Systems Nutrition of the Gut-Liver Axis and the Role of the Microbiome
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ISNN conference May 2016 in Tel Aviv (Israel) "You are what you eat"
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Systems Nutrition of the Gut-Liver Axis and the Role of the Microbiome
- 1. Systems nutrition of the gut-liver axis and the role of the microbiome Michael Müller Professor of Nutrigenomics & Systems Nutrition Director of the NRP Food & Health Alliance @nutrigenomics FAHAFood & Health Alliance
- 2. ‘No pain No gain’ We can’t change our genes but can improve the accessibility of the genome leading to improved resilience Hangelbroek R, Fazelzadeh P, Tieland T, Boekschoten M, Hooiveld G, van Duynhoven J, Timmons J, Verdijk L, de Groot L, van Loon L, Müller M . Expression of protocadherin gamma in skeletal muscle tissue is associated with age and muscle weakness. J. Cachexia, Sarcopenia & Muscle 2016 The molecular basis of adaptation to ‘stress’ challenges (here for exercise-related training) Improved skeletal muscle phenotypes after exercise in healthy & frail older subjects
- 3. The mechanisms that explain everything
- 4. 100 50 0 % Energy Low-fat meat Chicken Eggs Fish Fruits Vegetables 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 ‘genome challenges’ “Safe, processed” foods & less ‘challenges’
- 5. 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 approaches: One may have to target the gut to have health benefits in the liver or adipose tissue
- 6. Robust & concentration dependent effects in small intestine Differentially regulated genes by high fat diets De Wit et al Plos ONE 2011
- 7. Saturated fat stimulates obesity, the development of NAFLD by an enhanced overflow of dietary fat to the ileum and affecting the 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
- 8. Anti-inflammatory effects of plant food components Tilg H, Moschen AR. Food, immunity, and the microbiome Gastroenterology. 2015 May;148(6):1107-19.
- 9. 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
- 10. The abundance of the phyla Bacteroidetes and Firmicutes (A) and the ratio Firmicutes/Bacteroidetes (B) in pigs fed DS or RS for 2 wk Haenen et al. J. Nutr. 143: 1889–1898, 2013
- 11. 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)
- 12. Acetate, propionate, and butyrate concentrations in peripheral plasma of pigs fed the DS or the RS diet for 2 wk Haenen et al. J. Nutr. 143: 1889–1898, 2013
- 13. 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.
- 14. Biological processes regulated by dietary fibers
- 15. 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 Mol Nutr Food Res. 2015, 59,1590–1602.
- 16. 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. • Strongly linked to Clostridium cluster XIVa bacteria (butyrate producers) & likely governed by the transcription factor PPARg (Mol. Cell Biology 2013; & recent 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’! Sonnenburg et al. 2016
- 17. 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…
- 18. 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
- 19. Proposed mechanism of how microbiota facilitates heme-induced compensatory hyperproliferation Ijssennagger et al. PNAS 2015;112:10038-10043
- 20. C CR MF INT NASH development in C- and MF-fed mice, but not in mice on a CR or INT diet Mol. Nutr. Food Res. 2015, 59, 533–543 Age (w eeks) Bodyweight(g) 10 20 30 40 50 10 20 30 40 50 C CR MF INT C: Control CR: Cal Restriction MF: 25% Fat INT: intermittent (CR/MF
- 21. Our current interests is to better understand the molecular mechanisms of how gradients regulate immune-metabolic capacity of the gut-liver axis Nutrients Bioactives Metabolism SCFAs Microbiota Immunity 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 Bile acids Microbial Metabolism Drugs Unintended effects?
- 22. My 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). • Gut microbiota activities have broad effects on the intestinal & systemic metabolome and the related host metabolic regulation. • Transcription factors e.g. PPARg, FXR, AHR or NRF2 are involved in host sensing mechanisms of microbial metabolites. • “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 may improve gut and liver functions with strong implications for human health.
- 23. 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