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Findings from PREDICT:
The Personalized Responses
to Dietary Composition Trial
1
Speakers
Tim Spector, Ph.D
Professor of Genetic Epidemiology
King’s College London, UK
Sarah Berry, Ph.D
Senior Lecturer, Department
of Nutritional Sciences
Nicola Segata, Ph.D
Associate Professor,
Computational Metagenomics
Jose Ordovas, Ph.D
Director and Senior Scientist,
Nutrition and Genomics Lab
2
The PREDICT Programme
Tim Spector, Ph.D
Professor of Genetic Epidemiology
King’s College London, UK
3
Largest ongoing program to measure
postprandial responses to food in nutritional science
Nutrition
academia
Tech
companies
4Tim Spector King’s College London, UK
Jun 2018 - May 2019 Jan 2019 - May 2019
n=1,100
PREDICT - Carbs
n=100
Healthy
60% TwinsUK
Healthy Compliant
individuals from
PREDICT 1
Postprandial
responses
Meal order
Time of day
Clinic & Home
(UK/US)
Home (UK)
STATUS:
Complete
STATUS:
Complete
Validation of remote
study delivery
Postprandial responses
Microbiome profiling
Jun 2019 – Mar 2020
n=1,000
Healthy
Ethnicity
Home (US)
STATUS:
Complete
PREDICT - Cardio
Sep 2019 - Ongoing
n=50
High/Low CVD
risk subset of
PREDICT 1 Plus
Cardiometabolic
end-points
Liver fat
Vascular function
Clinic & Home
(UK)
Continuation of
PREDICT 1
Postprandial
responses
PREDICT 1 Plus
n=900
Jun 2019 - Ongoing
Healthy
TwinsUK
Clinic & Home
(UK)
STATUS:
n=250
Postprandial responses
Dietary assessment
Microbiome profiling
July 2020
n=10,000
Healthy
Ethnicity
Chronic disease
Home (US)
STATUS:
Pending enrolment
P R E D I C T 2
PREDICT
Postprandial
responses
P R E D I C T 3
5Tim Spector King’s College London, UK
P R E D I C T 1
STATUS:
Complete
Nutritional advice in the past and present…evidence is constantly evolving
Guidelines take on ‘one-size fits all’ approach
6Tim Spector King’s College London, UK
Lack of consensus
even amongst
expert nutritional
scientists
Even the world leading experts don’t agree…
7Tim Spector King’s College London, UK
With perfect agreement
1
2
3
1
2
3
4
5
6
7
8
9
10
11
12
13
In reality
13 independent experts
105 food items tested
Why?
We are complicated
and food
is complicated
Whole almonds Ground Almonds
0
50
100
150
200
Kcal/serving
• Thousands chemicals/nutrients in each food;
not just the nutrients listed on a label
• Nutrient-nutrient interactions
• Food matrix
• Processing
Why is food complicated?
Meals/foods containing same ingredients and/or
composition but differing in matrix can have
completely different effects
What does this mean?
That’s because food is complicated…
8Tim Spector King’s College London, UK
How meaningful is the mean?
9Tim Spector King’s College London, UK
Large inter-individual variability
in responses to food
Nutritional studies typically
show the mean response
Manipulation of lipid bioaccessibility of almond seeds influences postprandial
lipemia in healthy human subjects. Berry et al (2007)
The need for personalisation
Nutritional advice is based
on population averages
A difference of 106 kcal per serving
~742 kcal per week
4.6
2.3 kcal - 6.0 kcal range
62 kcal 168 kcal
“Poor”
metabolisers
“Good”
metabolisers
Average serving
28g
Metabolizable Energy from Nuts
kcal
Discrepancy between the Atwater factor predicted and empirically measured
energy values of almonds in human diets. Novotny et al (2012)
But how many of
us are average?
Quality&Precision
Quantity
Digital devices
• Mobile phone apps
• Clinical devices, continuous
glucose monitors, activity monitors
Remote clinical testing
DNA, microbiome, blood tests
Citizen science
Today we can look beyond the mean
10
Traditional
Randomized
Controlled Trials
Big Data
Opportunities
Tim Spector King’s College London, UK
Duplicate
Diet Records
Epidemiological
Studies
Food
Frequency
Questionnaires
Nutrition
academia
Tech
companies
Quality
and quantity
11
Largest ongoing program to measure
postprandial responses to food in nutritional science
11Tim Spector King’s College London, UK
What explains
these differences?
Can we PREDICT
individual responses using
machine learning?
MEAL
CONTEXT
GENETICSMICROBIOME
AGE /
SEX / BMI
MEAL
COMPOSITION
2. 3.
How much variability
between people?
1.
By using genetic, metabolomic, metagenomic and meal-context
information to predict individuals’ response to food
12Tim Spector King’s College London, UK
What makes our work so unique….we are looking at the integrated response and
interrelated multi-directional pathways….
13Tim Spector King’s College London, UK
How we respond to food… using postprandial responses
Single Meal
2
1.5
1.0
0.5
0 100 200 300 400 500
Minutes since breakfast
7
6
5
Traditional measures of disease risk
Typical Day
50g fat, 85g carb. AJCN. 2011. 94, 1433-41. n=50
2.0
1.5
1.0
06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00 02:00 04:00Time
7
6
5
Breakfast Lunch DinnerSnack Snack Snack
PLASMA TRIACYLGLYCEROL PLASMA GLUCOSE INSULIN
PlasmaTriacylglycerol(mmol/l)
PlasmaTriacylglycerol(mmol/l)
PlasmaGlucose(mmol/l)
PlasmaGlucose(mmol/l)
14Tim Spector King’s College London, UK
Time since breakfast
Astley, C. M. et al. Clin Chem 64, 192-200, doi:10.1373/clinchem.2017.280727 (2018). Bansal, S. et al. JAMA 298, 309-316, doi:10.1001/jama.298.3.309 (2007). Lindman, A. S., . et al. . Eur J Epidemiol 25, 789-798, doi:
10.1007/s10654-010-9501-1 (2010). Nordestgaard, B. G., . et al. . JAMA 298, 299-308, doi:10.1001/jama.298.3.299 (2007). Levitan, . et al. . Arch Intern Med 164, 2147-2155, doi:10.1001/archinte.164.19.2147 (2004).
Why do post-prandial peaks matter?
15
PLASMA TRIACYLGLYCEROL
PLASMA GLUCOSE
INSULIN
• Lipoprotein
Re-modelling
• Oxidative Stress
Inflammation
• Endothelial
Dysfunction
• Raised Insulin
Secretion
• Hunger & Appetite
Impact…
• Cardiovascular
Disease
• Metabolic Disease
(Type 2 Diabetes,
Fatty Liver, Insulin
Resistance)
• Weight gain
Increased risk for…
Tim Spector King’s College London, UK
Controlled Time (Mins)
BLOOD
Fasting 30 6015 120 180 240 2700 300 360
BLOOD
BLOOD
BLOOD
BLOOD
BLOOD
BLOOD
BLOOD
BLOOD
BLOOD
Questionnaires
FFQ, Lifestyle &
Medical
Anthropometry
DEXA, waist/hip &
BMI
Blood pressure
and heart rate
Genetics,
Clinical assays &
Metabolomics
Metabolomics,
Saliva & Urine
SALIVA
SALIVA
Metabolic challenge
Other test meals
Aims
Use genetic, metabolomic, metagenomic and meal-context information to predict individuals’ postprandial responses to food.
Validation Cohort
n=100
Main Cohort
n=1,002
Home Phase (Days 2-14)
Dietary
Assessment
Standardised
meals
Blood
Spot tests
Digital
devices
Stool
samples
Study app; weighed records; in-study support
Nutritionally varied test breakfasts and lunches
TAG, C-peptide assays
Continuous glucose, physical activity and sleep monitoring
Microbiome profiling
Clinic
Day 2 3 4 5 6 7 9 10 13 1411 128
Baseline Clinic Visit (Day 1)
16Tim Spector King’s College London, UKJun 2018 – May 2019 IRAS 236407 IRB 2018P002078 NCT03479866
2,022,000
CGM glucose
readings
Mean (SD)
Age (yr) 45.7 (12.0)
BMI (kg/m2) 25.6 (5.0)
Sex (%) 72 F/ 28 M
Triacylglycerol (mmol/L) 1.1 (0.5)
Insulin (IU/mL) 6.1 (4.3)
Glucose (mmol/L) 5.0 (0.5)
Total cholesterol (mmol/L) 5.0 (1.0)
n=1,002
MZ Twins 479
DZ Twins 172
Non-Twins 351
Drop-out 2.5%
The scale of the PREDICT 1 study
32,000
Muffins consumed
28,000
TAG readings
132,000
Meals logged
17Tim Spector King’s College London, UK
Decoding human responses
to food for precision nutrition
18
Sarah Berry, Ph.D
Senior Lecturer, Department of Nutritional
Sciences
King’s College London
Significant variability between healthy individuals
Baseline 6h rise
CV 50% 103%
Triacylglycerol Glucose Insulin
19Sarah Berry King’s College London, UK
Baseline 2h iAUC
CV 10% 68%
Baseline 2h iAUC
CV 69% 59%
TAG(mmol/L)
Glucose(mmol/L)
Insulin(mmol/L)
Clinic day data, n = 1,002
Intra-individual variability is lower than inter-individual variability
(6h rise, n=1018 meals at home and in clinic)
Interindividual CV is calculated for identical meals, between random pairs of individuals.
Intraindividual CV is calculated between pairs of nutritionally identical meals for the same individual
Triacylglycerol Glucose
(iAUC 0-2h, n=7898 meals at home)
20Sarah Berry King’s College London, UK
Differences
between
individuals are
repeatable
Intra-individual Inter-individual
CV 36% 68%
Intra-individual Inter-individual
CV 24% 40%
Identical twins have very different responses
Height Glucose
(iAUC 0-2h)
Triacylglycerol
(6h iAUC)
ACE Heritability Modelling Key:
21Sarah Berry King’s College London, UK
Genetics do not
explain most
nutritional
differences
Genetics Upbringing Environment
48%
5
%
48% 48% 52%46% 50% 4%
TwinMZ2GLU0-2hiAUC
Twin MZ 1 GLU 0-2h iAUC Twin MZ 1 Log scaled 6h TAG iAUCTwin MZ 1 Height
TwinMZ2Height
TwinMZ2Logscaled6hTAGiAUC
What causes the variability in responses?
22Sarah Berry King’s College London, UK
Glucose
iAUC 0-2h
R2 adjusted
Triacylglycerol
6hr rise
R2 adjusted
* P<0.05, ** P<0.01, *** P<0.001
Machine Learning can predict individual responses
Machine learning
model correlates
77%
to measured
glucose responses
23
Machine Learning model
uses test results to predict
responses to new meals
Individual takes test
Sarah Berry King’s College London, UK
Pearson R = 0.77; p = 0
High resolution and high density measures allows deep dive
24Sarah Berry King’s College London, UK
Meal context
Time of day, Meal sequence,
Exercise
Lipoprotein re-modelling
Oxidative stress
Inflammation
Endothelial dysfunction
Raised insulin secretion
Meal composition
Genetics
Microbiome
Age
Blood pressure
Serum measures
Anthropometry
Habitual diet
Sex
Hunger & appetite
0
2000
4000
6000
8000
10000
12000
14000
MealiAUC(mmol/l*2h)
Breakfast Lunch
Time of day influences the postprandial response,
but as we age, this largely disappears
13:00
25Sarah Berry King’s College London, UK
9:00
+4h
Home-based Intervention (Days 2-13)
Study app; weighed diet records; in-study support
Set-up
Day 1 2 3 4 5 6 7 9 10 118
Continuous glucose, physical activity and sleep monitoring
TAG TAG
12 13
Nutritionally varied test meals: breakfast, lunch, snack, sweetener preloads
Daily intervention timeline
Free-livingFasted 3-4h fast 3h fast 2h fast
Breakfast Lunch Snack
Microbiome profiling
Dietary
Assessment
Standardised
meals
Blood
Spot tests
Digital
devices
Stool
samples
1. Effects on glycaemic responses of:
i. carbohydrate staple foods
ii. composite meals
iii. sweetener preloads
iv. time-of-day
v. meal-sequence
2. Collect free-living dietary intake and energy
expenditure data to validate the Zoe app
Aims
Single-staple breakfasts
White bread Rye bread Pasta Mashed potatoes Rice
Composite staple lunches
White bread
& cheese
Rye bread
& cheese
Spaghetti
bolognaise
Cottage pie Chickpeas
& chicken
Staple snacks & sweeteners
Sucralose, Aspartame,
Stevia preloads
Biscuits and juicePotato
crisps
Chocolate
bar
Dietary Intervention
n=100
26Sarah Berry King’s College London, UK 26Jan 2019 – May 2019 IRAS 236407 NCT03479866
27INTERIM UNPUBLISHED DATA
Using carbohydrate-rich test meals at breakfast/lunch
Type of breakfast can impact glycaemic response at lunch eaten 4 hours later
Sarah Berry King’s College London, UK
Lunchtime response affected by breakfast meal
Breakfasts
Time since breakfast (min)
Glucose dip
Divergent responses seen 2-3 hours after a meal
28Sarah Berry King’s College London, UKINTERIM UNPUBLISHED DATA
High resolution and high density measures allows deep dive
29Sarah Berry King’s College London, UK
Lipoprotein re-modelling
Oxidative stress
Inflammation
Endothelial dysfunction
Raised insulin secretion
Hunger & appetite
Meal context
Time of day, Meal sequence,
Exercise
Meal composition
Genetics
Microbiome
Age
Blood pressure
Serum measures
Anthropometry
Habitual diet
Sex
Impact of glucose ‘dips’ on hunger and calorie intake
30
Individuals with smallest 25% of Glucose Drop (Q1),
versus largest 25% of Glucose Drop (Q4)
Sarah Berry King’s College London, UK
Glucose dip UK average meal (mmol/L)
Large inter-individual variability
in ‘dippers’ – even in response
to the same meal
Frequency
+9 (+/-4) -2 (+/-2) -25 mins(+/-10) +79 Kcal(+/-28) +321 Kcal(+/-87)
Hunger+2-3hpost-meal–pre-meal
Alertness+2-3hpost-meal
Minutessincefirstmeal(mins)
Calories(Kcal)
Calories(Kcal)
Q1 Q4 Q1 Q4 Q1 Q4 Q1 Q4 Q1 Q4
Increase in
hunger
Alertness
level
Time until
next meal
Calories
eaten 3-4h
Calories eaten
in full day
n=689, meals=5693
iAUC?
Increase
from fasting?
Duration?
Peak
concentration?
1.8
1.6
1.4
1.2
1.0
0.8
0.6
0 100 200 300 400 500
PlasmaTriacylglycerol(mmol/l)
Minutes since breakfast
Late postprandial rise?
The response curve is complicated – what feature matters most?
31Sarah Berry King’s College London, UK
• Peak Concentration?
• iAUC?
• Increase from fasting?
• Duration?
• Late postprandial rise?
AJCN. 2011. 94, 1433-41
Postprandial Lipoprotein remodelling associated with CVD
Inflammatory marker associated with CVD
Outcomes from the metabolomic analysis include measures
of cardiovascular inflammation and atherogenic lipoprotein remodelling
Lipoprotein subclasses Lipoprotein compositional re-modelling
32Sarah Berry King’s College London, UK
HDL VLDL
CE
TAG
PL
CE
TAG
PL
Cholesteryl ester
Transfer protein
Cholesteryl ester
Transfer protein
Diameter (nm)
Density(g/ml)
Postprandial-induced inflammation
IL-6 and GlycA
Incident CVD; FINRISK (n=7256), SABRE (n=2622), British Woman's Health Study (n=3563); Circulation, 2015.
The 6h increase in TAG from fasting values is most strongly
associated with intermediary cardiometabolic risk factors
33Sarah Berry King’s College London, UK
Atherogenic
lipoproteins and
inflammatory markers
most closely associated
with a prolonged
postprandial response
0.1
0.2
0.3
0.4
0.5
n=1,002
Remnant-C
HDL-C
Gp
XL-VLD-C
XL-VLD-P
XXL-VLD-C
XXL-VLD-P
4h
TAG iAUC
6h
TAG iAUC
4h
TAG
Concentration
4h
TAG
increase
6h
TAG
Concentration
6h
TAG increase
Food-induced inflammation is highly variable, clinically relevant
and determined mainly by postprandial lipaemia
IL-6 GlycA
• Significant, clinically
relevant increase
postprandially
• Correlated with peak in
glucose (r=0.239) and TG
(r=0.832)
• ML shows lipaemia is
stronger determinant,
specifically TG 6h-rise
• Increases
postprandially
• Not correlated with
glycaemica or lipaemia
Time (min)
0
(Breakfast)
240
(Lunch)
360
10
15
20
25
30
Interleukin-6(mmol/l)
10
15
20
25
30
Glycoproteinacetylation(mmol/l)
Time (min)
0
(Breakfast)
240
(Lunch)
360
34Sarah Berry King’s College London, UK
Doubled ASCVD risk for
individuals with >90th
percentile GlycA increase
Neck-to-knee XMR imaging
Liver lipid quantification
PREDICT 1 PlusPREDICT - Cardio
Pulse wave velocity Plaque grading
Carotid intima-media thickness
1. Measure clinical intermediary cardiometabolic
outcomes, in fasted PREDICT 1 Plus participants
2. Determine the link between postprandial glycaemic/
lipaemic responses and cardiometabolic disease
Clinic
Day 1
2 3 4 5 6 7 9 10 118
Aims
35Sarah Berry King’s College London, UK
Sub-cohort of PREDICT 1 Plus
n=50
Sep 2019 – Feb 2020 IRAS 236407 NCT03479866
Summary
36Sarah Berry King’s College London, UK
• Everyone is unique in food response
– even identical twins
• Genetics explains only a fraction of
how we respond to foods
• The composition of the meal
explains
<30% of our responses
• How and when we eat can impact
our response to food
• Dissecting the integrated, inter-
related multidirectional pathways
with large scale, high resolution data
makes precision nutrition achievable
The hidden human microbiome
diversity and personalized host-
microbiome interaction
37
Nicola Segata, Ph.D
Associate Professor, Computational Metagenomics,
CIBIO, University of Trento
@nsegata
Species-level
features
#samples 232 121 110 253 344 96
Cirrhosis Colorectal IBD Obesity T2D WT2D
Pasolli et al., PLoS Comput Biol, 2016
Human Microbiome Project, MetaHIT
Thomas, Manghi et al., Nat Med, 2019
Nine total (and
concordant) datasets
for Colorectal cancer
But what about the microbiome in “health” levels and pre-disease?
What is health and what is disease for the microbiome?
38Nicola Segata University of Trento, Italy
The microbiome in disease The microbiome in health
On the road to link the gut microbiome with food and metabolic health
39Nicola Segata University of Trento, Italy
Truth is, we are all unique
Even identical twins have very different responses to food
40Nicola Segata University of Trento, Italy
Subjects from around the world (~3000 sbj from 4 continents)
Subjects from US (from two universities)
Subjects from EU (6 countries)
Samples from same subjects collected at ~6 months
Subjects from EU
Subjects from US
Truong et al., Genome Research, 2017
Truth is, also our microbiome is unique
0.250
0.275
0.300
0.325
0.350
0.400
0.425
0.375
Commonspecies(%)
Twin pair Unrelated
41Nicola Segata University of Trento, Italy
The PREDICT 1 study at ZOE
42
1,002 samples
Predict 1 (UK Cohort)
100 samples
Predict 1 (US Cohort)
Food Frequency Questionnaire
Clinic data
Serum metabolomics
Continuous Glucose Monitor
Stool metagenomics
The microbiome data
769 species
29 spp. 90%
prevalent
91 spp. 50%
prevalent
174 spp. 20%
prevalent
UniRef90
1,910,069
UniRef50
878,520
KEGG KOs
6,163
Pathways
445
Taxonomic Functional Assembly
48,181 MAGs
29,035 MQ
19,146 HQ
8.8 avg. 2.2 sd. Gb/sample
58.3 avg 14.6 sd. Mreads/sample
Metadata
Age, BMI, weight, waist/hip
ratio, visceral fat, antibiotic
usage, blood pressure
Personal
Tot. 18
Foods, Food groups,
Nutrients, Nutrients % kcal,
Dietary patterns
Habitual diet
Tot. 275
Lipoproteins, ApoLipoproteins,
Risk scores, Glucose
mediated, FA’s metabolism
Fasting
Tot. 247
All fasting measures up to
7 timepoints including max
values and rises
Post prandial
Tot. 484
42Nicola Segata University of Trento, Italy
The workflow
of shotgun
metagenomics
43Nicola Segata University of Trento, ItalyQuince, Walker, Simpson, Loman, and Segata. Nature Biotechnology, 2017
The PREDICT 1 study at ZOE
4444Nicola Segata University of Trento, Italy
How strongly is the microbiome linked with habitual diet?
45Nicola Segata University of Trento, Italy
And the associations re reproducible in the US cohort!
aMed scoreHFD
46Nicola Segata University of Trento, Italy
What are the microbes most associated with foods?
47
Beef,
poultry,
sausages,
pork, ham
Shellfish,
oily fish,
eggs
Red wine
YogurtJam Dark
Chocolate
Tomato
Ketchup
Sauces
Support for health-association for the two clusters: p-value
< 1e-20
Baked
beans
47Nicola Segata University of Trento, Italy
What are the microbes most associated with foods?
48
Healthy plant-based Less healthy plant-based Unhealthy animal-based Healthy animal-based
48Nicola Segata University of Trento, Italy
What are the microbes most associated with habitual diet?
4949Nicola Segata University of Trento, Italy
From microbe-food links to microbe-obesity links
50Nicola Segata University of Trento, Italy
Postprandial Lipoprotein remodelling associated with CVD
Inflammatory marker associated with CVD
Metabolomics for measures of cardiometabolic health
Incident CVD; FINRISK (n=7256), SABRE (n=2622), British Woman's Health Study (n=3563); Circulation, 2015.
Lipoprotein subclasses Lipoprotein compositional re-modelling
HDL VLDL
CE
TAG
PL
CE
TAG
PL
Cholesteryl ester
Transfer protein
Cholesteryl ester
Transfer protein
Diameter (nm)
Density(g/ml)
Postprandial-induced inflammation
IL-6 and GlycA
51Nicola Segata University of Trento, Italy
The gut microbiome and fasting cardio-metabolic markers
52Nicola Segata University of Trento, Italy
53
The gut microbiome and fasting cardio-metabolic markers
53Nicola Segata University of Trento, Italy
Fasting and postprandial level are more predictable than rises
Total lipid concentrationsInflammatory measures Lipoprotein particle sizeLipoprotein concentrations Glycaemic mediatedApoLipoproteins
54Nicola Segata University of Trento, Italy
5555Nicola Segata University of Trento, Italy
An overall signature of the “healthy” microbiome “in health”
56Nicola Segata University of Trento, Italy
• Thousands of
unknown species
• Millions of
unsampled genes
• Missing links with
diseases and conditions
…but a lot of the human microbiome diversity is still unexplored
Mapping reads (%)
Yes
No
0 20 40 60 80 100
Average mapping reads (%)
Skin
Oral Cavity
Stool
Vagina
0 20 40 60 80 100
Westernized
57Nicola Segata University of Trento, Italy
The future of
precision Nutrition
58
Jose Ordovas, Ph.D
Director and Senior Scientist,
Nutrition and Genomics Lab, Tufts University
International Food Information Council Foundation: 2018 Food and Health Survey. 2018.
https://foodinsight.org/wp-content/uploads/2018/05/2018-FHS-Report-FINAL.pdf. 59Jose Ordovas Tufts, USA
Before moving into the future let’s peek the present:
Cardiovascular Health Top Desired Benefit from Food
Weight loss, energy, and brain function also rank as top benefits consumers are interested in getting from food.
24% of African Americans
ranked weight loss as a
top three health benefit,
compared to 41% of
non-Hispanic whites
More older adults (65+)
ranked bone health and
diabetes management in
top 3 benefits from food
Interest in health benefits from food and nutrients
59
Source: https://www.foodnavigator.com/Article/2019/02/06/Food-confusion-prevalent-in-Europe-says-Arla-Foods#
Eighty per cent of consumers
report finding information about
food and nutrition conflicting.
Fifty-nine per cent say that
conflicting information makes them
doubt their choices.
This significant consumer segment
also experiences heightened
stress while shopping
Jose Ordovas Tufts, USA
International Food Information Council Foundation: 2018 Food and Health Survey. 2018.
https://foodinsight.org/wp-content/uploads/2018/05/2018-FHS-Report-FINAL.pdf.
The Concern:
Consumer confusion about food and nutrition is a prevalent issue
60
Jose Ordovas Tufts, USA
International Food Information Council Foundation: 2018 Food and Health Survey. 2018.
https://foodinsight.org/wp-content/uploads/2018/05/2018-FHS-Report-FINAL.pdf.
Conflicting information creates “Confusion”
61
Jose Ordovas Tufts, USA
International Food Information Council Foundation: 2018 Food and Health Survey. 2018.
https://foodinsight.org/wp-content/uploads/2018/05/2018-FHS-Report-FINAL.pdf.
Level of trust vs. Reliance as a source
Health professionals trusted and used by consumers to guide health and food decisions
Relation between trust and reliance
62
With limited access/knowledge to clear, science-based, unbiased nutrition
information, public trust in generalized nutrition guidelines is compromised.
Jose Ordovas Tufts, USA
International Food Information Council Foundation: 2018 Food and Health Survey. 2018.
https://foodinsight.org/wp-content/uploads/2018/05/2018-FHS-Report-FINAL.pdf.
Familiarity with the MyPlate graphic
59% Have seen
the MyPlate graphic
69% of parents with
children under 18 have
seen the MyPlate graphic
Younger consumers. Those in better health, parents and women are particularly familiar with the icon
More education is needed: Three in ten know a lot/fair amount about MyPlate
63
• In 2017 ~11 million global deaths and 255 million
disability-adjusted life years (DALYs) could be
attributed to dietary risk factors.
• Treating Chronic Diseases within the current
healthcare model accounts for a staggering 90% of
the United States $3.3 trillion healthcare costs.
• Global nutrition recommendations have failed to
reduce the incidence of chronic disease.
Jose Ordovas Tufts, USA
Why is precision nutrition needed?
64
1995 2000 2005 2010
2003
2015
2011
Dietary guidelines for Americans
USDA
A “Proof of Principle” study of Personalised
Nutrition across Europe:
The Food4Me intervention study
This project has received funding from the European Union’s Seventh Framework Programme
for research, technological development and demonstration. (Contract n°265494) Jose Ordovas Tufts, USA
Does precision nutrition work?
65
Is personalised nutrition advice more
effective than general healthy eating
guidelines?
Is phenotypic or genotypic information
more effective than diet-based advice alone?
Is the internet a successful
delivery method?
Research questions
Jose Ordovas Tufts, USA 66
Level 0: Generic dietary advice (Control)
Level 1: Personalization based on DIETARY analysis
Level 2: Personalization based on DIETARY + PHENOTYPIC analysis
Level 3: Personalization based on DIETARY + PHENOTYPIC + GENOMIC analysis
Randomized to 4 Arms
Jose Ordovas Tufts, USA 67
Celis-Morales C et al. (2017) Int. J. Epidemiol. 46, 578-588 Jose Ordovas Tufts, USA
Personalized nutrition improved dietary behaviour (All participants)
RedMeatIntake
(g.day-1)
HealthyEating
index
Control
(LO)
Personalized
nutrition
(Mean L1, L2, L3)
L1 L2 L3
68
Celis-Morales C et al. (2017) Int. J. Epidemiol. 46, 578-588 Jose Ordovas Tufts, USA
PN improved dietary behaviour (participants receiving targeted advice)
SaturatedFatIntake
(%fromtotalenergy)
FolateIntake
(μg.day-1)
Control
(LO)
Personalized
nutrition
(Mean L1, L2, L3)
L1 L2 L3
69
Challenge - Nutrition research:
Data management, study design and translation.
Meeting the challenge:
Precision Nutrition research and data (PREDICT)
Large Datasets
Nutrition trials
Integrated responses
Dynamic responses
Jose Ordovas Tufts, USA
Meeting the Challenges of Nutrition with Precision Nutrition
70
Summary
Tim Spector, Ph.D
Professor of Genetic Epidemiology
King’s College London, UK
71
Traditional targets for
personalisation
Integrating multiple factors for
comprehensive personalisation
Past, present, and future of precision nutrition
The past (1950s – present) The present (2020)
Meal composition
Genetics
Meal context
Serum glycemic markers
Microbiome
Age
Serum lipid markers
Blood pressure
Anthropometry
Other serum markers
FFQ
Sex
New Studies
• PREDICT 2
• PREDICT 3
New Technologies
• Non-invasive Real time Biosensors
• POC Lab-on-a-chip
• Artificial Intelligence 2.0
New Knowledge for Professionals and
Individuals
• Empowering the Health Professional
• Empowering the Individual
• Precision Public Health
• Insurance Coverage
The future
72Tim Spector King’s College London, UK
73Tim Spector King’s College London, UK
PREDICT - Carbs
PREDICT - Cardio
PREDICT 1 Plus
P R E D I C T 2
PREDICT
P R E D I C T 3
PREDICT1
J F M A M J J A S O N D J F M A M J J AJ J A S O N D
2018 2019 2020
Completed Ongoing Pending enrolment
The PREDICT program
PREDICT Ongoing
King’s College London
Tim Spector
Sarah Berry
Deborah Hart
ZOE
Richard Davies
Jonathan Wolf
George Hadjigeorgiou
University of Trento, Italy
Nicola Segata (PI)
Francesco Asnicar
Massachusetts General Hospital
& Harvard University
Linda Delahanty
Oxford University
Leanne Hodson
Mark McCarthy
Massachusetts General Hospital
Andrew T. Chan
David Drew
Lund University, Sweden
Paul Franks
Acknowledgements
Harvard University
Curtis Huttenhower
University of Leeds
John Blundell
University of Nottingham
Ana Valdes
Tufts University
Jose Ordovas

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Key findings from the PREDICT personalized nutrition study

  • 1. Findings from PREDICT: The Personalized Responses to Dietary Composition Trial 1
  • 2. Speakers Tim Spector, Ph.D Professor of Genetic Epidemiology King’s College London, UK Sarah Berry, Ph.D Senior Lecturer, Department of Nutritional Sciences Nicola Segata, Ph.D Associate Professor, Computational Metagenomics Jose Ordovas, Ph.D Director and Senior Scientist, Nutrition and Genomics Lab 2
  • 3. The PREDICT Programme Tim Spector, Ph.D Professor of Genetic Epidemiology King’s College London, UK 3
  • 4. Largest ongoing program to measure postprandial responses to food in nutritional science Nutrition academia Tech companies 4Tim Spector King’s College London, UK
  • 5. Jun 2018 - May 2019 Jan 2019 - May 2019 n=1,100 PREDICT - Carbs n=100 Healthy 60% TwinsUK Healthy Compliant individuals from PREDICT 1 Postprandial responses Meal order Time of day Clinic & Home (UK/US) Home (UK) STATUS: Complete STATUS: Complete Validation of remote study delivery Postprandial responses Microbiome profiling Jun 2019 – Mar 2020 n=1,000 Healthy Ethnicity Home (US) STATUS: Complete PREDICT - Cardio Sep 2019 - Ongoing n=50 High/Low CVD risk subset of PREDICT 1 Plus Cardiometabolic end-points Liver fat Vascular function Clinic & Home (UK) Continuation of PREDICT 1 Postprandial responses PREDICT 1 Plus n=900 Jun 2019 - Ongoing Healthy TwinsUK Clinic & Home (UK) STATUS: n=250 Postprandial responses Dietary assessment Microbiome profiling July 2020 n=10,000 Healthy Ethnicity Chronic disease Home (US) STATUS: Pending enrolment P R E D I C T 2 PREDICT Postprandial responses P R E D I C T 3 5Tim Spector King’s College London, UK P R E D I C T 1 STATUS: Complete
  • 6. Nutritional advice in the past and present…evidence is constantly evolving Guidelines take on ‘one-size fits all’ approach 6Tim Spector King’s College London, UK Lack of consensus even amongst expert nutritional scientists
  • 7. Even the world leading experts don’t agree… 7Tim Spector King’s College London, UK With perfect agreement 1 2 3 1 2 3 4 5 6 7 8 9 10 11 12 13 In reality 13 independent experts 105 food items tested Why? We are complicated and food is complicated
  • 8. Whole almonds Ground Almonds 0 50 100 150 200 Kcal/serving • Thousands chemicals/nutrients in each food; not just the nutrients listed on a label • Nutrient-nutrient interactions • Food matrix • Processing Why is food complicated? Meals/foods containing same ingredients and/or composition but differing in matrix can have completely different effects What does this mean? That’s because food is complicated… 8Tim Spector King’s College London, UK
  • 9. How meaningful is the mean? 9Tim Spector King’s College London, UK Large inter-individual variability in responses to food Nutritional studies typically show the mean response Manipulation of lipid bioaccessibility of almond seeds influences postprandial lipemia in healthy human subjects. Berry et al (2007) The need for personalisation Nutritional advice is based on population averages A difference of 106 kcal per serving ~742 kcal per week 4.6 2.3 kcal - 6.0 kcal range 62 kcal 168 kcal “Poor” metabolisers “Good” metabolisers Average serving 28g Metabolizable Energy from Nuts kcal Discrepancy between the Atwater factor predicted and empirically measured energy values of almonds in human diets. Novotny et al (2012) But how many of us are average?
  • 10. Quality&Precision Quantity Digital devices • Mobile phone apps • Clinical devices, continuous glucose monitors, activity monitors Remote clinical testing DNA, microbiome, blood tests Citizen science Today we can look beyond the mean 10 Traditional Randomized Controlled Trials Big Data Opportunities Tim Spector King’s College London, UK Duplicate Diet Records Epidemiological Studies Food Frequency Questionnaires
  • 11. Nutrition academia Tech companies Quality and quantity 11 Largest ongoing program to measure postprandial responses to food in nutritional science 11Tim Spector King’s College London, UK
  • 12. What explains these differences? Can we PREDICT individual responses using machine learning? MEAL CONTEXT GENETICSMICROBIOME AGE / SEX / BMI MEAL COMPOSITION 2. 3. How much variability between people? 1. By using genetic, metabolomic, metagenomic and meal-context information to predict individuals’ response to food 12Tim Spector King’s College London, UK
  • 13. What makes our work so unique….we are looking at the integrated response and interrelated multi-directional pathways…. 13Tim Spector King’s College London, UK
  • 14. How we respond to food… using postprandial responses Single Meal 2 1.5 1.0 0.5 0 100 200 300 400 500 Minutes since breakfast 7 6 5 Traditional measures of disease risk Typical Day 50g fat, 85g carb. AJCN. 2011. 94, 1433-41. n=50 2.0 1.5 1.0 06:00 08:00 10:00 12:00 14:00 16:00 18:00 20:00 22:00 00:00 02:00 04:00Time 7 6 5 Breakfast Lunch DinnerSnack Snack Snack PLASMA TRIACYLGLYCEROL PLASMA GLUCOSE INSULIN PlasmaTriacylglycerol(mmol/l) PlasmaTriacylglycerol(mmol/l) PlasmaGlucose(mmol/l) PlasmaGlucose(mmol/l) 14Tim Spector King’s College London, UK
  • 15. Time since breakfast Astley, C. M. et al. Clin Chem 64, 192-200, doi:10.1373/clinchem.2017.280727 (2018). Bansal, S. et al. JAMA 298, 309-316, doi:10.1001/jama.298.3.309 (2007). Lindman, A. S., . et al. . Eur J Epidemiol 25, 789-798, doi: 10.1007/s10654-010-9501-1 (2010). Nordestgaard, B. G., . et al. . JAMA 298, 299-308, doi:10.1001/jama.298.3.299 (2007). Levitan, . et al. . Arch Intern Med 164, 2147-2155, doi:10.1001/archinte.164.19.2147 (2004). Why do post-prandial peaks matter? 15 PLASMA TRIACYLGLYCEROL PLASMA GLUCOSE INSULIN • Lipoprotein Re-modelling • Oxidative Stress Inflammation • Endothelial Dysfunction • Raised Insulin Secretion • Hunger & Appetite Impact… • Cardiovascular Disease • Metabolic Disease (Type 2 Diabetes, Fatty Liver, Insulin Resistance) • Weight gain Increased risk for… Tim Spector King’s College London, UK
  • 16. Controlled Time (Mins) BLOOD Fasting 30 6015 120 180 240 2700 300 360 BLOOD BLOOD BLOOD BLOOD BLOOD BLOOD BLOOD BLOOD BLOOD Questionnaires FFQ, Lifestyle & Medical Anthropometry DEXA, waist/hip & BMI Blood pressure and heart rate Genetics, Clinical assays & Metabolomics Metabolomics, Saliva & Urine SALIVA SALIVA Metabolic challenge Other test meals Aims Use genetic, metabolomic, metagenomic and meal-context information to predict individuals’ postprandial responses to food. Validation Cohort n=100 Main Cohort n=1,002 Home Phase (Days 2-14) Dietary Assessment Standardised meals Blood Spot tests Digital devices Stool samples Study app; weighed records; in-study support Nutritionally varied test breakfasts and lunches TAG, C-peptide assays Continuous glucose, physical activity and sleep monitoring Microbiome profiling Clinic Day 2 3 4 5 6 7 9 10 13 1411 128 Baseline Clinic Visit (Day 1) 16Tim Spector King’s College London, UKJun 2018 – May 2019 IRAS 236407 IRB 2018P002078 NCT03479866
  • 17. 2,022,000 CGM glucose readings Mean (SD) Age (yr) 45.7 (12.0) BMI (kg/m2) 25.6 (5.0) Sex (%) 72 F/ 28 M Triacylglycerol (mmol/L) 1.1 (0.5) Insulin (IU/mL) 6.1 (4.3) Glucose (mmol/L) 5.0 (0.5) Total cholesterol (mmol/L) 5.0 (1.0) n=1,002 MZ Twins 479 DZ Twins 172 Non-Twins 351 Drop-out 2.5% The scale of the PREDICT 1 study 32,000 Muffins consumed 28,000 TAG readings 132,000 Meals logged 17Tim Spector King’s College London, UK
  • 18. Decoding human responses to food for precision nutrition 18 Sarah Berry, Ph.D Senior Lecturer, Department of Nutritional Sciences King’s College London
  • 19. Significant variability between healthy individuals Baseline 6h rise CV 50% 103% Triacylglycerol Glucose Insulin 19Sarah Berry King’s College London, UK Baseline 2h iAUC CV 10% 68% Baseline 2h iAUC CV 69% 59% TAG(mmol/L) Glucose(mmol/L) Insulin(mmol/L) Clinic day data, n = 1,002
  • 20. Intra-individual variability is lower than inter-individual variability (6h rise, n=1018 meals at home and in clinic) Interindividual CV is calculated for identical meals, between random pairs of individuals. Intraindividual CV is calculated between pairs of nutritionally identical meals for the same individual Triacylglycerol Glucose (iAUC 0-2h, n=7898 meals at home) 20Sarah Berry King’s College London, UK Differences between individuals are repeatable Intra-individual Inter-individual CV 36% 68% Intra-individual Inter-individual CV 24% 40%
  • 21. Identical twins have very different responses Height Glucose (iAUC 0-2h) Triacylglycerol (6h iAUC) ACE Heritability Modelling Key: 21Sarah Berry King’s College London, UK Genetics do not explain most nutritional differences Genetics Upbringing Environment 48% 5 % 48% 48% 52%46% 50% 4% TwinMZ2GLU0-2hiAUC Twin MZ 1 GLU 0-2h iAUC Twin MZ 1 Log scaled 6h TAG iAUCTwin MZ 1 Height TwinMZ2Height TwinMZ2Logscaled6hTAGiAUC
  • 22. What causes the variability in responses? 22Sarah Berry King’s College London, UK Glucose iAUC 0-2h R2 adjusted Triacylglycerol 6hr rise R2 adjusted * P<0.05, ** P<0.01, *** P<0.001
  • 23. Machine Learning can predict individual responses Machine learning model correlates 77% to measured glucose responses 23 Machine Learning model uses test results to predict responses to new meals Individual takes test Sarah Berry King’s College London, UK Pearson R = 0.77; p = 0
  • 24. High resolution and high density measures allows deep dive 24Sarah Berry King’s College London, UK Meal context Time of day, Meal sequence, Exercise Lipoprotein re-modelling Oxidative stress Inflammation Endothelial dysfunction Raised insulin secretion Meal composition Genetics Microbiome Age Blood pressure Serum measures Anthropometry Habitual diet Sex Hunger & appetite
  • 25. 0 2000 4000 6000 8000 10000 12000 14000 MealiAUC(mmol/l*2h) Breakfast Lunch Time of day influences the postprandial response, but as we age, this largely disappears 13:00 25Sarah Berry King’s College London, UK 9:00 +4h
  • 26. Home-based Intervention (Days 2-13) Study app; weighed diet records; in-study support Set-up Day 1 2 3 4 5 6 7 9 10 118 Continuous glucose, physical activity and sleep monitoring TAG TAG 12 13 Nutritionally varied test meals: breakfast, lunch, snack, sweetener preloads Daily intervention timeline Free-livingFasted 3-4h fast 3h fast 2h fast Breakfast Lunch Snack Microbiome profiling Dietary Assessment Standardised meals Blood Spot tests Digital devices Stool samples 1. Effects on glycaemic responses of: i. carbohydrate staple foods ii. composite meals iii. sweetener preloads iv. time-of-day v. meal-sequence 2. Collect free-living dietary intake and energy expenditure data to validate the Zoe app Aims Single-staple breakfasts White bread Rye bread Pasta Mashed potatoes Rice Composite staple lunches White bread & cheese Rye bread & cheese Spaghetti bolognaise Cottage pie Chickpeas & chicken Staple snacks & sweeteners Sucralose, Aspartame, Stevia preloads Biscuits and juicePotato crisps Chocolate bar Dietary Intervention n=100 26Sarah Berry King’s College London, UK 26Jan 2019 – May 2019 IRAS 236407 NCT03479866
  • 27. 27INTERIM UNPUBLISHED DATA Using carbohydrate-rich test meals at breakfast/lunch Type of breakfast can impact glycaemic response at lunch eaten 4 hours later Sarah Berry King’s College London, UK Lunchtime response affected by breakfast meal
  • 28. Breakfasts Time since breakfast (min) Glucose dip Divergent responses seen 2-3 hours after a meal 28Sarah Berry King’s College London, UKINTERIM UNPUBLISHED DATA
  • 29. High resolution and high density measures allows deep dive 29Sarah Berry King’s College London, UK Lipoprotein re-modelling Oxidative stress Inflammation Endothelial dysfunction Raised insulin secretion Hunger & appetite Meal context Time of day, Meal sequence, Exercise Meal composition Genetics Microbiome Age Blood pressure Serum measures Anthropometry Habitual diet Sex
  • 30. Impact of glucose ‘dips’ on hunger and calorie intake 30 Individuals with smallest 25% of Glucose Drop (Q1), versus largest 25% of Glucose Drop (Q4) Sarah Berry King’s College London, UK Glucose dip UK average meal (mmol/L) Large inter-individual variability in ‘dippers’ – even in response to the same meal Frequency +9 (+/-4) -2 (+/-2) -25 mins(+/-10) +79 Kcal(+/-28) +321 Kcal(+/-87) Hunger+2-3hpost-meal–pre-meal Alertness+2-3hpost-meal Minutessincefirstmeal(mins) Calories(Kcal) Calories(Kcal) Q1 Q4 Q1 Q4 Q1 Q4 Q1 Q4 Q1 Q4 Increase in hunger Alertness level Time until next meal Calories eaten 3-4h Calories eaten in full day n=689, meals=5693
  • 31. iAUC? Increase from fasting? Duration? Peak concentration? 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0 100 200 300 400 500 PlasmaTriacylglycerol(mmol/l) Minutes since breakfast Late postprandial rise? The response curve is complicated – what feature matters most? 31Sarah Berry King’s College London, UK • Peak Concentration? • iAUC? • Increase from fasting? • Duration? • Late postprandial rise? AJCN. 2011. 94, 1433-41
  • 32. Postprandial Lipoprotein remodelling associated with CVD Inflammatory marker associated with CVD Outcomes from the metabolomic analysis include measures of cardiovascular inflammation and atherogenic lipoprotein remodelling Lipoprotein subclasses Lipoprotein compositional re-modelling 32Sarah Berry King’s College London, UK HDL VLDL CE TAG PL CE TAG PL Cholesteryl ester Transfer protein Cholesteryl ester Transfer protein Diameter (nm) Density(g/ml) Postprandial-induced inflammation IL-6 and GlycA Incident CVD; FINRISK (n=7256), SABRE (n=2622), British Woman's Health Study (n=3563); Circulation, 2015.
  • 33. The 6h increase in TAG from fasting values is most strongly associated with intermediary cardiometabolic risk factors 33Sarah Berry King’s College London, UK Atherogenic lipoproteins and inflammatory markers most closely associated with a prolonged postprandial response 0.1 0.2 0.3 0.4 0.5 n=1,002 Remnant-C HDL-C Gp XL-VLD-C XL-VLD-P XXL-VLD-C XXL-VLD-P 4h TAG iAUC 6h TAG iAUC 4h TAG Concentration 4h TAG increase 6h TAG Concentration 6h TAG increase
  • 34. Food-induced inflammation is highly variable, clinically relevant and determined mainly by postprandial lipaemia IL-6 GlycA • Significant, clinically relevant increase postprandially • Correlated with peak in glucose (r=0.239) and TG (r=0.832) • ML shows lipaemia is stronger determinant, specifically TG 6h-rise • Increases postprandially • Not correlated with glycaemica or lipaemia Time (min) 0 (Breakfast) 240 (Lunch) 360 10 15 20 25 30 Interleukin-6(mmol/l) 10 15 20 25 30 Glycoproteinacetylation(mmol/l) Time (min) 0 (Breakfast) 240 (Lunch) 360 34Sarah Berry King’s College London, UK Doubled ASCVD risk for individuals with >90th percentile GlycA increase
  • 35. Neck-to-knee XMR imaging Liver lipid quantification PREDICT 1 PlusPREDICT - Cardio Pulse wave velocity Plaque grading Carotid intima-media thickness 1. Measure clinical intermediary cardiometabolic outcomes, in fasted PREDICT 1 Plus participants 2. Determine the link between postprandial glycaemic/ lipaemic responses and cardiometabolic disease Clinic Day 1 2 3 4 5 6 7 9 10 118 Aims 35Sarah Berry King’s College London, UK Sub-cohort of PREDICT 1 Plus n=50 Sep 2019 – Feb 2020 IRAS 236407 NCT03479866
  • 36. Summary 36Sarah Berry King’s College London, UK • Everyone is unique in food response – even identical twins • Genetics explains only a fraction of how we respond to foods • The composition of the meal explains <30% of our responses • How and when we eat can impact our response to food • Dissecting the integrated, inter- related multidirectional pathways with large scale, high resolution data makes precision nutrition achievable
  • 37. The hidden human microbiome diversity and personalized host- microbiome interaction 37 Nicola Segata, Ph.D Associate Professor, Computational Metagenomics, CIBIO, University of Trento @nsegata
  • 38. Species-level features #samples 232 121 110 253 344 96 Cirrhosis Colorectal IBD Obesity T2D WT2D Pasolli et al., PLoS Comput Biol, 2016 Human Microbiome Project, MetaHIT Thomas, Manghi et al., Nat Med, 2019 Nine total (and concordant) datasets for Colorectal cancer But what about the microbiome in “health” levels and pre-disease? What is health and what is disease for the microbiome? 38Nicola Segata University of Trento, Italy The microbiome in disease The microbiome in health
  • 39. On the road to link the gut microbiome with food and metabolic health 39Nicola Segata University of Trento, Italy
  • 40. Truth is, we are all unique Even identical twins have very different responses to food 40Nicola Segata University of Trento, Italy
  • 41. Subjects from around the world (~3000 sbj from 4 continents) Subjects from US (from two universities) Subjects from EU (6 countries) Samples from same subjects collected at ~6 months Subjects from EU Subjects from US Truong et al., Genome Research, 2017 Truth is, also our microbiome is unique 0.250 0.275 0.300 0.325 0.350 0.400 0.425 0.375 Commonspecies(%) Twin pair Unrelated 41Nicola Segata University of Trento, Italy
  • 42. The PREDICT 1 study at ZOE 42 1,002 samples Predict 1 (UK Cohort) 100 samples Predict 1 (US Cohort) Food Frequency Questionnaire Clinic data Serum metabolomics Continuous Glucose Monitor Stool metagenomics The microbiome data 769 species 29 spp. 90% prevalent 91 spp. 50% prevalent 174 spp. 20% prevalent UniRef90 1,910,069 UniRef50 878,520 KEGG KOs 6,163 Pathways 445 Taxonomic Functional Assembly 48,181 MAGs 29,035 MQ 19,146 HQ 8.8 avg. 2.2 sd. Gb/sample 58.3 avg 14.6 sd. Mreads/sample Metadata Age, BMI, weight, waist/hip ratio, visceral fat, antibiotic usage, blood pressure Personal Tot. 18 Foods, Food groups, Nutrients, Nutrients % kcal, Dietary patterns Habitual diet Tot. 275 Lipoproteins, ApoLipoproteins, Risk scores, Glucose mediated, FA’s metabolism Fasting Tot. 247 All fasting measures up to 7 timepoints including max values and rises Post prandial Tot. 484 42Nicola Segata University of Trento, Italy
  • 43. The workflow of shotgun metagenomics 43Nicola Segata University of Trento, ItalyQuince, Walker, Simpson, Loman, and Segata. Nature Biotechnology, 2017
  • 44. The PREDICT 1 study at ZOE 4444Nicola Segata University of Trento, Italy
  • 45. How strongly is the microbiome linked with habitual diet? 45Nicola Segata University of Trento, Italy
  • 46. And the associations re reproducible in the US cohort! aMed scoreHFD 46Nicola Segata University of Trento, Italy
  • 47. What are the microbes most associated with foods? 47 Beef, poultry, sausages, pork, ham Shellfish, oily fish, eggs Red wine YogurtJam Dark Chocolate Tomato Ketchup Sauces Support for health-association for the two clusters: p-value < 1e-20 Baked beans 47Nicola Segata University of Trento, Italy
  • 48. What are the microbes most associated with foods? 48 Healthy plant-based Less healthy plant-based Unhealthy animal-based Healthy animal-based 48Nicola Segata University of Trento, Italy
  • 49. What are the microbes most associated with habitual diet? 4949Nicola Segata University of Trento, Italy
  • 50. From microbe-food links to microbe-obesity links 50Nicola Segata University of Trento, Italy
  • 51. Postprandial Lipoprotein remodelling associated with CVD Inflammatory marker associated with CVD Metabolomics for measures of cardiometabolic health Incident CVD; FINRISK (n=7256), SABRE (n=2622), British Woman's Health Study (n=3563); Circulation, 2015. Lipoprotein subclasses Lipoprotein compositional re-modelling HDL VLDL CE TAG PL CE TAG PL Cholesteryl ester Transfer protein Cholesteryl ester Transfer protein Diameter (nm) Density(g/ml) Postprandial-induced inflammation IL-6 and GlycA 51Nicola Segata University of Trento, Italy
  • 52. The gut microbiome and fasting cardio-metabolic markers 52Nicola Segata University of Trento, Italy
  • 53. 53 The gut microbiome and fasting cardio-metabolic markers 53Nicola Segata University of Trento, Italy
  • 54. Fasting and postprandial level are more predictable than rises Total lipid concentrationsInflammatory measures Lipoprotein particle sizeLipoprotein concentrations Glycaemic mediatedApoLipoproteins 54Nicola Segata University of Trento, Italy
  • 55. 5555Nicola Segata University of Trento, Italy
  • 56. An overall signature of the “healthy” microbiome “in health” 56Nicola Segata University of Trento, Italy
  • 57. • Thousands of unknown species • Millions of unsampled genes • Missing links with diseases and conditions …but a lot of the human microbiome diversity is still unexplored Mapping reads (%) Yes No 0 20 40 60 80 100 Average mapping reads (%) Skin Oral Cavity Stool Vagina 0 20 40 60 80 100 Westernized 57Nicola Segata University of Trento, Italy
  • 58. The future of precision Nutrition 58 Jose Ordovas, Ph.D Director and Senior Scientist, Nutrition and Genomics Lab, Tufts University
  • 59. International Food Information Council Foundation: 2018 Food and Health Survey. 2018. https://foodinsight.org/wp-content/uploads/2018/05/2018-FHS-Report-FINAL.pdf. 59Jose Ordovas Tufts, USA Before moving into the future let’s peek the present: Cardiovascular Health Top Desired Benefit from Food Weight loss, energy, and brain function also rank as top benefits consumers are interested in getting from food. 24% of African Americans ranked weight loss as a top three health benefit, compared to 41% of non-Hispanic whites More older adults (65+) ranked bone health and diabetes management in top 3 benefits from food Interest in health benefits from food and nutrients 59
  • 60. Source: https://www.foodnavigator.com/Article/2019/02/06/Food-confusion-prevalent-in-Europe-says-Arla-Foods# Eighty per cent of consumers report finding information about food and nutrition conflicting. Fifty-nine per cent say that conflicting information makes them doubt their choices. This significant consumer segment also experiences heightened stress while shopping Jose Ordovas Tufts, USA International Food Information Council Foundation: 2018 Food and Health Survey. 2018. https://foodinsight.org/wp-content/uploads/2018/05/2018-FHS-Report-FINAL.pdf. The Concern: Consumer confusion about food and nutrition is a prevalent issue 60
  • 61. Jose Ordovas Tufts, USA International Food Information Council Foundation: 2018 Food and Health Survey. 2018. https://foodinsight.org/wp-content/uploads/2018/05/2018-FHS-Report-FINAL.pdf. Conflicting information creates “Confusion” 61
  • 62. Jose Ordovas Tufts, USA International Food Information Council Foundation: 2018 Food and Health Survey. 2018. https://foodinsight.org/wp-content/uploads/2018/05/2018-FHS-Report-FINAL.pdf. Level of trust vs. Reliance as a source Health professionals trusted and used by consumers to guide health and food decisions Relation between trust and reliance 62
  • 63. With limited access/knowledge to clear, science-based, unbiased nutrition information, public trust in generalized nutrition guidelines is compromised. Jose Ordovas Tufts, USA International Food Information Council Foundation: 2018 Food and Health Survey. 2018. https://foodinsight.org/wp-content/uploads/2018/05/2018-FHS-Report-FINAL.pdf. Familiarity with the MyPlate graphic 59% Have seen the MyPlate graphic 69% of parents with children under 18 have seen the MyPlate graphic Younger consumers. Those in better health, parents and women are particularly familiar with the icon More education is needed: Three in ten know a lot/fair amount about MyPlate 63
  • 64. • In 2017 ~11 million global deaths and 255 million disability-adjusted life years (DALYs) could be attributed to dietary risk factors. • Treating Chronic Diseases within the current healthcare model accounts for a staggering 90% of the United States $3.3 trillion healthcare costs. • Global nutrition recommendations have failed to reduce the incidence of chronic disease. Jose Ordovas Tufts, USA Why is precision nutrition needed? 64 1995 2000 2005 2010 2003 2015 2011 Dietary guidelines for Americans USDA
  • 65. A “Proof of Principle” study of Personalised Nutrition across Europe: The Food4Me intervention study This project has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration. (Contract n°265494) Jose Ordovas Tufts, USA Does precision nutrition work? 65
  • 66. Is personalised nutrition advice more effective than general healthy eating guidelines? Is phenotypic or genotypic information more effective than diet-based advice alone? Is the internet a successful delivery method? Research questions Jose Ordovas Tufts, USA 66
  • 67. Level 0: Generic dietary advice (Control) Level 1: Personalization based on DIETARY analysis Level 2: Personalization based on DIETARY + PHENOTYPIC analysis Level 3: Personalization based on DIETARY + PHENOTYPIC + GENOMIC analysis Randomized to 4 Arms Jose Ordovas Tufts, USA 67
  • 68. Celis-Morales C et al. (2017) Int. J. Epidemiol. 46, 578-588 Jose Ordovas Tufts, USA Personalized nutrition improved dietary behaviour (All participants) RedMeatIntake (g.day-1) HealthyEating index Control (LO) Personalized nutrition (Mean L1, L2, L3) L1 L2 L3 68
  • 69. Celis-Morales C et al. (2017) Int. J. Epidemiol. 46, 578-588 Jose Ordovas Tufts, USA PN improved dietary behaviour (participants receiving targeted advice) SaturatedFatIntake (%fromtotalenergy) FolateIntake (μg.day-1) Control (LO) Personalized nutrition (Mean L1, L2, L3) L1 L2 L3 69
  • 70. Challenge - Nutrition research: Data management, study design and translation. Meeting the challenge: Precision Nutrition research and data (PREDICT) Large Datasets Nutrition trials Integrated responses Dynamic responses Jose Ordovas Tufts, USA Meeting the Challenges of Nutrition with Precision Nutrition 70
  • 71. Summary Tim Spector, Ph.D Professor of Genetic Epidemiology King’s College London, UK 71
  • 72. Traditional targets for personalisation Integrating multiple factors for comprehensive personalisation Past, present, and future of precision nutrition The past (1950s – present) The present (2020) Meal composition Genetics Meal context Serum glycemic markers Microbiome Age Serum lipid markers Blood pressure Anthropometry Other serum markers FFQ Sex New Studies • PREDICT 2 • PREDICT 3 New Technologies • Non-invasive Real time Biosensors • POC Lab-on-a-chip • Artificial Intelligence 2.0 New Knowledge for Professionals and Individuals • Empowering the Health Professional • Empowering the Individual • Precision Public Health • Insurance Coverage The future 72Tim Spector King’s College London, UK
  • 73. 73Tim Spector King’s College London, UK PREDICT - Carbs PREDICT - Cardio PREDICT 1 Plus P R E D I C T 2 PREDICT P R E D I C T 3 PREDICT1 J F M A M J J A S O N D J F M A M J J AJ J A S O N D 2018 2019 2020 Completed Ongoing Pending enrolment The PREDICT program PREDICT Ongoing
  • 74. King’s College London Tim Spector Sarah Berry Deborah Hart ZOE Richard Davies Jonathan Wolf George Hadjigeorgiou University of Trento, Italy Nicola Segata (PI) Francesco Asnicar Massachusetts General Hospital & Harvard University Linda Delahanty Oxford University Leanne Hodson Mark McCarthy Massachusetts General Hospital Andrew T. Chan David Drew Lund University, Sweden Paul Franks Acknowledgements Harvard University Curtis Huttenhower University of Leeds John Blundell University of Nottingham Ana Valdes Tufts University Jose Ordovas

Notas del editor

  1. We gave experts from a bunch of institutions a list of foods to score for frequency of consumption for a healthy person. Roughly translates to red = unhealthy, limit intake, green = healthy, eat without limits. If all were 100% in agreement, each column would have a single solid colour and there would be a smooth transition from red to green [top bar]. That is not the case. [bottom bar appears] The speckling shows the disagreement between experts about each food – the more speckled a column is, the more disagreement. Two things become clear from this map: there is a lot of disagreement about most foods, and stronger agreement about the extremes.
  2. Precision nutrition
  3. PREDICT 1 design. Updated from master doc. Please use as you want
  4. Middle plot axis changed to glucose Colour bars updated
  5. PREDICT 1
  6. Differences in shapes of curves despite similar peaks
  7. Added benefit of using PP responses over fasting; By comparing 2 multivariate linear models, 1 which has only fasting and medication, age, sex, height weight, fasting inculisn, TG and glucose The 2nd which all of the above, plus postprandial response on the y axis. Each cell is the difference in pearsons correlation between two models for each lipoprotein
  8. PREDICT 1
  9. There are extensive studies of microbiome investigating the diversity and variability of the human microbiome in healthy conditions to establish a baseline for disease And there are many investigations trying to link the human microbiome with specific disease, with a large body or literature on IBD and diabetes, just to mention a couple For colorectal cancer, for example, there are now 9 distinct metagenomics cohort and a meta-analysis we performed on them showed reproducible signature of disease across populations for this disease What is still almost completely missing, instead, is an understanding of how the microbiome is linked with cardiometabolic indicators of different health levels and and pre-disease states
  10. The link between the gut microbiome and nutrition has been already investigated But with a very few exception the results are almost anecdotal We know from longitudinal sampling of small cohorts that the microbiome is sensible to changes in dietary patters Also, diet-related metabolic health markers are partially recapitulated by the gut microbiome according to a few large-scale studies, but overall the characterization of circulating fasting and postprandial metabolites with respect to the gut microbiome are still missing
  11. We thus present here our contribution in this direction. But to set the stage of the let me revamp a slide already presented by Sarah (or Tim). She convinced you that even genetically identical individuals have different response to food, suggesting that despite common genetic background our body is unique
  12. When looking at our microbiome, not even its (microbial) genetics is comparable across individual Twins share around 37% of their intestinal bacterial species and unrelated individual just a slightly reduced 35% suggesting that genetics and common environment have only a small effect on the overall microbiome composition But things are even more surprising at the level of strains, which are the specific genetic variant of a bug within a species. Strains from the same species can be phenotypically very different, think for example at commensal vs pathogenic E. coli, Here I show the genetic distance between strains in the same species from different individual. This means that if we pick a species which is common between two of the persons in the audience, when we look at the genomes of this species in the two individual we will usually find more than 5% genetic diversity and no more than 75% of genes in common. Seen from the other side, it is very rare that two unrelated individuals share two very similar strains. And this is not a methodological flaw, as the example in which we compared the microbiome of the same person 6 months apart should convince you. As you can see, I have more than 70-80% of strains that were there in my microbiome 6 months ago or so So, while different individuals share over 99.9% of their genome, they share no more than 0.1% of their microbiome, meaning that our gut microbiome is completely unique although is pretty genetically stable in time Any attempt at linking nutrition or metabolic health with the gut microbiome thus need to take this uniqueness into account and consider very large sample sizes
  13. This is what we attempted to do in the already introduced Predict 1 study Introduce the number, microbiome data, and the four kind of metadata
  14. - Description of shogun metagenomics, this can go from 30 seconds to 5 minutes as needed
  15. One initial message: - Microbiome richness is connected with some metadata. Age and BMI as already shown and as expected. But visceral fat is stronger than BMI, and several cholesterol indicators are also reasonable and consistent. [FIGURE TO BE UPDATED WITH THE LATEST VERSION, AND MAYB CUT INTO TWO SPECIES TO MAKE BETTER USE OF THE SPACE?]
  16. Then we investigated the links in our large cohort between the gut microbiome and long-term dieat as assessed by the FFQs. Introduce the machine learning approach Introduce some aspects of single foods and food groups Discuss nutrients and especially dietary patterns [NON-NORMALIZED NUTRIENTS TO BE REMOVED, PLOTS TO BE UPDATED TO THE LATEST VERSIONS] I can make the point here of Coffee with Lawsonibacter
  17. - Show some validated correlations eg. HFD and aMed [BUT NEED TO BE UPDATED WITH THE LATEST RESULTS]
  18. Introduce the attempt ad correlating microbiome species with foods Give the example of the very reasonable and expected link between B. animalis and yogurt Highlight the clustering in two distinct classes strongly associated with health plants and unhealthy plants/animals Highlight that the few incongruences are actually very reasonable, and that red wine is in the “good” class
  19. This slide reiterates the main point of the previous slide, I can mke a specific point that Firmicutes CAG 95 is significantly associated with half of the healthy plants and of the healthy animals. C. unnocuum basically vicevers.
  20. CAN SIMPLIFY THIS AND SHOW ONLY DIETARY PATTERNS. - On the dietary patterns I can highlight HFD which is the strongest
  21. Here I can briefly make the point that obesity is also associated with specific gut microbes: Can point at some species already mentioned for diet Can say that the signatures are reproducible in external datasets THIS SLIDE CAN BE REMOVED IF NEEDED