and calcium) in
the level of HDL; and the risk of TCF7L2 and the level of uric the PNG compared with those in the CG. This was the
acid (Supplementary Table 10). The effects of PN intervention first RCT to show the health benefits of PN intervention in
on the change from baseline in anthropometric characteristics, overweight/obese Chinese adults. In the Food4Me study, there
including body weight, BMI, waist circumference, and body fat was no significant difference in clinical outcomes between PN
percent, as well as on the changes in blood levels of TG, TC, and control groups, though a trend was observed in weight,
HDL, and LDL, appeared to bring more benefits to the subjects BMI, waist circumference, and blood TC (5). The reason might
carrying risk alleles of FTO, APOE, FADS1, and TCF7L2 genes be the lack of inclusion criteria on BMI in the Food4Me study,
than to those with normal alleles, though none of the interactions while in this study we included overweight/obese adults because
between the genotype and intervention group were significant there is evidence that people are more open to health-promoting
(Supplementary Tables 11, 12). information when the individuals recognize themselves as being
highly susceptible to preventable diseases (9, 30).
PN Intervention Improved Clinical Diet is among the most important modifiable lifestyle factors
Outcomes by Changing the Behavior contributing to NCDs risk (9). Diets with high intake of energy-
We analyzed the longitudinal correlation network among the dense and highly refined carbohydrate foods are associated with
advice in the PN report, changes in lifestyle, and changes in obesity and type 2 diabetes (31). Changes in diet, especially a
clinical outcomes. Following the given advice, the subjects in personalized diet, can prevent the onset of disease (9). Zeevi
PNG increased their PA and optimized nutrient intake, which et al. continuously monitored glucose levels in an 800-person
led to the increase of beneficial nutrients in the blood and to cohort, measured responses to 46,898 meals, and found high
the decrease of “bad” blood biomarkers and anthropometrics variability in the response to identical meals, suggesting that
(Figure 5). In the PNG, the decrease of BMI was mostly universal dietary recommendations may have limited utility

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Kan et al. PN Intervention Improves Health Status

TABLE 2 | Blood biomarkers at baseline and at week 12 in both groups.

CG PNG Between-group difference

N = 152 N = 166
LS Mean (95% CI) P-value

TG, mmol/L a Baseline 1.12 (0.82, 1.68) 1.27 (0.93, 1.81) −0.03 (−0.05, −0.001) 0.045
Week 12 0.99 (0.76, 1.36) 1.03 (0.72, 1.41)
TC, mmol/L Baseline 5.21 (0.93) 5.28 (0.93) −0.15 (−0.25, −0.05) 0.004
Week 12 5.07 (0.88) 4.97 (0.89)
HDL, mmol/L Baseline 1.51 (0.28) 1.51 (0.26) 0.04 (−0.003, 0.08) 0.067
Week 12 1.59 (0.31) 1.63 (0.28)
LDL, mmol/L Baseline 2.93 (0.71) 2.94 (0.72) −0.10 (−0.19, −0.02) 0.020
Week 12 2.67 (0.69) 2.58 (0.77)
Glucose, mmol/L a Baseline 4.70 (4.45, 5.20) 4.70 (4.50, 5.30) −0.005 (−0.02, 0.01) 0.455
Week 12 4.50 (4.10, 5.25) 4.60 (4.30, 5.10)
Insulin, µU/mL a Baseline 10.58 (6.24, 15.90) 8.98 (5.93, 12.34) −0.04 (−0.10, 0.01) 0.143
Week 12 9.39 (5.64, 15.33) 7.78 (5.59, 10.79)
Uric acid, mmol/L Baseline 328.07 (80.50) 337.08 (93.59) −10.36 (−19.39, −1.33) 0.025
Week 12 320.65 (74.85) 316.85 (76.49)
ALT, U/L a Baseline 28.75 (17.45, 44.50) 25.65 (15.90, 40.70) −0.04 (−0.08, 0.01) 0.150
Week 12 28.10 (21.15, 57.05) 24.30 (17.00–40.80)
AST, U/L a Baseline 23.60 (18.20, 31.35) 22.30 (17.90, 28.80) −0.01 (−0.05, 0.02) 0.539
Week 12 23.15 (18.90, 34.65) 21.75 (18.80–27.80)
Vitamin A, mg/L Baseline 1.04 (0.29) 1.01 (0.27) −0.01 (−0.05, 0.04) 0.738
Week 12 1.06 (0.25) 1.04 (0.22)
Vitamin B9, ng/mL Baseline 9.49 (5.06) 9.49 (5.05) 2.27 (1.37, 3.16) <0.0001
Week 12 11.71 (4.79) 13.98 (5.86)
Vitamin B12, pg/mL a Baseline 378.95 (284.07, 510.99) 357.84 (238.98, 461.68) 0.02 (−0.01, 0.04) 0.174
Week 12 369.20 (281.27, 506.65) 371.07 (275.55, 485.98)
Homocysteine, mmol/L Baseline 19.87 (7.36) 21.83 (8.42) −1.24 (−1.94, −0.54) 0.0005
Week 12 13.57 (3.93) 12.93 (4.02)
25(OH)D3 , ng/mL Baseline 29.81 (8.94) 28.15 (8.38) −0.23 (−1.08, 0.63) 0.602
Week 12 30.10 (6.35) 28.84 (6.88)
DHA, % Baseline 5.84 (1.15) 5.64 (1.07) −0.10 (−0.28, 0.08) 0.262
Week 12 5.88 (1.01) 5.66 (1.07)
EPA, % a Baseline 0.42 (0.32, 0.55) 0.37 (0.30, 0.49) 0.09 (0.05, 0.14) <0.0001
Week 12 0.49 (0.32, 0.70) 0.52 (0.38, 0.72)
Calcium, mmol/L Baseline 1.65 (0.12) 1.67 (0.10) 0.03 (0.004, 0.05) 0.023
Week 12 1.68 (0.13) 1.71 (0.10)
Magnesium, mmol/L Baseline 1.52 (0.15) 1.52 (0.13) 0.01 (−0.02, 0.03) 0.489
Week 12 1.54 (0.14) 1.54 (0.13)
Iron, mmol/L Baseline 8.62 (0.89) 8.70 (0.82) 0.07 (−0.04, 0.18) 0.205
Week 12 8.66 (0.70) 8.78 (0.71)
Zinc, µmol/L Baseline 98.37 (10.97) 100.80 (10.65) 1.59 (−0.39, 3.57) 0.115
Week 12 99.49 (10.21) 102.24 (10.33)
Copper, µmol/L Baseline 16.71 (1.91) 16.53 (1.89) −0.01 (−0.38, 0.37) 0.978
Week 12 16.87 (1.53) 16.84 (1.86)

Data are presented as mean (standard deviation), or median (1st quartile, 3rd quartile) for non-normal and highly skewed data.
Unless otherwise stated, intergroup difference at week 12 was evaluated using analysis of covariance (ANCOVA) adjusted for baseline values.
a Intergroup difference at week 12 was evaluated using ANCOVA on log10 of the original data, adjusted for baseline values. Difference of least squares (LS) mean and 95% confidence

interval (CI) are presented on a log10 scale.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; HDL, high-density lipoprotein; LDL, low-density lipoprotein;
TC, total cholesterol; TG, triglycerides.

(7). In the PREDICT1 study, a machine-learning model was These leading-edge studies shed new light on the personalized
created to predict both triglyceride and glycemic responses diet intervention. In a previous RCT on PN, changing dietary
to food intake for developing personalized diet strategies (4). intake to better align with the MedDiet—widely recognized as

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Kan et al. PN Intervention Improves Health Status

TABLE 3 | Dietary intake and physical activity at baseline and week 12 in both groups.

CG PNG Between-group difference

N = 152 N = 166
P-value

Diet
Energy, kcal/d Baseline 1491.5 (1168.5, 1947.0) 1481.0 (1158.0, 1959.0) 0.485
Week 12 1481.5 (1137.0, 1905.0) 1411.0 (1079.0, 1767.0)
Whole grain, g/d Baseline 7.1 (0.0, 28.6) 8.6 (0.0, 28.6) <0.0001
Week 12 12.0 (0.0, 46.4) 35.7 (14.3, 57.1)
Vegetables, g/d Baseline 187.1 (111.8, 315.0) 191.4 (100.0, 365.7) <0.0001
Week 12 262.9 (162.1, 380.7) 323.4 (257.1, 402.9)
Dark green vegetables, g/d Baseline 128.6 (71.4, 214.3) 137.9 (64.3, 228.6) <0.0001
Week 12 201.8 (109.3, 296.4) 260.0 (194.3, 337.1)
Fruits, g/d Baseline 127.1 (57.1, 228.6) 107.1 (57.1, 200.0) <0.0001
Week 12 133.9 (56.4, 264.3) 221.4 (146.4, 303.6)
Dairy products, g/d Baseline 114.3 (34.3, 250.0) 142.9 (47.1, 235.7) 0.002
Week 12 128.6 (57.1, 242.9) 200.0 (85.7, 292.9)
Red meat, g/d Baseline 57.1 (28.6, 100.0) 64.3 (32.9, 114.3) 0.614
Week 12 57.1 (29.3, 392.9) 53.2 (32.1, 81.4)
Nuts, g/d Baseline 0 (0, 15.7) 0 (0, 214.3) 0.014
Week 12 0 (0, 13.6) 7.1 (0, 20.0)
Salt, g/d Baseline 8.0 (6.0, 10.0) 7.0 (5.0, 12.0) 0.484
Week 12 6.0 (5.0, 10.0) 6.0 (4.3, 8.0)
CDGI Baseline 55.7 (11.7) 55.7 (11.4) <0.0001
Week 12 58.6 (12.2) 67.0 (10.9)
Physical activity
Vigorous MET, min/w Baseline 0 (0, 480) 0 (0, 960) 0.0009
Week 12 0 (0, 0) 0 (0, 960)
Moderate MET, min/w Baseline 320 (0, 960) 360 (0, 1080) <0.0001
Week 12 240 (0, 840) 720 (240, 1680)
Walking MET, min/w Baseline 1386 (693, 2079) 1386 (693, 1485) 0.372
Week 12 1040 (693, 1601) 1386 (693, 1733)
Total MET, min/w Baseline 2418 (1386, 3359) 2127 (1215, 3564) <0.0001
Week 12 1695 (962, 3066) 2757 (1392, 4558)
Sitting duration, h/d Baseline 5 (0, 13) 5 (0, 13) 0.042
Week 12 5.75 (0, 12.5) 5 (0.08, 12)
Sleeping duration, h/d Baseline 7 (3, 12) 7 (3, 10) 0.389
Week 12 7 (1, 10) 7 (1, 10)

Data are presented as median (1st quartile, 3rd quartile) or mean (standard deviation).
Intergroup differences at week 12 were evaluated using Wilcoxon–Mann–Whitney test or ANCOVA adjusted for baseline values.
CDGI, China dietary guidelines index; MET, metabolic equivalents of task.

a healthy eating pattern—produced substantial health benefits modulating serum TG, TC, homocysteine, and folic acid, and
(8). The participants who received PN intervention consumed facilitating the decrease in BMI, body fat percentage and waist
less red meat, salt, and saturated fat, and had higher healthy circumference. This was within expectation since MVM offered a
eating index score (5). In our study, we observed similar dietary wide range of nutrients, which might generate synergistic effects
behavior changes in PNG, including increased consumption of in promoting health outcomes. MVM would be an optimal choice
whole grains, vegetables, especially dark green vegetables, fruits, for the overweight/obese adults who aim to lose weight.
dairy products, and nuts, and an improved CDGI, which again, In addition to diet, PA is another important modifiable
validated that PN intervention is more efficacious than the lifestyle factor included in PN intervention (32). Sedentary
conventional nutrition intervention. One of the novelties of the behavior and physical inactivity are among the leading modifiable
current study is the application of dietary supplements, especially risk factors worldwide for cardiovascular disease and all-cause
among the subjects with high risk of deficiencies. Among all mortality (33). For all-cause mortality, spending > 3–4 h/day in
the supplements, MVM displayed the most potent efficacy by watching television and > 6–8 h/day in any sitting activity have

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Kan et al. PN Intervention Improves Health Status

FIGURE 4 | Spearman correlation with clustered clinical outcomes (anthropometric measurements and blood biomarkers) and supplement usage. Blue color
indicates strong reverse correlation; red color indicates strong positive correlation. *P < 0.05, **P < 0.01, ***P < 0.001. ALT, alanine aminotransferase; AST, aspartate
aminotransferase; BFP, body fat percentage; BMI, body mass index; Ca, calcium; Cu, copper; DBP, diastolic blood pressure; DHA, docosahexaenoic acid; EPA,
eicosapentaenoic acid; Fe, iron; GLU, glucose; HCY, homocysteine; HDL, high density lipoprotein; INS, insulin; LDL, low density lipoprotein; Mg, magnesium; MVM,
multiple vitamin mineral; SBP, systolic blood pressure; TC, total cholesterol; TG, triglycerides; SBP, systolic blood pressure; Suppl, supplement; UA, uric acid; VA,
vitamin A; VB, vitamin B; VC, vitamin C; VD, vitamin D; VE, vitamin E; WC, waist circumference; WHR, waist-to-hip ratio; Zn, zinc.

been suggested as detrimental (34). Although the health benefits anthropometrics. For instance, BMI decrease was associated
of PA and exercise are evident, the research on personalized with the increase of moderate MET, and the intake of dietary
PA intervention is still limited. The Food4Me study showed vitamin B2, B6, and B12. The results suggested that our PN
that PA attenuated the effect of the FTO genotype on obesity intervention improved the clinical outcomes by changing the
traits in European adults (12). It is important to note that, subjects’ behavior. An important element to consider relating to
subjects in the CG and PNG recieved the exercise notifications the efficacy of PN intervention is the sustainability of behavior
at the same frequency, so the differences in MET were not change, or longer-term adherence to personalized diet and
due to the subjects’ awareness. Previous RCTs have shown that lifestyle recommendations (10). That would require a precise
tailored training, or personal training, are superior to untailored and validated algorithm, professional and trustworthy guidance
trainging in promoting PA (35, 36), potentially through changing from registered dietitian, and compassionate and sustainable
the participants’ attitudes in PA. In this case, the subjects communication with a service team.
in the PNG might feel more motivated when they read the According to several publications, the PN intervention
tailored notifications, which led to promoted PA duration and strategies that include genetic information have greater potential
intensity. These findings suggested the important contribution of than the ones based on the phenotype alone for improving health
individualized PA advice to PN intervention. (38–40). Adding a genetic component and disclosure of genetic
PN advice promotes changes in individual dietary and PA information may bring crisis awareness and improve motivation
behaviors, which may result in health or function improvement and compliance (38). In addition, people who carry risk alleles
(10). In the P100 study, specific recommendations based on may develop certain nutrient deficiency even when their intake
personal data were customized by a coach to help participants meets recommended levels (41, 42). Since the efficacy of diet
modify their behaviors, which potentially improved their clinical could be modulated or impaired by the SNPs of certain enzymes
biomarkers (37). The Food4Me study successfully led to health- (43), it is critical to apply dietary supplements among the
related behavioral changes but failed to bring significant population that are genetically at risk of deficiencies. Although
improvement in clinical outcomes (5). In our study, following the PN intervention effects on the changes in anthropometric
PN advice, the subjects improved their PA and nutrient intake, characteristics and blood biomarkers were similar for subjects
which was associated with the increase of beneficial nutrients with risk or non-risk allele of FTO, APOE, FADS1, and TCF7L2
in the blood and the decrease of “bad” blood biomarkers and genes, we still observed that subjects with a risk allele experienced

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Kan et al. PN Intervention Improves Health Status

FIGURE 5 | Longitudinal correlation network of advice, genotype, lifestyles, and clinical outcomes. Connections were calculated by Spearman or Point-Biserial with
Benjamini-Hochberg-corrected P < 0.05 and then plotted as a network by Cytoscape. Nodes are colored according to (1) group of advice, including genetic risk
notification (e.g., FTO), lifestyle guidance (e.g., lose weight), and nutritional supplements (e.g., Suppl MVM), (2) change in lifestyles (diet and PA), and (3) change in
clinical outcomes (anthropometric measurements and blood biomarkers). Node sizes are proportional to betweenness centrality. Edge weights are proportional to the
correlation strength, and colors correspond to the direction of association (positive: red; negative: blue). Sub-network in top right shows an example of how “BMI”
change be associated with the advice, genotype, lifestyles, and clinical outcomes. ALT, alanine aminotransferase; AST, aspartate aminotransferase; BFP, body fat
percentage; BMI, body mass index; Ca, calcium; Cu, copper; DBP, diastolic blood pressure; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; Fe, iron; GLU,
glucose; HCY, homocysteine; HDL, high density lipoprotein; I, iodine; LDL, low density lipoprotein; MET, metabolic equivalent of task; Mg, magnesium; MVM, multiple
vitamin mineral; Na, sodium; SBP, systolic blood pressure; SFA, saturated fatty acid; TC, total cholesterol; TG, triglycerides; UA, uric acid; VA, vitamin A; VB, vitamin B;
VC, vitamin C; VD, vitamin D; VE, vitamin E; WC, waist circumference; WHR, waist-to-hip ratio; Zn, zinc.

greater improvement in certain clinical outcomes. Follow up FTO polymorphisms affected weight loss. As an RNA N6 -
studies are warranted in the future to further explore the methyladenosine (m6 A) demethylase, the group of FTO proteins
association between genotype and PN intervention effect. are described as a regulator of m6 A level of hormones, such
As expected, the decrease of BMI was significantly associated as ghrelin, to modify energy intake and adipogenesis (23, 49).
with the “lose weight” advice, since a series of suggestions were In addition to FTO and MTHFR, TMPRSS6 polymorphism
provided under the “lose weight” node, which included dietary is another key genetic factor in the longitudinal correlation
changes and PA modifications, the most critical modifiable network. This is interesting since no evidence has shown that
lifestyle factors that are related to weight loss (44). The B TMPRSS6 affects energy metabolism. As reported, TMPRSS6
complex vitamins play an important role in maintaining energy genotype influences iron metabolism, and the mutations in
homeostasis. Vitamin B2, for example, is a vital cofactor within TMPRSS6 may lead to iron deficiency (27, 50). Previous studies
the electron transport chain, Krebs cycle, and beta-oxidation (fat have shown that a low iron level may result in exercise
burning) (45), which explained why the increased vitamin B2 intolerance, weakness, and impaired muscle strength (51, 52).
intake is a major contributor of BMI reduction. Vitamin B6 and Iron supplementation in the iron-depleted females significantly
vitamin B12 are involved in one-carbon metabolism, in which improved their progressive fatigue resistance during exercise
MTHFR plays a critical role (46). Although there is a lack of clear (53). Considering that the increase in moderate MET is one of the
evidence of how promoted one-carbon metabolism is related major contributors to BMI decrease, it is possible that the subjects
to weight loss, it is reported that vitamin B intake is positively with TMPRSS6 risk alleles may have experienced more fatigue
associated with fat-free mass in overweight/obese females (47), during exercises, which potentially affected their PA duration and
and according to a meta-analysis with 9,075 participants, higher intensity, and subsequently sabotaged their plan on weight loss.
serum vitamin B12 levels are inversely associated with obesity Admittedly, there are several limitations in this study. PN
(48). Expectedly, as the first identified obesity-related gene, intervention is a holistic and integrated solution, in which

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Kan et al. PN Intervention Improves Health Status

continuous follow-up action and motivation are part of the intervention. PN intervention improved the clinical outcomes
whole PN intervention strategy to help the subjects achieve of anthropometric characteristics and blood biomarkers by
the goal (54). In this study, we cautiously designed the changing the dietary and PA behaviors of subjects. The approach
intervention of CG and PNG to minimize bias between the and the associated outcomes presented here open up the
groups. Nevertheless, we admit that the intensity of intervention possibility for positive health outcomes in a general population
cannot be completely consistent between the groups, which is should a similar program become widely available.
due to the nature of PN intervention (15, 54). Another limitation
is the lack of objective biomarkers for assessing adherence. DATA AVAILABILITY STATEMENT
Unlike non-personalized dietary intervention trials, it is difficult
to identify certain objective biomarker(s) to fully indicate the The original contributions presented in the study are included
adherence in the personalized setting. As alternatives to objective in the article/Supplementary Material, further inquiries can be
biomarkers, CDGI, step count, and pill count were used in directed to the corresponding author/s.
our study to show the compliance of diet, PA, and nutritional
supplements, respectively. Previous studies have shown that
microbiota phenotypes might modulate physiological responses ETHICS STATEMENT
to diet, especially postprandial TG, glucose, and insulin (4,
The studies involving human participants were reviewed and
7). The analysis of “omics” data, such as metagenomics and
approved by the Institutional Review Board (IRB) of the
metabolomics data, may provide a broad perspective on the
Shanghai Nutrition Society. The participants provided their
changes of large sets of biomarkers (4, 55). In the near future,
written informed consent to participate in this study.
we will add more parameters to the PN report by including the
multi-omics data.
Our current study has advanced our knowledge from AUTHOR CONTRIBUTIONS
previously published PN studies. It is important to note that
this is the first RCT in China that showed the health benefits JK, HG, and JD designed the research. JK, KX, and PW conducted
of PN intervention in overweight/obese adults, which provided the research. JN, FW, JC, and JZ analyzed the data. JK and
a model of framework for developing the personalized advice JC wrote the manuscript. JK, JC, MR, JN, FW, and JZ revised
that leads to modification of lifestyle and improvement of the manuscript. JD and HG had primary responsibility for final
clinical outcomes. In previous studies, nutritional supplements content. All authors read and approved the final manuscript.
were usually neglected by investigators, even though taking
supplements is suggested when the residents are limiting dietary ACKNOWLEDGMENTS
intake (56), which leaves a major gap of knowledge in the study
of PN intervention. In contrast, we provided a holistic and We would like to thank Dr. Li Zhang and his colleagues from
integrated solution, containing both diet (supplements were used SPRIM China for their excellent work in coordinating the clinical
as a tool to fill the gap) and PA, to each individual in the PNG. trial. We also appreciate the kind help from Prof. John Mathers
Moreover, we combined two critical elements in the delivery of for providing Food4Me decision trees and Shanghai Nutrition
PN report: the validated decision trees as an algorithm to develop Society for providing support of registered dietitians. We thank
a PN report and the registered dietitians certificated to provide LetPub (www.letpub.com) for its linguistic assistance during the
the solution. Currently, we are coding the decision trees to preparation of this manuscript.
develop a mini application to carry out a real-world study, which
may expand our data sources and facilitate our understanding on SUPPLEMENTARY MATERIAL
the efficacy of PN intervention in everyday environments.
In conclusion, we demonstrated that PN intervention The Supplementary Material for this article can be found
showed greater benefits to health status in overweight/obese online at: https://www.frontiersin.org/articles/10.3389/fnut.2022.
Chinese adults compared with the benefits from conventional 919882/full#supplementary-material

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Frontiers in Nutrition | www.frontiersin.org 13 June 2022 | Volume 9 | Article 919882