Dieta mediterranea e Nutraceutica per la cura delle dislipidemie e la prevenzione cardiovascolare

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Sheena Dorthy Jennings
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Dieta mediterranea e Nutraceutica per la cura delle dislipidemie e la prevenzione cardiovascolare Lecce, 27 maggio 2017 Polo Universitario ECOTEKNE dell Università degli Studi di Lecce Via per

1 Dieta mediterranea e Nutraceutica per la cura delle dislipidemie e la prevenzione cardiovascolare Lecce, 27 maggio 2017 Polo Universitario ECOTEKNE dell Università degli Studi di Lecce Via per Monteroni Ecotekne, snc Lettura Magistrale 1 Microbioma intestinale e rischio cardiovascolare Raffaele De Caterina Università G. d Annunzio Chieti e Fondazione G. Monasterio Pisa, Italia 27 maggio 2017, 10:20-10:50

2 Prof. Raffaele De Caterina Conflitti d interesse Co-author ESC Guidelines on Atrial Fibrillation Steering Committee member, National Coordinator for Italy, and Co-author of APPRAISE-2, ARISTOTLE, AVERROES, ENGAGE-AF, Re-DUAL PCI Fees, honoraria and research funding from Sanofi-Aventis, Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi-Sankyo, Novartis, Merck None on this topic

3 Concept 1 - Systems biology: Our phenotype is always the product of gene/environment interaction Genes Environment

4 Concept 2: Diet interacts not only with the genes in the nuclei of our own cells, but also with genes of the trillion bacteria that we host, which may be a new target for preventive and therapeutic measures

CREDIT TO: Stanley Hazen, MD, PhD Cleveland Clinic Cleveland, OH, USA Z Wang (2011) Nature RA Koeth (2013) Nature Medicine WHW Tang (2013) New Engl J Med B Bennett (2013) Cell Metab Z Wang (2014) Eur

5 CREDIT TO: Stanley Hazen, MD, PhD Cleveland Clinic Cleveland, OH, USA Z Wang (2011) Nature RA Koeth (2013) Nature Medicine WHW Tang (2013) New Engl J Med B Bennett (2013) Cell Metab Z Wang (2014) Eur Heart J WHW Tang (2014) JACC RA Koeth (2014) Cell Metab WHW Tang (2015) Circ Res M Warrier (2015) Cell Reports J Gregory (2015) J Biol Chem Z Wang (2015) Cell C Organ (2016) Circ Heart Fail W Zhu (2016) Cell

Some background and take-home concepts The human body is an integrated circuit between our gut microbes and our human genes The microbiome is a filter of our largest environmental exposure what we

6 Some background and take-home concepts The human body is an integrated circuit between our gut microbes and our human genes The microbiome is a filter of our largest environmental exposure what we eat The microbiome can be considered as our largest endocrine organ The microbiome is a "drugable" target Dietary choline & carnitine Heart disease TMAO CKD TMA Gut flora Hepatic FMOs Atherosclerosis

Wang (2014) Eur Heart J WHW Tang (2014) JACC RA Koeth (2014) Cell Metab WHW Tang (2015) Circ Res M Warrier

7 Diet and Intestinal Microbes are Mechanistically Linked to Atherosclerotic Heart Disease Carnitine Z Wang (2011) Nature RA Koeth (2013) Nature Medicine WHW Tang (2013) New Engl J Med B Bennett (2013) Cell Metab Z Wang (2014) Eur Heart J WHW Tang (2014) JACC RA Koeth (2014) Cell Metab WHW Tang (2015) Circ Res M Warrier (2015) Cell Reports J Gregory (2015) J Biol Chem Z Wang (2015) Cell C Organ (2016) Circ Heart Fail W Zhu (2016) Cell

8 Pathways Linking Dietary Phosphatidylcholine, Intestinal Microbiota, and Incident Adverse Cardiovascular Events Tang WH et al. N Engl J Med ;17

9 A meta organismal pathway, requiring (i) gut microbes, and (ii) host hepatic FMOs

10 Early observations Phosphatidylcholine, carnitine in the diet and TMA plasma levels track with atherosclerosis but Only if the animals have intestinal microbes no associations in germ free animals

11 Effect of TMAO on cholesterol and sterol metabolism TMAO modulates cholesterol and sterol metabolism at multiple sites in vivo with a net effect of increase in atherosclerosis Koeth et al. Nat Med. 2013;19:

12 Dietary carnitine (from red meat) induction of atherosclerosis and its reversal with antibiotics eradicating the gut flora Koeth et al. Nat Med. 2013;19:

Apoe null mice tissue macrophages from the peritoneal cavity by the same amount of total and LDL cholesterol in plasma Choline increases lipid uptake

13 Apoe null mice tissue macrophages from the peritoneal cavity by the same amount of total and LDL cholesterol in plasma Choline increases lipid uptake (Oil Red-O) in macrophages Wang Z. et al: Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease Nature 472, (07 April 2011)

14 The Emerging Role of Gut Microbiota in CVD and Thrombosis

15 Gut microbial choline metabolite TMAO enhances platelet reactivity and thrombotic risk Zhu W. et al. Cell March ;165(1): doi: /j.cell

16 Gut microbial choline metabolite TMAO enhances platelet reactivity and thrombotic risk Zhu W. et al. Cell March ;165(1): doi: /j.cell

17 Brief exposure to TMAO enhances human platelet responsiveness to multiple agonists Zhu W. et al. Cell March ;165(1): doi: /j.cell

18 Brief exposure to TMAO enhances human platelet responsiveness to multiple agonists Zhu W. et al. Cell March ;165(1): doi: /j.cell

Dietary choline enhances thrombosis susceptibility in vivo in a mouse carotid artery thrombosis model through TMAO Carotid artery injury in vivo

19 Dietary choline enhances thrombosis susceptibility in vivo in a mouse carotid artery thrombosis model through TMAO Carotid artery injury in vivo thrombosis model Vital microscopy imaging of fluorescent labeled platelets Zhu W. et al. Cell March ;165(1): doi: /j.cell

20 Gut microbial choline metabolite TMAO enhances platelet reactivity and thrombotic risk Elevated TMAO levels predict incident risk (at 3 years) for thrombotic events in human subjects ((n > 4,000) TMAO enhances sub-maximal stimulusdependent platelet activation Dietary choline, gut microbes, and TMAO are linked to thrombotic potential in vivo Microbial transplantation shows that thrombosis potential is a transmissible trait Zhu W. et al. Cell March ;165(1): doi: /j.cell

21 And now, given all this, how do we intervene? Brown JM and Hazen SL. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases. (2015) Annu Rev Med

22 And now, given all this, how do we intervene? Brown JM and Hazen SL. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases. (2015) Annu Rev Med

And now, given all this, how do we Addressing the diet: Decreasing carnitine (from red meat) But choline is everywhere, and is an essential nutrient intervene?

23 And now, given all this, how do we Addressing the diet: Decreasing carnitine (from red meat) But choline is everywhere, and is an essential nutrient intervene? Brown JM and Hazen SL. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases. (2015) Annu Rev Med;. Li & Vance, J Lipid Res 2008

24 Chronic Dietary Choices Impact TMAO Levels Gut microbiota - Original article High-level adherence to a Mediterranean diet beneficially impacts the gut microbiota and associated metabolome, including lower TMAO levels Francesca De Filippis, et al. De Filippis et al. Gut

25 And now, given all this, how do we intervene? Brown JM and Hazen SL. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases. (2015) Annu Rev Med

26 And now, given all this, how do we intervene? Brown JM and Hazen SL. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases. (2015) Annu Rev Med

27 And now, given all this, how do we 1. Addressing the diet 1. Decreasing carnitine (from red meat) 2. But choline is everywhere, and is an essential nutrient 2. Targeting FMO3, the enzyme converting TMA into TMAO 3 reports as of showing less athero in animal models the rotten fish smell problem intervene? Brown JM and Hazen SL. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases. (2015) Annu Rev Med;. Li & Vance, J Lipid Res 2008

And now, given all this, how do we 3. Targeting bacteria the TMA lyase inhibitors (choline analogues) 3,3 dimethyl butanol and congener compounds intervene?

28 And now, given all this, how do we 3. Targeting bacteria the TMA lyase inhibitors (choline analogues) 3,3 dimethyl butanol and congener compounds intervene? Brown JM and Hazen SL. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases. (2015) Annu Rev Med;. Li & Vance, J Lipid Res 2008

29 Sources of DMB

Non-lethal microbial enzyme targeting as a therapeutic

30 Microbial TMAO lyase inhibition attenuates choline enhanced atherosclerosis New concept! Non-lethal microbial enzyme targeting as a therapeutic Small molecule inhibition of microbial choline TMA-lyase activity Wang et al. Cell (2015)

31 Drugging the Microbiome Is it in Our Future CVD Therapeutics? Brown JM and Hazen SL. The Gut Microbial Endocrine Organ: Bacterially-Derived Signals Driving Cardiometabolic Diseases. (2015) Annu Rev Med

32 Therefore Dietary interventions, as well as interventions targeting our microbiome may prove to be the future in CVD prevention New research avenues from the nutrigenomic effects of diet on the intestinal microbiome The human microbiome as a target for specific therapeutics

33 Thank You

Gut Microbes as Participants and Targets in Cardiometabolic Diseases

Gut Microbes as Participants and Targets in Cardiometabolic Diseases Stanley L Hazen, MD, PhD Section Head, Preventive Cardiology, Cleveland Clinic Chair, Dept. of Cellular & Molecular Medicine, Lerner