We are what we eat – insights from nutrigenomics research to understand how diet is shaping our health

Michael Müller Professor of Nutrigenomics & Systems Nutrition

Director of the NRP Food & Health Alliance

Norwich Medical School

@nutrigenomics

Outline of my talk

One cannot change the genome but how to use it.

The most potent genome challenges: exercise,

fasting/CR, microbiome challenges & “healthy”

nutrition.

“Beneficial” commensal bacteria may behave less

“beneficial” under the wrong circumstances.

How to use this information for precision

treatments or personalized nutrition.

“You are what you eat, have eaten & host”

100

50

0

% Energy

Low-fat meat Chicken

Eggs

Fish

Fruits

Vegetables (carrots) Nuts

Honey

100

50

0

% Energy

Fruits

Vegetables

Beans

Meat

Chicken

Fish

Grain

Milk/-products

Isolated Carbs

Isolated Fat/Oil Alcohol

1.200.000 Generations between feast en famine

Paleolithic era

3-4 Generations in energy abundance

Modern Times

Our “paleolithic” ‘hunter-gatherer’ genes + modern diets

Real Foods with ‘challenges’ “Safe, processed” foods = Less challenges

No pain, no gain The molecular basis of adaptation

Transcriptional regulatory networks

in positive and negative energy balance – why

nutrition matters

Biological systems multi-omics

Nature Reviews Genetics | AOP, published online 13 January 2015

Phenome

• Metabolic

Syndrome

CVD

NAFLD

• Inflammatory

Diseases

• Prostate

Cancer

The most powerful trigger next to exercise is ‘eating less’

Weight Gain Survival

Age (weeks)

Su

rviv

al (

%)

52 65 78 91 104

50

75

100

C

CR

MFINT

*

***

Age (month)

Bo

dy w

eig

ht (g

)

15

25

35

45

55

65 CCRMFINT

6 12 24 28

From local problems to systemic diseases – the contribution of the gut (microbiome)

Feed your gut

1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10 1 2 3 4 5 6 7 8 9 10

AHR activation11622_at Ahr

Detoxification

13076_at Cyp1a1

14858_at Gsta2

14859_at Gsta3

14862_at Gstm1

18104_at Nqo1

Inflammation (ILCs and IELs)

19885_at Rorc (ILC)

12501_at Cd3e (IEL)

12502_at Cd3g (IEL)

12525_at Cd8a (IEL)

20302_at Ccl3 (IEL)

20304_at Ccl5 (IEL)

432729_at Tcrg-C (IEL)

17067_at Ly6c1 (IEL, type a)

16636_at Klra5 (IEL, type b)

12504_at Cd4 (T helper)

12475_at Cd14 (Monocytes)

12478_at Cd19 (B cells)

HF-Chow HF-LF Chow-LF

Different diets are leading to different gut phenotypes (small intestine)

Dietary impact on the activation of the AhR essential for the gut immune system

3 Diets =

3 functional states

of the gut

What is a healthy diet? "Eat food, not too much, mostly plants"

Michael Pollan, The Omnivore's Dilemma

Anti-inflammatory effects of plant food components

Tilg H, Moschen AR. Food, immunity, and the microbiome Gastroenterology. 2015 May;148(6):1107-19.

Role of dietary fibres on gut function in mice

SCFA

INULIN,

FOS,

GuarGum,

NAXUS (Arabinoxylan),

Resistant Starch,

Control = Starch

microbiota 10 days

Lange K, Hugenholtz F, Jonathan MC, Schols HA, Kleerebezem M, Smidt H, Müller M, Hooiveld GJ.

Mol Nutr Food Res. 2015, 59,1590–1602.

Integration of epithelial cell gene expression with luminal microbiota composition

Bacterial groups within

Clostridium cluster XIVa

positively correlated

with genes involved in

energy metabolism (1)

Lange K, Hugenholtz F, Jonathan MC, Schols HA, Kleerebezem M, Smidt H, Müller M, Hooiveld GJ.

Mol Nutr Food Res. 2015, 59,1590–1602.

PPARg targets 1

Activation score per dietary fiber

RS FOS AX IN GG

PPARG

2.83 2.01 4.23 3.07

HNF4A

2.58 3.50

TP53

2.36 2.82

ATF4

2.61

2.43

PPARGC1A

2.39 2.08

XBP1

2.93

NR5A2

2.61 SREBF1

2.58

FOXC2

2.43 SREBF2

2.22

PTTG1

2.21 NR1I2

2.09

CEBPB

2.02 KDM5B 2.00

NCOA2

2.00 TP63

-2.15

STAT5B

-2.16

MBD2

-2.23 STAT5A

-2.36

MYC

-2.63

Upstream regulator

Role of Pparg in fibre-dependent gene regulation Fibre-specific effects on PPARy transcriptome

Lange K, Hugenholtz F, Jonathan MC, Schols HA, Kleerebezem M, Smidt H, Müller M, Hooiveld GJ.

Mol Nutr Food Res. 2015, 59,1590–1602.

Role of gut microbiota in heme induced stress

• Consumption of red meat is associated with

increased colorectal cancer risk. We show

that the gut microbiota is pivotal in this

increased risk.

• Mice receiving a diet with heme, a proxy for

red meat, show a damaged gut epithelium

and a compensatory hyperproliferation that

can lead to colon cancer.

• Mice receiving heme together with

antibiotics do not show this damage and

hyperproliferation.

Proposed mechanism of how microbiota facilitates

heme-induced compensatory hyperproliferation

Noortje Ijssennagger et al. PNAS 2015;112:10038-10043

We are what we fed them…?

‘our gastrointestinal tract is not only the body's most under-appreciated organ,

but "the brain's most important adviser”’.

Future Perspective: Stratification and precision treatments

Identification and personalized treatments of patients at risk for developing type 2 diabetes based on their microbiota

http://personalnutrition.org

Summary

One cannot change the genome but the use of genome capacity =>

phenotype plasticity is an essential feature of health.

The most potent genome challenges: exercise, fasting/CR,

microbiome challenges & “healthy” nutrition.

"Eat food, not too much, mostly plants”: many bioactive molecules.

Transcription factors (e.g. PPARg, FXR, AHR or NRF2) are involved

in host sensing mechanisms of microbial metabolites & food

bioactives.

“Beneficial” commensal bacteria may behave less “beneficial” under

the wrong circumstances (e.g. dietary heme or other dietary

stressors).

Embrace challenges from young to old – with diverse foods &

lifestyles that ‘mildly’ challenge the genome.

Precision treatments of people at risk for developing non-

communicable diseases based on genome/phenome data.

>2017 The Norwich Centre for Food and Health