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We are what we eat - The role of diets in the gut-microbiota-health interaction

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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. 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. 2. What is a healthy diet? "Eat food, not too much, mostly plants" Michael Pollan, The Omnivore's Dilemma
  3. 3. Biological systems multi-omics Nature Reviews Genetics 2015 Phenome • Metabolic Syndrome CVD NAFLD • Inflammatory Diseases • Prostate Cancer
  4. 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. 5. The mechanisms that explain everything Camerino 2014 Camerino 2016 Nutrition / Nutrigenomics
  6. 6. “You are what you eat, have eaten & host”
  7. 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. 8. Inflammatory mechanisms of food components Tilg H, Moschen AR. Food, immunity, and the microbiome Gastroenterology. 2015 May;148(6):1107-19.
  9. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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.
  19. 19. Biological processes regulated by dietary fibers Mol Nutr Food Res. 2015, 59,1590–1602.
  20. 20. 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 Pparg transcriptome Mol Nutr Food Res. 2015, 59,1590–1602.
  21. 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. 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. 23. Complex fibres => Complex microbiota We should not deplete our microbial genetic potential…. Nature. 2016;529: 212–215
  24. 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
  25. 25. Diets have an important impact on small intestinal gene expression 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 Triglyceride/FFA metabolism Transport 12491_at Cd36 26458_at Slc27a2 26569_at Slc27a4 14080_at Fabp1 14079_at Fabp2 Oxidation omega 13117_at Cyp4a10 11522_at Adh1 26876_at Adh4 11668_at Aldh1a1 beta 11363_at Acadl 11370_at Acadvl 14081_at Acsl1 12894_at Cpt1a 12896_at Cpt2 51798_at Ech1 97212_at Hadha 57279_at Slc25a20 TG/Chylomicron synthesis 110446_at Acat1 238055_at Apob 11813_at Apoc2 13350_at Dgat1 67800_at Dgat2 17777_at Mttp FA synthesis 104112_at Acly 14104_at Fasn 20249_at Scd1 20250_at Scd2 Transcription regulation 19013_at Ppara 19015_at Ppard 19016_at Pparg 19017_at Ppargc1a Cholesterol/oxysterol metabolism Transport 11303_at Abca1 27409_at Abcg5 67470_at Abcg8 237636_at Npc1l1 Cholesterol synthesis 74754_at Dhcr24 15357_at Hmgcr Transcription regulation 22260_at Nr1h2/Lxrb 22259_at Nr1h3/Lxra 20787_at Srebf1 20788_at Srebf2 Bile acid metabolism Transport 16204_at Fabp6 106407_at Osta 330962_at Ostb 20494_at Slc10a2 Transcription regulation 23957_at Nr0b2/Shp 20186_at Nr1h4/Fxr HF-Chow HF-LF Chow-LF Control what you feed the animals!
  26. 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. 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. 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. 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. 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. 31. Target the gut to target the liver & improve metabolic health
  32. 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. 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. 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

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