You can not change your genome but can influence how it is used by healthy food patterns and lifestyle. This talk focuses on the gut as a primary gatekeeper between foods, the microbiota and the immuno-metabolic system of the host. The underlying biology is complex but well regulated if the system is not chronically overloaded.

1. You are what you eat - more than a gut feeling
Michael Müller
Professor of Nutrigenomics & Systems Nutrition
Norwich Medical School

2. You are what you eat, have eaten, host & what you fed them
2 Meals/day, work as long as possible & embrace challenges
Walter Breuning (1896 – 2011, aged 114 years, 205 days)
(Breuning was also a lifelong cigar smoker, but quit in 1999 when he was 103 because it became too expensive)

3. “You are what you eat, have eaten & host”
Germany
Chad
UK Ecuador

4. The non-western & western reality:
The challenges of non-communicable diseases

5. Non-communicable diseases are complex
“Too much non-resolving metabolic & pro-inflammatory stress”
Non-communicable diseases are caused by chronic organ overload & dysregulation

6. Chronic organ overload
Simplified endocrinology of “too much”
Too much sat. fat /
carbs
Too much sat. fat
Too much fructose/
sat. fat
Too much glucose/
sat. fat
No exercise & too much
glucose / sat. fat
Too much pro-inflammatory
stress
Metabolic Syndrome
‘Systemic Disease’
Chronic non-resolving
pro-inflammatory
systemic stress
Misbalanced
secretion of
Enterokines
Adipokines
Hepatokines
Insulin & …
Myokines
Cytokines

7. % Energy
100
50
0
Our “paleolithic” genes + modern diets
Paleolithic era
Low-fat meat
Chicken
Eggs
Fish
Fruits
Vegetables (carrots)
Nuts
Honey
% Energy
100
50
0
Grain
Milk/-products
Isolated Carbs
Isolated Fat/Oil
Alcohol
Meat
Chicken
Fish
Fruits
Vegetables
Beans
1.200.000 Generations
between feast en famine
Modern Times
3-4 Generations
in energy abundance
Real foods with ‘challenges’ “Safe, processed” foods = Less challenges

8. “A state of complete physical,
mental and social well-being and
not merely the absence of disease
or infirmity.” WHO 1948
‘‘The states of health or disease are
the expressions of the success or
failure experienced by the organism
in its efforts to respond adaptively to
environmental challenges’’
Rene Dubos, 1965
Optimized ability of an individual
to adapt to immuno-metabolic
challenges (2014)
What is
“Health as the ability to adapt
and to self manage”
BMJ 2011

9. “We are what we eat, have eaten and what we host”
4Rs: Received, Recorded, Remembered & Revealed
© Prof. John Mathers

10. No pain, no gain
The molecular basis of adaptation

11. Metabolic homeostasis is regulated by nutrient sensors
Ronald M. Evans , David J. Mangelsdorf Nuclear Receptors, RXR, and the Big Bang Cell, Volume 157, Issue 1, 2014, 255 - 266

12. Understanding Nutrition: Identifying the mechanisms involved in the
regulation of chromatin activity and gene transcription
Impact on
metabolic capacity
& health of organs
& the epigenetic
memory
Transgenic mice
(e.g. k.o. for NRF2,
HIF1, AHR, PPARs etc)
How can we use our genomes in a more optimal way with healthy nutrition & lifestyles?

13. Nutrient-sensing transcription factors are
linking cellular biology to systems biology
Liver
PPAR
Heart
Intestine
small intestine
0 25 50 75 100
heart
liver
kidney
skeletal muscle
brain
ovary
spleen
colon
esophagus
lung
adipose
thyroid
cervix
testes
prostate
bladder
thymus
trachea
placenta
% % % %
Pnliprp2 , Pnliprp1, Mgll,
Lipe, Lipa, Pla2g6,
Pnpla2, Pnpla8, Daglb,
Ces1, Ces3
TAG (re)-synthesis
Chylomicron assembly
& secretion
Apolipoproteins & related
Fatty acid
transport &
binding
Mitochondrial,
microsomal, peroxisomal
fatty acid oxidation
Ketone body synthesis
Intestinal lipases &
phospholipases
Fat/Cd36, Slc27a2,
Slc27a4, Acsl1, Acsl3,
Acsl5, Fabp2, Fabp1,
Scarb2, Scarb1
Gpat1, Mogat2,
Dgat1, Dgat2,
Gpat3, Agpat3
Mttp, Stx5a, Vti1a,
Bet1, Sar1a
Apob, Apoa1 , Apoa2, Angptl4,
Apoa4, Apoc2, Vldlr, Apoc3,
Apoe, Apol3, Apool
Acaa2, Acad10, Acad8, Acad9,
Acadl, Acadm, Acads, Acadsb,
Acadvl, Acot10, Acot2, Acot9,
Aldh9a1, Cpt1a, Cpt2, Crat, Dci,
Decr1, Hadha, Hadhb, Hibch,
Slc22a5, Slc25a20, Aldh3a2,
Cyp4a10, Abcd3, Acaa1a,
Acaa1b, Acot3, Acot4, Acot5,
Acot8, Acox1, Acox2, Crot,
Decr2, Ech1, Ehhadh,
Hsd17b4, Peci, Pecr,
Ppara
Acat1, Hmgcl, Hmgcs2
P
P
A
R
α

14. Context-dependent gene regulation by the
nutrient-sensing transcription factor PPARa
WY
Fibrate
“Drug”
Liver Intestine
DHA
PUFA
“Food”

15. Higher resolution biology:
We need a google map of metabolic pathways
Here we are

16. A systems nutrition view of health & disease
de Wit NJ, Afman LA, Mensink M, Müller M
Phenotyping the effect of diet on non-alcoholic
fatty liver disease J Hepatol 2012
.

17. A systems view on the
GUT

18. Response to the intestine to different
doses of dietary fat
De Wit et al Plos ONE 2011

19. Study to show metabolic plasticity of the gut
Dose-dependent effects of dietary fat on development of obesity in
relation to intestinal differential gene expression in C57BL/6J mice
De Wit et al Plos ONE 2011

20. Robust & concentration dependent effects in small intestine
Differentially regulated intestinal genes by a high fat diet
C1 C2 C3 C4 C5 C6 C7 C8 C9 C10
De Wit et al Plos ONE 2011

21. Cellular localization and specific lipid metabolism-related
function of fat-dose dependently regulated genes
De Wit et al Plos ONE 2011

22. Do not overload organs
C1 C2 C3 C4 C5 C6 C7 C8 C9 C10
45% FAT
10% FAT
40 cm
4 cm
chronically
De Wit et al Plos ONE 2011

23. Is there a difference between dietary fats in
overloading the intestinal capacity ?
Yes a High Fat Palm Oil-diet reduced microbial diversity and
increased the Firmicutes-to-Bacteroidetes ratio
De Wit et al AmJPhysiol 2012

24. Do not chronically overload your organs
• Saturated fat (but not or to a less extent unsaturated fat) stimulates obesity and
the development of fatty liver disease and affects gut microbiota composition &
diversity by an enhanced overflow of dietary fat to the distal intestine.
• Unsaturated fats are more effectively taken up by the small intestine, likely by
more efficiently activating nutrient sensing systems (PPARs) and thereby
contributing to the prevention of organ overload & the development of early
pathology (e.g. NASH).
Food Colon

25. Chow
LFD
HFD
You are what you eat?
Impact of different diets on the mouse gut
Macronutrient composition
Chow LF HF
Protein % 24 20 20
Fat % 6 10 45
C16:0 1.2 2.8 18.7
C18:0 0 0.4 1.8
C18:1 2.2 3.2 17.4
C18:2 2.6 3.6 7.1
CHO % 64 70 35
Sugar 27 27
Starch 42 7
Fiber 4 1 1
Nitrogen-free extract 60
Ash % 6
Total 100 100 100

26. Dietary impact on the activation of the AhR
essential for the gut immune system
HF-Chow HF-LF Chow-LF
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 activation
11622_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)

27. "Eat food, not too much, mostly plants"

28. The gut microbiome can rapidly respond to altered diet, potentially
facilitating the diversity of human dietary lifestyles
Faecal concentration of SCFAs from
carbohydrate (a) and amino acid (b)
Animal-based diets decreases diversity
Turnbaugh et al Nature 2013
fermentation

29. We are what we fed them…?
How strong is the science yet?
‘our gastrointestinal tract is not only the body's most under-appreciated organ,
but "the brain's most important adviser”’.

30. Health and disease
Changes in gut microbiota composition and metabolism
Nature Reviews Endocrinology 10, 74–76 (2014)

31. Introduction of metagenomic tools into clinical practice
is facing major technical as well as biological obstacles
 long analysis times,
 evolving definitions of
reference microbiota,
 missing standards of
analysis methods,
algorithms, and
databases,
 lack of well-defined
physiological ranges, and
 missing evidence for
cause–effect relationships.
Ingeborg Klymiuk, Christoph Högenauer, Bettina Halwachs, Gerhard G. Thallinger, W. Florian Fricke, Christoph Steininger.
A Physicians' Wish List for the Clinical Application of Intestinal Metagenomics 2014 DOI: 10.1371/journal.pmed.1001627

32. Synthesis of short chain fatty
acids (SCFAs) by commensal
bacteria and regulation of
immunity by SCFAs
Dietary
Fibres

33. Role of dietary fibres in the colon
• Differential regulation of genes involved in metabolic,
energy-generating and oxidative processes & those
involved in adhesion dynamics and signalling by different
dietary fibres
• Strongly linked to certain butyrate producers
• Because of different fermentation behaviour fibres will
have a diverse location-specific impact
• So not ‘one fibre fits all’: Diverse food patterns are
recommended to keep our guts flexible and healthy!

34. Gradients are essential for immuno-metabolic health
Distribution of environmental factors along the length of the intestine

35. Signalling role of SCFA gradients in the gut/colon

36. Gradients regulate organ capacity and plasticity
Nutrients
Bioactives
Metabolism
SCFAs
Microbiota
Immunity

37. Our topics for the future
• Molecular nutrition of plant food components with
a specific focus on immuno-metabolism in the
small intestine (UEA Med PhD)
• Impact of plant food bioactives for the gut-brain
axis (UEA Med RF)
• Implication of SIRT1 function during cholestatic
liver disease and cirrhosis (IFR RF & PhD)
• From Nutrigenomics to Systems Nutrition –
Systems integration of nutritional Omics data &
translation from mice to humans (UEA/TGAG RF)

38. Future plans – more specific
• Impact of gut sensing mechanisms of nutrition-related
gradients for health and disease
• Role of non-coding RNAs in the regulation of immuno-metabolism
in the gut
• Role of liver bile secretion and bile salts for small intestinal
function
• Role of the microbiota (endogenous or food-borne) in the
small intestine
– Impact on bioavailability of food bioactives
– Impact on nutrient deficiencies & liver diseases
• ‘Google Map of the Gut’: Improved resolution of the
regulation of intestinal metabolic pathways

39. Genomics Data
KEGG/GO
pathways
Functional
Epigenetic
regulation
Knowledge Base
Analytical Tools
(R and Bioconductor)
Single
Cell Data
Text Mining
Interaction
Networks
Transcriptomics
Metabolomics
“Multi”Omics
Epigenomics
(incl. miRNA)
Microbiome
Genome
analysis
Transcription
factor analysis
New functional knowledge
New physiological understanding
New testable hypothesis
Statistical
Analysis
Machine
learning
Visualization
Gut-
Microbe-
Dietome
Nutrigenomics:
Big Data for
Nutritional Science

40. FAHA: Food and Immuno-Metabolic Health Alliance
Plant Foods
(JIC/IFR/UEA)
Human Nutrition
(UEA/IFR/NNUH)
Molecular
Nutrition
(UEA/IFR/JIC)
Gut-Food-
Microbe
Interaction
(IFR/UEA)
Food-borne
pathogens in the
gut (IFR/UEA)
Gut Mucosal
Immunity
(IFR/UEA)
Network analysis
& Systems
integration
(TGAG/UEA/IFR)
Stem cells &
organ memory
(IFR/UEA)
The impact of the
gut for systemic
diseases
(UEA/NNUH/IFR)
Human Gut
(Patho)biology
(NNUH/UEA/IFR)

41. Using Nutrigenomics and Systems Nutrition
 To define the mechanistic framework of nutrition (evidence-based
nutrition);
 To stratify cohorts (participants) for intervention studies by using
individual Omics-data (e.g. genotype, epigenome, microbiome,
‘metabotype’);
 To quantify the nutritional needs for optimized fitness at different life
stages (“personalized” health);
 To improve early diagnostics of immuno-metabolic disorders;
 To support the development of “smart healthy food patterns” for
modern mankind (healthy, tasty, sustainable, affordable);
 To enable the transition of nutritional science to nutritional science 2.0.

42. Take home message
A new systems nutrition approach is essential to understand causal
relationships between food patterns and organ and systemic health =>
next-generation nutritional sciences.
"Eat food, not too much, mostly plants”. Diverse food patterns (calories
& composition) will keep our body flexible & healthy: “genetic richness”
is an essential feature of health.
A healthy gut is an essential gatekeeper for a human health.
We need a comprehensive understanding of the host-microbe-food
interactions indispensable for the development of more healthy modern
foods and improved (customized) therapies.

43. Thank you very much!