Lecture at Summer School Nutrigenomics in Camerino Italy Sept. 2016.
The (small) intestine has increasingly been recognized to play a key role in the early phase of pro-inflammatory disturbances e.g. by enhanced overflow of dietary components to the distal intestine (ileum, colon) and affecting the gut microbiota & their metabolites (e.g. bile acids, short chain fatty acids). Transcription factors e.g. PPARγ, FXR, AHR or NRF2 are involved in host sensing mechanisms of microbial metabolites. Strong impact of dietary composition on small and large intestinal microbiota and their metabolic functions.
Targeting the (small) intestine and its microbiota with (plant) foods, bioactives, probiotics and drugs will improve gut and liver functions with strong implications for human health during life.
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We are what we eat - The role of diets in the gut-microbiota-health interaction
1. We are what we eat
How the microbiome is shaped by diets
Michael Müller
Professor of Nutrigenomics & Systems Nutrition
Director of the NRP Food & Health Alliance
@nutrigenomics
FAHAFood & Health Alliance
2. What is a healthy diet?
"Eat food, not too much, mostly plants"
Michael Pollan, The Omnivore's Dilemma
4. ‘No pain No gain’
We can’t change our genes but can improve the accessibility
of the genome leading to improved resilience
The molecular basis of adaptation to ‘stress’ challenges
(here for exercise-related training)
5. The mechanisms that explain everything
Camerino 2014 Camerino 2016
Nutrition / Nutrigenomics
7. de Wit NJ, Afman LA, Mensink M, Müller M
Phenotyping the effect of diet on non-alcoholic fatty
liver disease J Hepatol 57:1370-3 (2012)
.
The power of systems nutrition or medicine
Targeting the gut to treat the liver
8. Inflammatory mechanisms of food components
Tilg H, Moschen AR. Food, immunity, and the microbiome Gastroenterology. 2015 May;148(6):1107-19.
9. Mechanisms of signaling from the gut microbiota to the host
Sonnenburg JL, Bäckhed F. Diet-microbiota interactions as moderators
of human metabolism. Nature. 2016 Jul 6;535(7610):56-64.
10. Adaptive response to a switch from high starch to
high sat. fat diet in the mouse small intestine
De Wit et al Plos ONE 2011
11. High sat. fat diets induce obesity & development of NAFLD
=> enhanced overflow of dietary sat. fat to the ileum
and remodelling of gut microbiota
A high-sat. fat-diet reduced microbial diversity and increased the
Firmicutes-to-Bacteroidetes ratio
Am J Physiol Gastrointest Liver Physiol. 2012;303:G589-99
Oils
Palm
Olive
Safflower
Palm
12. Anti-inflammatory effects of plant food components
Tilg H, Moschen AR. Food, immunity, and the microbiome Gastroenterology. 2015 May;148(6):1107-19.
13. Resistant starch leads to changes in the microbiome &
related host responses in the proximal colon of male pigs
• Consumption of resistant starch (RS) has been associated with various intestinal
health benefits, but knowledge of its effects on global gene expression in the
colon is limited.
• Ten 17-wk-old male pigs (Landrace barrows), fitted with a cannula in the
proximal colon for repeated collection of tissue biopsy samples and luminal
content, were fed a digestible starch (DS) diet or a diet high in RS (34%) for 2
consecutive periods of 14 d in a crossover design.
.
Haenen et al. J. Nutr. 143: 274-293 & 1889–1898, 2013
14. Resistant starch in pigs:
Increased bacteroidetes & plasma SCFAs
The abundance of the phyla Bacteroidetes
and Firmicutes in pigs fed DS or RS for 2 wk
Acetate, propionate, and butyrate
concentrations in peripheral plasma
Haenen et al. J. Nutr. 143: 274-293 & 1889–1898, 2013
15. Effects of resistant starch on colonic gene expression
positively enriched gene sets (TCA cycle or lipid metabolism)
negatively enriched gene sets (adaptive or innate immune response)
16. Resistant starch induces catabolic but suppresses immune and
cell division pathways and changes the microbiome in the
proximal colon of male pigs
• The nuclear receptor peroxisome proliferator-activated receptor g was
identified as a potential key upstream regulator.
• Increased relative abundance of several butyrate-producing microbial
groups, including the butyrate producers Faecalibacterium prausnitzii
and Megasphaera elsdenii, and reduced the abundance of potentially
pathogenic members of the genus Leptospira and the phylum
Proteobacteria.
• Concentrations in carotid plasma of the 3 main short-chain fatty acids
acetate, propionate, and butyrate were significantly higher with RS
consumption compared with DS consumption.
.
Haenen et al. J. Nutr. 143: 274-293 & 1889–1898, 2013
17. Role of dietary fibres on gut function in mice
SCFA
INULIN,
FOS,
GuarGum,
NAXUS (Arabinoxylan),
Resistant Starch,
Control = Starch
microbiota
10 days
Mol Nutr Food Res. 2015, 59,1590–1602.
18. 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)
Mol Nutr Food Res. 2015, 59,1590–1602.
21. 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
dietary fibres (MNFR 2015).
• Strongly linked to Clostridium cluster XIVa bacteria (butyrate producers) & likely
governed by the transcription factor PPARg (MCB 2013; & data with organoids from
gut-specific Pparg-k.o. mice).
• Because of different fermentation behaviour fibres will have a diverse location-
specific impact on the microbiome and the host immune-metabolic responses.
• Not ‘one fibre fits all’: Diverse food patterns (rich in plant
foods) are recommended to keep our guts ‘flexible and
healthy’!
22. Interactions between the diet & the gut microbiota
dictate the production of short-chain fatty acids
Sonnenburg JL, Bäckhed F. Diet-microbiota interactions as moderators
of human metabolism. Nature. 2016 Jul 6;535(7610):56-64.
23. Complex fibres => Complex microbiota
We should not deplete our microbial genetic potential….
Nature. 2016;529: 212–215
24. Chow
LFD
HFD
Impact of different diets on the mouse gut
We have to know what mice eat & have to standardize the diets !
20
25
30
35
40
45
BodyWeight(g)
Chow
LF
HF
*
*
*
*Chow
LFHS
HFLS
0 1 2 3 4 5 6 7 8
Weeks
26. Evidence for a beneficial effect of Akkermansia
muciniphila on metabolic functions
• AM is a mucin-degrading Gram-negative bacterium (a genus in the
phylum Verrucomicrobia) constituting 3–5% of the intestinal
microbiota
• Concentrations inversely correlated with obesity and diabetes in many
experimental and human studies
• Prebiotic consumption such as oligofructose is metabolically beneficial
and increases A muciniphila concentrations
• Administration of A muciniphila to mice improves weight loss,
metabolic control and adipose tissue inflammation
• Metformin increases A muciniphila concentrations
• Improves dextrane sulfate colitis
• Controversies: some animal/human studies show conflicting results; in
some experimental situations rather pro-inflammatory…
• Feeding of the dietary stressor heme increases A muciniphilia…
27. Gut microbiota facilitates dietary heme-
induced epithelial hyperproliferation by
opening the mucus barrier in colon
• 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.
Ijssennagger et al. PNAS 2015;112:10038-10043
28. Context is important
How microbiota may facilitate heme-induced
compensatory hyperproliferation in the colon
Noortje Ijssennagger et al. PNAS 2015;112:10038-10043
29. 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”’.
30. Strategies for modulating the gut microbiota
to improve individual human health
Sonnenburg JL, Bäckhed F. Diet-microbiota interactions as moderators
of human metabolism. Nature. 2016 Jul 6;535(7610):56-64.
31. Target the gut to target the liver &
improve metabolic health
32. Challenges
• How to predict the impact of diets on the microbiome
(bioactivity)?
• How to interpret metagenome data (beneficial vs
detrimental)? Diversity & genetic richness? Dysbiosis?
• Causes or consequences of inter-individual variations?
• How much do we know about an agreement of in vivo
& in vitro mechanisms (food bioactives)?
• What is the connection between the epigenetic “clock”
and the microbiome? Direct (e.g. butyrate =>
chromatin activity) or indirect (e.g. immune system?)
• How much does the fecal microbiome tells us about
gut/systemic health? Alternatives (smart pills)?
33. Take home summary
• The (small) intestine has increasingly been recognized to play a key role in the
early phase of pro-inflammatory disturbances e.g. by enhanced overflow of
dietary components to the distal intestine (ileum, colon) and affecting the gut
microbiota & their metabolites (e.g. bile acids, short chain fatty acids).
• Transcription factors e.g. PPARg, FXR, AHR or NRF2 are involved in host sensing
mechanisms of microbial metabolites.
• Strong impact of dietary composition on small and large intestinal microbiota
and their metabolic functions.
• “Beneficial” commensal bacteria (A. muciniphila) may behave less “beneficial”
under the wrong circumstances (e.g. dietary heme or other dietary stressors).
• Targeting the (small) intestine and its microbiota with (plant) foods,
bioactives, probiotics and drugs will improve gut and liver functions with
strong implications for human health during life.
34. Britt Blokker
Naiara Beraza
David Vauzour
Sander Kersten
Lydia Afman
Guido Hooiveld
Wilma Steegenga
Philip de Groot
Mark Boekschoten
Nicole de Wit
Rinke Stienstra
Fenny Rusli
Katja Lange
Danielle Haenen
& many PhDs
Christian Trautwein
Folkert Kuipers
Ben van Ommen
Hannelore Daniel
Bart Staels
Edith Feskens
Leif Sander
Dirk Haller
Eline Slagboom
Daniel Thome
Mihai Nitea
& many more
FAHAFood & Health Alliance